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Journal articles on the topic 'Macrophag'
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Poetri, Okti Nadia, Retno D. Soejoedono, Agustin Indrawati, and I. Wayan T. Wibawan. "PERAN ANTIBODI KUNING TELUR (IgY) SEBAGAI OPSONIN UNTUK PENCEGAHAN SERANGAN MUTAN STREPTOCOCCUS SEROTIPE D (STREPTOCOCCUS SOBRINUS)." Berkala Penelitian Hayati 13, no. 2 (June 30, 2008): 129–34. http://dx.doi.org/10.23869/bphjbr.13.2.20086.
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The aim of this study was to explore the role of serotype d Mutan Streptococcus (Streptococcus sobrinus) spesific immunoglobulin Y (IgY-Ss) as opsonin against the same strain. The eggs were collected from Single Comb Brown Leghorn which has been immunized with Streptococcus sobrinus. Agar gel precipitation test was applied to detect IgY-Ss in serum and egg. Egg containing IgY-Ss was collected and extracted by PEG-Amonium sulphate and purified using fast protein liquid chromatography. The purity of IgY-Ss was determined by UV spectrophotometer. Molecular weight was established by SDS-PAGE (sodium dedocyl sulphate-poly acrilamide gel electrophoresis). Biological activities of IgY-Ss as opsonin was determined by phagocytosis assay. Phagositic activity of macrophages was not increased by preincubation of both S. sobrinus (107 CFU/ml) and 100 μg of IgY-S, however the phagositic capacity was increased from 1.6 bacterial cell/ macrophag to 5.17 bacterial cell/ macrophag. These finding suggest that IgY-Ss obtained from hens immunized with S. sobrinus provide an alternative to prevent S. sobrinus infection.
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Saidah, Makfiyah, Beta Widya Oktiani, and Irham Taufiqurrahman. "THE EFFECT OF FLAVONOID PROPOLIS KELULUT (Trigona spp) EXTRACT ON MACROPHAGE CELL NUMBER IN PERIODONTITIS (IN VIVO STUDY IN MALE WISTAR RATE (Rattus novergicus) GINGIVA)." Dentino : Jurnal Kedokteran Gigi 5, no. 1 (March 12, 2020): 28. http://dx.doi.org/10.20527/dentino.v5i1.8117.
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Background : Periodontitis is a condition where there is an increase in the number of inflammatory cells, namely macrophages in periodontal tissue. Macrophag cell is 12-15μm in oval shape cell with purplish blue cytoplasm and this cell’s function is to phagocytes bacteria and infiltrate gingival tissue. Propolis kelulut contains flavonoid that have an anti-inflammatory effect by suppressing the signal pathway p38 MAPK, JNK 1/2 and NF-kB that it can reduce the number of macrophage cells in inflammatory periodontal tissues. Objective: The purpose of this study was to determine the effect of 0.5 mg dose flavonoid propolis extract on the number of macrophage cells in gingiva wistar rats that have been made into a periodontitis condition. Method: This study used a pure experimental method with a post test only with control group design. There were 9 treatment groups, including flavonoid propolis extract on 1,3,5 days, ibuprofen gel on 1,3,5 days and negative control on 1,3 dan 5 days. Results: There was an effect of giving 0.5 mg flavonoids propolis kelulut extract to the number of macrophage cells in periodontitis. Conclusion: Flavonoid propolis kelulut extract has an effect in increasing the number of macrophage cells on day 3 and decreasing the number of macrophage cells on the 5th day.
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HAMADA, MASAFUMI, EIKO SONOTAKE, SHIGERU YAMAMOTO, and SATORU MORIGUCHI. "Conagenin Derived from Streptomyces roseosporus Enhances Macrophag Functions." Journal of Antibiotics 52, no. 6 (1999): 548–51. http://dx.doi.org/10.7164/antibiotics.52.548.
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Műzes, Györgyi, Hajnal Székely, and Zsolt Tulassay. "Whipple’s disease: current problems." Orvosi Hetilap 148, no. 26 (July 1, 2007): 1225–30. http://dx.doi.org/10.1556/oh.2007.28144.
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A Whipple-kór bakteriális fertőzés okozta, ritkán előforduló, számos szerv érintettségével, így változatos klinikummal társuló, alattomos kezdetű, relapsusokkal kísért idült lefolyású, kezelés nélkül fatális gyulladásos betegség. A kórkép gyanúját a jellegzetes (de nem specifikus) tüneti triász (fogyás, krónikus hasmenés, arthralgia) megjelenése sugallhatja. Elhúzódó, intermittáló jellegű láz és lymphadenopathia társulásakor fennállásának különösen nagy a valószínűsége. A Whipple-kór vonatkozásában meghatározó jelentőségű volt az egyedi tulajdonságokkal bíró kórokozó, a Tropheryma whipplei felismerése. A bakteriális fertőzés vélhetően gyakori, betegség viszont csak a hajlamosító immunológiai tényező(k) megléte esetén alakul ki. Tekintettel az alapvetően a macrophagokban perzisztáló és szaporodó baktériumokra, főként a mononuclearis-phagocyta rendszer kóros funkciója tételezhető fel. (A Whipple-kór elsősorban macrophag betegségként értelmezhető.) A klinikai kép sokszínű. Bár a Whipple-kórt eredetileg a gastrointestinalis rendszer megbetegedésének vélték, ma szisztémás betegségnek tekintik. A fertőzés gyanújakor az elsőként választandó vizsgálat a gasztroszkópia: jellegzetes esetben a postbulbaris duodenum és a jejunum területén az erythemas, erodált, sérülékeny nyálkahártyán szétszórt halványsárgás plaque-ok mutatkoznak. A szövettani mintákban előtérben áll a kifejezett macrophag infiltráció (a baktérium intracelluláris inváziójával). A betegség igazolásának klasszikus eszköze a vékonybél-biopsziás minták PAS-festése, valamint a kórokozó PCR-ral történő igazolása. A megfelelő antibiotikum kiválasztása és a terápia időtartama napjainkban is nagyrészt empirikus.
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Vokhmintseva, L. V., N. N. Mayanskaya, S. S. Rymar′, P. A. Zheleznyi, A. P. Nadeyev, and V. V. Vanyunina. "Peculiarities of functional neutrophil activity in rats having periodontitis in thesetting of toxic hepatitis." Bulletin of Siberian Medicine 6, no. 2 (June 30, 2007): 11–16. http://dx.doi.org/10.20538/1682-0363-2007-2-11-16.
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Experimental toxic hepatitis was induced by single administration of Acetaminophen ( paracetamol) in a dose of 1000 mg per 1 kg of body mass in Wistar rats. Inflammation pathology was modeled by wounding the upper maxilla gingiva in toxic hepatitis rats on the 6-th day. Intact rats were controls. On the 1-st and 7-th day, ratio of neutrophil-macrophag was determined in smears of the upper maxillas gingival, oxygen-dependent functional activity of neutrophils was assessed based upon HST-test, functional activity reserves were assessed by the stimulation index. On the 7-th and 13-th day, alaninaminotransferase and aspartataminotransferase activity, level of general and indirect bilirubin, general blood protein were assessed in blood serum of these rats. Toxic hepatitis was established to be accomplished by increased biocidity of phagocytes, decreased functional reserves of neutrophils and their migration into the parodontium. In experimental inflammation, suppurative processes in parodontium tissues are revealed in toxic hepatitis rats by 1.5 times less than in controls due to lower biocide activity of phagocyte cells and increased migration of macrophages.
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Rodriguez, Eric, Frederic Boudard, Michele Mallié, Jean-Marie Bastide, and Madeleine Bastide. "Murine macrophage elastolytic activity induced by Aspergillus fumigatus strains in vitro: evidence of the expression of two macrophage-induced protease genes." Canadian Journal of Microbiology 43, no. 7 (July 1, 1997): 649–57. http://dx.doi.org/10.1139/m97-092.
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The interaction between Aspergillus fumigatus conidia and murine macrophages of various origins was investigated. Cocultures were carried out between A. fumigatus strains and freshly isolated murine pulmonary alveolar macrophages or two murine macrophage cell-lines: murine alveolar cell-line MALU and murine astrocytoma cell-line J774. By measuring the variation of elastolytic activity in the coculture supernatants with two elastin substrates, we demonstrated that either viable or fixed A. fumigatus or C. albicans yeasts or nonspecific particles induced significant macrophage elastolytic activity. The effect of A. fumigatus supernatant or the purified A. fumigatus galactomannan suggested also the possible involvement of this polysaccharide in macrophage-protease gene expression, release, and activity in invasive aspergillosis. The effect of inhibitory compounds demonstrated the potential implication of a macrophagic metalloprotease and a macrophagic cysteine protease. RNA analysis allowed us to demonstrate the induction of expression of two macrophagic protease genes in stimulated macrophages. Two distinctive mechanisms appeared to be implicated in macrophage protease induction: nonspecific phagocytosis in the earliest times of the coculture and (or) specific galactomannan recognition after its gradual release by the mycelium.Key words: Aspergillus fumigatus, macrophages, proteases, invasive aspergillosis, galactomannan.
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Karatieieva, S. "THE CHANGES OF WOUND MACROPHAGES IN PATIENTS WITH DIABETES." Clinical anatomy and operative surgery 19, no. 3 (November 26, 2020): 48–52. http://dx.doi.org/10.24061/1727-0847.19.3.2020.40.
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Purulent-necrotic lesions of the extremities require amputation in 30-50% of cases. Among all cases of lower extremity amputations 50-70% are due to diabetes. Moreover, 5 out of 6 amputations, not related to the traumatic injury of the limb, are performed in patients with diabetes. The mortality rate among patients with diabetes, who undergo amputation varies from 28 to 40%, and 5-year surveillance is only 10-25%. The study of ultrastructural changes of macrophages on the 3rd day of treatment revealed masses of chaotically located fibrillar structures in the cytoplasm of macrophages that occasionally had an increased electron density. This phenomenon was observed in the purulent-necrotic areas of soft tissues of patients from the main group, compared to the control group. In all cases, mitochondria were enlarged in size, swollen, with a light matrix and contained a reduced amount of cristae. The cristae were deformed and shortened. Swollen matrix in mitochondria led to the formation of vacuoles on their place containing fine-grained contents. The nucleus had a usual form and size with the presence of single invaginations. Chromatin was predominantly concentrated in the form of solid electron-dense masses or evenly distributed throughout the nucleus. There were nuclei with partial chromatin dispersion. The contents of the nuclei included granular, fibrillar, and fine vacuolar material. The nuclear membrane folding did not fluctuate significantly. The folds did not cover the whole surface of the nucleus. In some areas invaginates were represented by the continuation of perinuclear space only. The nuclear envelop pores, which connect the contents of the cytoplasm and nucleoplasm, have been observed. The cytoplasm between the zones of the plate complex was occupied by small mitochondria, single polysomal rosettes, and cisternae of granular endoplasmic reticulum, which was represented by extended intracellular channels and vacuolar formations. The smooth endoplasmic reticulum was predominantly located in the central part. The surface of macrophages in the process of their differentiation from monocytes was relatively plane. Occasionally there occurred small processes or pseudopodia. The number of pinocytic vesicles surrounded by a border was reduced in poorly differentiated cells. Ozone therapy stimulates the functional activity of wound macrophages, as it causes destructive changes in these cells without necrotic lesions. Intravenous introduction of ozonized saline con-tributes to the elimination of wound macrophag-es, mainly through genetically programmed cell death (apoptosis), which plays a significant role in the regulatory mechanisms of the inflammato-ry process.
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Vuarchey, Clément, Sushil Kumar, and Reto Schwendener. "Albumin coated liposomes: a novel platform for macrophage specific drug delivery." Nanotechnology Development 1, no. 1 (July 19, 2011): 2. http://dx.doi.org/10.4081/nd.2011.e2.
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Here we report a new and efficient approach of macrophage specific drug delivery by coating liposomes with albumin. Activated albumin was reacted with liposomes containing polyethylene glycol (PEG) as hydrophilic spacers to create a flexible layer of covalently bound albumin molecules on the liposome surface. Albumin coated liposomes were taken up faster and more efficiently than uncoated liposomes by murine macrophages. Liposome uptake was significantly higher in macropha - ges as compared to other cell types tested (endothelial cells, fibroblasts, tumor cells), suggesting specificity for macrophages. In vivo, splenic macrophages phagocytosed BSA coated liposomes (BSA-L) at faster rates compared to conventional liposomes (L) and PEG liposomes (PEG-L). To prove the effectiveness of this new macrophage specific drug carrier, the bisphosphonates clodronate and zoledronate were encapsulated in BSA-L and compared with conventional liposomes. <em>In vitro</em>, treatment of macrophages with clodronate or zoledronate in BSA-L led to cytotoxic activity within a very short time and to up to 50-fold reduced IC50 concentrations. <em>In vivo</em>, clodronate encapsulated in BSA-L depleted splenic macrophages at a 5-fold lower concentration as conventional clodronate-liposomes. Our results highlight the pharmaceutical benefits of albumin-coated liposomes for macrophage specific drug delivery.
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Liu, Shuangqing, Huilei Zhang, Yanan Li, Yana Zhang, Yangyang Bian, Yanqiong Zeng, Xiaohan Yao, et al. "S100A4 enhances protumor macrophage polarization by control of PPAR-γ-dependent induction of fatty acid oxidation." Journal for ImmunoTherapy of Cancer 9, no. 6 (June 2021): e002548. http://dx.doi.org/10.1136/jitc-2021-002548.
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BackgroundThe peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent upregulation of fatty acid oxidation (FAO) mediates protumor (also known as M2-like) polarization of tumor-associated macrophages (TAMs). However, upstream factors determining PPAR-γ upregulation in TAM protumor polarization are not fully identified. S100A4 plays crucial roles in promotion of cancer malignancy and mitochondrial metabolism. The fact that macrophage-derived S100A4 is major source of extracellular S100A4 suggests that macrophages contain a high abundance of intracellular S100A4. However, whether intracellular S100A4 in macrophages also contributes to cancer malignancy by enabling TAMs to acquire M2-like protumor activity remains unknown.MethodsGrowth of tumor cells was evaluated in murine tumor models. TAMs were isolated from the tumor grafts in whole-body S100A4-knockout (KO), macrophage-specific S100A4-KO and transgenic S100A4WT−EGFP mice (expressing enhanced green fluorescent protein (EGFP) under the control of the S100A4 promoter). In vitro induction of macrophage M2 polarization was conducted by interleukin 4 (IL-4) stimulation. RNA-sequencing, real-time quantitative PCR, flow cytometry, western blotting, immunofluorescence staining and mass spectrometry were used to determine macrophage phenotype. Exogenous and endogenous FAO, FA uptake and measurement of lipid content were used to analyze macrophage metabolism.ResultsTAMs contain two subsets based on whether they express S100A4 or not and that S100A4+ subsets display protumor phenotypes. S100A4 can be induced by IL-4, an M2 activator of macrophage polarization. Mechanistically, S100A4 controls the upregulation of PPAR-γ, a transcription factor required for FAO induction during TAM protumor polarization. In S100A4+ TAMs, PPAR-γ mainly upregulates CD36, a FA transporter, to enhance FA absorption as well as FAO. In contrast, S100A4-deficient TAMs exhibited decreased protumor activity because of failure in PPAR-γ upregulation-dependent FAO induction.ConclusionsWe find that macrophagic S100A4 enhances protumor macrophage polarization as a determinant of PPAR-γ-dependent FAO induction. Accordingly, our findings provide an insight into the general mechanisms of TAM polarization toward protumor phenotypes. Therefore, our results strongly suggest that targeting macrophagic S100A4 may be a potential strategy to prevent TAMs from re-differentiation toward a protumor phenotype.
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Hansen, F., L. Stenbygaard, and T. Skovsgaard. "Reduction by granulocyte-macrophag colonystimulating factor (GM-CSF) of hematologic toxicity induced by high-dose chemotherapy in patients with metastatic breast cancer." European Journal of Cancer 29 (January 1993): S53. http://dx.doi.org/10.1016/0959-8049(93)90886-k.
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Torre, Donato, Luisa Gennero, F. M. Baccino, Filippo Speranza, Gilberto Biondi, and Agostino Pugliese. "Impaired Macrophage Phagocytosis of Apoptotic Neutrophils in Patients with Human Immunodeficiency Virus Type 1 Infection." Clinical and Vaccine Immunology 9, no. 5 (September 2002): 983–86. http://dx.doi.org/10.1128/cdli.9.5.983-986.2002.
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ABSTRACT Dysfunction of neutrophils (polymorphonuclear leukocytes [PMNL]) and macrophagic cells occurs as a consequence of human immunodeficiency virus type 1 (HIV-1) infection. Macrophages contribute to the resolution of early inflammation ingesting PMNL apoptotic bodies. This study investigated macrophage ability to phagocytose PMNL apoptotic bodies in patients with HIV-1 infection in comparison with uninfected individuals and the effect of HIV Nef protein on apoptotic body phagocytosis to determine if phagocytic activity is impaired by HIV infection. Monocytes/macrophages were isolated from 10 HIV-1-infected patients and from five healthy volunteers, whereas PMNL were isolated from healthy volunteers. Macrophage phagocytosis of apoptotic PMNL was determined by staining of apoptotic bodies with fluorescein-conjugated concanavalin A or with fluorescein-labeled phalloidin. Our data show significant impairment of PMNL apoptotic body macrophage phagocytosis in subjects with HIV-1 infection presenting a concentration of CD4+ T lymphocytes of >200/mm3 and in particular in those with <200 CD4+ T lymphocyte cells/mm3. In addition, HIV-1 recombinant Nef protein is able to decrease phagocytosis of apoptotic PMNL from normal human macrophages in a dose-dependent manner. The results of our study suggest that impaired macrophage phagocytosis of PMNL apoptotic bodies may contribute to the persistence of the inflammatory state in HIV-infected subjects, especially during opportunistic infections that are often favored by defective phagocytic activity.
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Martins, Flávia, Rosa Oliveira, Bruno Cavadas, Filipe Pinto, Ana Patrícia Cardoso, Flávia Castro, Bárbara Sousa, et al. "Hypoxia and Macrophages Act in Concert Towards a Beneficial Outcome in Colon Cancer." Cancers 12, no. 4 (March 28, 2020): 818. http://dx.doi.org/10.3390/cancers12040818.
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In colon cancer, the prognostic value of macrophages is controversial, and it is still unknown how hypoxia modulates macrophage–cancer cell crosstalk. To unravel this, co-cultures of human primary macrophages and colon cancer cells were performed at 20% and 1% O2, followed by characterization of both cellular components. Different colon cancer patient cohorts were analyzed for hypoxia and immune markers, and their association with patient overall survival was established. A positive correlation between HIF1A and CD68 in colon cancer patients was identified but, unexpectedly, in cases with higher macrophage infiltration, HIF1A expression was associated with a better prognosis, in contrast to breast, gastric, and lung cancers. Under hypoxia, co-cultures’ secretome indicated a shift towards a pro-inflammatory phenotype. These alterations occurred along with increased macrophage phagocytic activity and decreased SIRPα expression. Cancer cells were more invasive and exhibited higher CD47 expression. We hypothesize that the better prognosis associated with HIF1AHighCD68High tumors could occur due to macrophagic pro-inflammatory pressure. Indeed, we found that tumors HIF1AHighCD68High expressed increased levels of CD8A, which is positively correlated with HIF1A. In conclusion, we show that in colon cancer, hypoxia drives macrophages into a pro-inflammatory phenotype, concomitant with increased infiltration of anti-tumor immune cells, favoring better disease outcome.
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Bonetti, Justine, Alessandro Corti, Lucie Lerouge, Alfonso Pompella, and Caroline Gaucher. "Phenotypic Modulation of Macrophages and Vascular Smooth Muscle Cells in Atherosclerosis—Nitro-Redox Interconnections." Antioxidants 10, no. 4 (March 26, 2021): 516. http://dx.doi.org/10.3390/antiox10040516.
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Monocytes/macrophages and vascular smooth muscle cells (vSMCs) are the main cell types implicated in atherosclerosis development, and unlike other mature cell types, both retain a remarkable plasticity. In mature vessels, differentiated vSMCs control the vascular tone and the blood pressure. In response to vascular injury and modifications of the local environment (inflammation, oxidative stress), vSMCs switch from a contractile to a secretory phenotype and also display macrophagic markers expression and a macrophagic behaviour. Endothelial dysfunction promotes adhesion to the endothelium of monocytes, which infiltrate the sub-endothelium and differentiate into macrophages. The latter become polarised into M1 (pro-inflammatory), M2 (anti-inflammatory) or Mox macrophages (oxidative stress phenotype). Both monocyte-derived macrophages and macrophage-like vSMCs are able to internalise and accumulate oxLDL, leading to formation of “foam cells” within atherosclerotic plaques. Variations in the levels of nitric oxide (NO) can affect several of the molecular pathways implicated in the described phenomena. Elucidation of the underlying mechanisms could help to identify novel specific therapeutic targets, but to date much remains to be explored. The present article is an overview of the different factors and signalling pathways implicated in plaque formation and of the effects of NO on the molecular steps of the phenotypic switch of macrophages and vSMCs.
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AlQasrawi, Dania, and Saleh A. Naser. "Nicotine Modulates MyD88-Dependent Signaling Pathway in Macrophages during Mycobacterial Infection." Microorganisms 8, no. 11 (November 17, 2020): 1804. http://dx.doi.org/10.3390/microorganisms8111804.
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Recently, we reported that cigarette smoking, and especially nicotine, increases susceptibility to mycobacterial infection and exacerbates inflammation in patients with Crohn’s disease (CD). The macrophagic response to Mycobacterium avium subspecies paratuberculosis (MAP) in CD and Mycobacteria tuberculosis (MTB) continues to be under investigation. The role of toll-like-receptors (TLRs) and cytoplasmic adaptor protein (MyD88) in proinflammatory response during Mycobacterial infection has been suggested. However, the mechanism of how nicotine modulates macrophage response during infection in CD and exacerbates inflammatory response remain unclear. In this study, we elucidated the mechanistic role of nicotine in modulating MyD88-dependent/TLR pathway signaling in a macrophage system during mycobacterial infection. The data demonstrated that MAP infection in THP-1 derived macrophages was mediated through TLR2 and MyD88 leading to increase in IL-8 in expression and production. On the other hand, LPS-representing, Gram-negative bacteria mediated macrophage response through TLR4. Blocking TLR2 and TLR4 with antagonists voided the effect of MAP, and LPS, respectively in macrophages and reversed response with decrease in expression of iNOS, TNF-α and IL-8. Interestingly, nicotine in infected macrophages significantly (1) downregulated TLR2 and TLR4 expression, (2) activated MyD88, (3) increased M1/M2 ratio, and (4) increased expression and secretion of proinflammatory cytokines especially IL-8, as seen in CD smokers. We also discovered that blocking macrophages during MAP infection with MyD88 antagonist significantly decreased response which illustrates the key role for MyD88 during infection. Surprisingly, dual treatment of MAP-infected macrophages with MyD88 antagonist and nicotine absolutely impaired immune response and decreased MAP viability, which clearly validate the inflammatory role of nicotine in macrophages through TLR2/MyD88 pathway during infection. This is the first report to describe the mechanism by which nicotine modulates TLR2/MyDD88 and exacerbates inflammation in CD smokers associated with infection.
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Careau, Éric, Léa-Isabelle Proulx, Philippe Pouliot, Annie Spahr, Véronique Turmel, and Élyse Y. Bissonnette. "Antigen sensitization modulates alveolar macrophage functions in an asthma model." American Journal of Physiology-Lung Cellular and Molecular Physiology 290, no. 5 (May 2006): L871—L879. http://dx.doi.org/10.1152/ajplung.00219.2005.
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We have previously demonstrated that adoptive transfer of alveolar macrophages from allergy-resistant rats to alveolar macrophage-depleted allergic rats prevents airway hyperresponsiveness development, suggesting an important role for alveolar macrophages in asthma pathogenesis. Given that ovalbumin sensitization can modulate alveolar macrophage cytokine production, we investigated the role of sensitized and unsensitized alveolar macrophages in an asthma model. Alveolar macrophages from unsensitized or sensitized Brown Norway rats were transferred to alveolar macrophage-depleted sensitized rats 24 h before allergen challenge. Airway responsiveness to methacholine and airway inflammation were measured the following day. Methacholine concentration needed to increase lung resistance by 200% was significantly higher in alveolar macrophage-depleted sensitized rats that received unsensitized alveolar macrophages compared with alveolar macrophage-depleted sensitized rats that received sensitized alveolar macrophages. Tumor necrosis factor levels in bronchoalveolar lavage fluid of sensitized rats that received unsensitized alveolar macrophages were significantly lower compared with rats that received sensitized alveolar macrophages. Interestingly, alveolar macrophages of unsensitized animals showed higher phagocytosis activity compared with alveolar macrophages of sensitized rats, suggesting that sensitization modulates alveolar macrophage phagocytosis function. Our data suggest an important role of allergen sensitization on alveolar macrophage function in asthma pathogenesis.
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Taylor, Sarah A., Shang-Yang Chen, Gaurav Gadhvi, Liang Feng, Kyle D. Gromer, Hiam Abdala-Valencia, Kiwon Nam, et al. "Transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations." PLOS ONE 16, no. 1 (January 7, 2021): e0244743. http://dx.doi.org/10.1371/journal.pone.0244743.
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Background & aims Limited understanding of the role for specific macrophage subsets in the pathogenesis of cholestatic liver injury is a barrier to advancing medical therapy. Macrophages have previously been implicated in both the mal-adaptive and protective responses in obstructive cholestasis. Recently two macrophage subsets were identified in non-diseased human liver; however, no studies to date fully define the heterogeneous macrophage subsets during the pathogenesis of cholestasis. Here, we aim to further characterize the transcriptional profile of macrophages in pediatric cholestatic liver disease. Methods We isolated live hepatic immune cells from patients with biliary atresia (BA), Alagille syndrome (ALGS), and non-cholestatic pediatric liver by fluorescence activated cell sorting. Through single-cell RNA sequencing analysis and immunofluorescence, we characterized cholestatic macrophages. We next compared the transcriptional profile of pediatric cholestatic and non-cholestatic macrophage populations to previously published data on normal adult hepatic macrophages. Results We identified 3 distinct macrophage populations across cholestatic liver samples and annotated them as lipid-associated macrophages, monocyte-like macrophages, and adaptive macrophages based on their transcriptional profile. Immunofluorescence of liver tissue using markers for each subset confirmed their presence across BA (n = 6) and ALGS (n = 6) patients. Cholestatic macrophages demonstrated reduced expression of immune regulatory genes as compared to normal hepatic macrophages and were distinct from macrophage populations defined in either healthy adult or pediatric non-cholestatic liver. Conclusions We are the first to perform single-cell RNA sequencing on human pediatric cholestatic liver and identified three macrophage subsets with distinct transcriptional signatures from healthy liver macrophages. Further analyses will identify similarities and differences in these macrophage sub-populations across etiologies of cholestatic liver disease. Taken together, these findings may allow for future development of targeted therapeutic strategies to reprogram macrophages to an immune regulatory phenotype and reduce cholestatic liver injury.
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Dende, Chaitanya, Mihir Pendse, Daniel Propheter, Gabriella Quinn, and Lora V. Hooper. "Vitamin A regulates phagocytosis by resident macrophages of the small intestine." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 113.23. http://dx.doi.org/10.4049/jimmunol.208.supp.113.23.
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Abstract Intestinal Tim4+ CD4+ macrophages are a distinctive macrophage subset that express Tim4, a receptor for phosphatidylserine on dying apoptotic cells, Unlike other macrophage subsets, they do not depend on blood monocytes for their turnover, instead self-maintained in the small intestine. The signal(s) responsible for the self-maintenance and function of Tim4+ CD4+ macrophages is not known. We have discovered that maintenance of the gut resident Tim4+ CD4+ macrophage population depends on dietary vitamin A and its derivative retinoic acid (RA). Retinoic acid receptors, which direct RA-dependent transcription, were required for maintenance of Tim4+ CD4+ macrophages. Chemical blockade of retinoic acid receptor (RAR) signaling and macrophage-specific genetic inactivation of RARs in mice further revealed that macrophage-intrinsic RARα signaling was required for Timd4 expression and maintenance of Tim4+ CD4+ macrophages. Macrophage RARα signaling was furthermore essential for phagocytosis by Tim4+ CD4+ macrophages. Ongoing studies are examining the role of Tim4+ CD4+ macrophages and vitamin A in the clearance of apoptotic intestinal epithelial cells. Our findings reveal that vitamin A provides an essential dietary signal for the maintenance and function of a gut resident macrophage subset. Supported by Welch foundation grant I-1874
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Cotechini, Tiziana, Aline Atallah, and Arielle Grossman. "Tissue-Resident and Recruited Macrophages in Primary Tumor and Metastatic Microenvironments: Potential Targets in Cancer Therapy." Cells 10, no. 4 (April 20, 2021): 960. http://dx.doi.org/10.3390/cells10040960.
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Macrophages within solid tumors and metastatic sites are heterogenous populations with different developmental origins and substantially contribute to tumor progression. A number of tumor-promoting phenotypes associated with both tumor- and metastasis-associated macrophages are similar to innate programs of embryonic-derived tissue-resident macrophages. In contrast to recruited macrophages originating from marrow precursors, tissue-resident macrophages are seeded before birth and function to coordinate tissue remodeling and maintain tissue integrity and homeostasis. Both recruited and tissue-resident macrophage populations contribute to tumor growth and metastasis and are important mediators of resistance to chemotherapy, radiation therapy, and immune checkpoint blockade. Thus, targeting various macrophage populations and their tumor-promoting phenotypes holds therapeutic promise. Here, we discuss various macrophage populations as regulators of tumor progression, immunity, and immunotherapy. We provide an overview of macrophage targeting strategies, including therapeutics designed to induce macrophage depletion, impair recruitment, and induce repolarization. We also provide a perspective on the therapeutic potential for macrophage-specific acquisition of trained immunity as an anti-cancer agent and discuss the therapeutic potential of exploiting macrophages and their traits to reduce tumor burden.
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García-Rodas, Rocío, Fernando González-Camacho, Juan Luis Rodríguez-Tudela, Manuel Cuenca-Estrella, and Oscar Zaragoza. "The Interaction between Candida krusei and Murine Macrophages Results in Multiple Outcomes, Including Intracellular Survival and Escape from Killing." Infection and Immunity 79, no. 6 (March 21, 2011): 2136–44. http://dx.doi.org/10.1128/iai.00044-11.
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ABSTRACTCandida kruseiis a fungal pathogen of interest for the scientific community for its intrinsic resistance to fluconazole. Little is known about the interaction of this yeast with host immune cells. In this work, we have characterized the outcome of the interaction betweenC. kruseiand murine macrophages. OnceC. kruseiwas internalized, we observed different phenomena. In a macrophage-like cell line,C. kruseisurvived in a significant number of macrophages and induced filamentation and macrophage explosion. Phagocytosis ofC. kruseiled to actin polymerization around the yeast cells at the site of entry. Fluorescent specific staining with anti-Lamp1 and LysoTracker indicated that after fungal internalization, there was a phagolysosome maturation defect, a phenomenon that was more efficient when the macrophages phagocytosed killed yeast cells. Using cell line macrophages, we also observed macrophage fusion after cell division. When we used primary resident peritoneal macrophages in addition to macrophage explosion, we also observed a strong chemotaxis of uninfected macrophages to regions whereC. krusei-infected macrophages were present. We also noticed yeast transfer phenomena between infected macrophages. Primary macrophages inhibited pseudohypha elongation more efficiently than the macrophage-like cell line, suggesting thatC. kruseiinfection was better controlled by the former macrophages. Primary macrophages induced more tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) than the macrophage-like cell line. Our results demonstrate thatC. kruseican exploit the macrophages for replication, although other different outcomes are also possible, indicating that the interaction of this pathogen with phagocytic cells is very complex and regulated by multiple factors.
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Doherty, T. M., R. Kastelein, S. Menon, S. Andrade, and R. L. Coffman. "Modulation of murine macrophage function by IL-13." Journal of Immunology 151, no. 12 (December 15, 1993): 7151–60. http://dx.doi.org/10.4049/jimmunol.151.12.7151.
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Abstract Activated macrophages are important effector cells for immune response to many parasites and immune responses are strongly modulated in part by the effect of Th cell-derived cytokines on macrophages. Th1-derived cytokines such as IFN-gamma are strong stimulators of macrophage activation, while cytokines produced by Th2 cells, including IL-4 and IL-10, have been shown under some conditions to inhibit macrophage activities associated with inflammatory responses. IL-13, a recently described cytokine produced by Th2 cells, is also capable of down-modulating macrophage activity in a manner similar to that previously described for IL-4. Treatment of activated macrophages with IL-13 reduces the production of inflammatory monokines in response to IFN-gamma or LPS, both potent stimulators of these factors. In addition, IL-13 decreases the production of nitric oxide by activated macrophages. Nitric oxide has been implicated in both macrophage cytotoxicity and macrophage-associated immunosuppression. The suppression of nitric oxide by IL-13 leads to a decrease in parasiticidal activity by activated macrophages. However, our data indicate that IL-13 has pleiotropic effects, while the inflammatory potential of activated macrophages is significantly reduced, the potential of other macrophage subsets is unimpaired. These data indicate that IL-13 could be a potent modulator of immune responses in vivo, with effects that may embrace both macrophage suppressive and macrophage potentiating functions.
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Randolph, Gwendalyn J. "Monocyte Trafficking, Inflammation, and Atherosclerosis." Blood 122, no. 21 (November 15, 2013): SCI—53—SCI—53. http://dx.doi.org/10.1182/blood.v122.21.sci-53.sci-53.
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Abstract Macrophages are central to the progression of atherosclerosis. An increased number of macrophages in plaque are associated with larger, more stenotic lesions. Furthermore, activated plaque macrophages promote rupture, the most significant clinical event affecting mortality. Plaque macrophages derive from monocytes that are recruited from blood. We have thus focused our efforts on understanding the mechanisms that regulate plaque macrophages, with emphasis on how macrophage-burden might be reduced to lower disease risk. We have developed techniques to discern whether macrophage contraction in plaques is due to emigration out of the plaque environment. Although this idea was our leading hypothesis, data obtained in a model of regression carried out in apoE-/- mice indicates that emigration of macrophages does not occur during regression. The idea was based on previous literature that monocyte-derived cells might be removed from sites of acute inflammation by emigrating to local lymph nodes. After finding that emigration of macrophages from resolving plaque in apoE-/- mice was poor, we revisited models of acute inflammation; in particular, thioglycollate-induced peritonitis, where emigration had been claimed to account for macrophage removal. New methodology to improve the quantification of macrophage loss from the peritoneum indicated that, like atherosclerosis, emigration of macrophages was a minor contributor to the contraction of macrophages associated with resolution. Instead, in both settings, macrophage loss was associated with a strong suppression of monocyte recruitment, coupled with ongoing macrophage apoptosis. These data strongly suggest that methods to block monocyte recruitment may provide a viable approach to reversing atherosclerosis. Current efforts focus on integrating the role of monocyte recruitment with local proliferation of macrophages in plaques, investigating macrophage motility in plaques during different disease states, and evaluating contraction of macrophages from plaques using other models of disease regression. Disclosures: No relevant conflicts of interest to declare.
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Aziz, Athar, Laurent Vanhille, Peer Mohideen, Louise M. Kelly, Claas Otto, Youssef Bakri, Noushine Mossadegh, Sandrine Sarrazin, and Michael H. Sieweke. "Development of Macrophages with Altered Actin Organization in the Absence of MafB." Molecular and Cellular Biology 26, no. 18 (September 15, 2006): 6808–18. http://dx.doi.org/10.1128/mcb.00245-06.
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ABSTRACT In the hematopoietic system the bZip transcription factor MafB is selectively expressed at high levels in monocytes and macrophages and promotes macrophage differentiation in myeloid progenitors, whereas a dominant-negative allele can inhibit this process. To analyze the requirement of MafB for macrophage development, we generated MafB-deficient mice and, due to their neonatal lethal phenotype, analyzed macrophage differentiation in vitro, in the embryo, and in reconstituted mice. Surprisingly we observed in vitro differentiation of macrophages from E14.5 fetal liver (FL) cells and E18.5 splenocytes. Furthermore we found normal numbers of F4/80+/Mac-1+ macrophages and monocytes in fetal liver, spleen, and blood as well as in bone marrow, spleen, and peritoneum of adult MafB−/− FL reconstituted mice. MafB−/− macrophages showed intact basic macrophage functions such as phagocytosis of latex beads or Listeria monocytogenes and nitric oxide production in response to lipopolysaccharide. By contrast, MafB−/− macrophages expressed increased levels of multiple genes involved in actin organization. Consistent with this, phalloidin staining revealed an altered morphology involving increased numbers of branched protrusions of MafB−/− macrophages in response to macrophage colony-stimulating factor. Together these data point to an unexpected redundancy of MafB function in macrophage differentiation and a previously unknown role in actin-dependent macrophage morphology.
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Xie, Linglin, M. Teresa Ortega, Silvia Mora, and Stephen K. Chapes. "Interactive Changes between Macrophages and Adipocytes." Clinical and Vaccine Immunology 17, no. 4 (February 17, 2010): 651–59. http://dx.doi.org/10.1128/cvi.00494-09.
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ABSTRACT Obesity is associated with a proinflammatory state, with macrophage infiltration into adipose tissue. We tested the hypothesis that communication between macrophages and adipocytes affects insulin resistance by disrupting insulin-stimulated glucose transport, adipocyte differentiation, and macrophage function. To test this hypothesis, we cocultured 3T3-L1 adipocytes with C2D macrophages or primary peritoneal mouse macrophages and examined the impacts of macrophages and adipocytes on each other. Adipocytes and preadipocytes did not affect C2D macrophage TNF- α, IL-6, or IL-1 β transcript concentrations relative to those obtained when C2D macrophages were incubated alone. However, preadipocytes and adipocytes increased PEC-C2D macrophage IL-6 transcript levels, while preadipocytes inhibited IL-1 β transcript levels compared to those obtained when PEC-C2D macrophages were incubated in medium alone. We found that adipocyte coculture increased macrophage consumption of tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), and, in some cases, IL-6. C2D macrophages increasingly downregulated GLUT4 transcript levels in differentiated adipocytes. Recombinant TNF-α, IL-1β, and IL-6 also downregulated GLUT4 transcript levels relative to those for the control. However, only IL-6 was inhibitory at concentrations detected in macrophage-adipocyte cocultures. IL-6 and TNF-α, but not IL-1β, inhibited Akt phosphorylation within 15 min of insulin stimulation, but only IL-6 was inhibitory 30 min after stimulation. Lastly, we found that adipocyte differentiation was inhibited by macrophages or by recombinant TNF-α, IL-6, and IL-1β, with IL-6 having the most impact. These data suggest that the interaction between macrophages and adipocytes is a complex process, and they support the hypothesis that the macrophage-adipocyte interaction affects insulin resistance by disrupting insulin-stimulated glucose transport, adipocyte differentiation, and macrophage function.
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Ulndreaj, Antigona, Angela Li, Yonghong Chen, Rickvinder Besla, Shaun Pacheco, Marwan G. Althagafi, Myron I. Cybulsky, Thomas Lindsay, Clinton S. Robbins, and John S. Byrne. "Adventitial recruitment of Lyve-1− macrophages drives aortic aneurysm in an angiotensin-2-based murine model." Clinical Science 135, no. 10 (May 2021): 1295–309. http://dx.doi.org/10.1042/cs20200963.
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Abstract Objective: Aortic macrophage accumulation is characteristic of the pathogenesis of abdominal aortic aneurysm (AAA) but the mechanisms of macrophage accumulation and their phenotype are poorly understood. Lymphatic vessel endothelial receptor-1 (Lyve-1+) resident aortic macrophages independently self-renew and are functionally distinct from monocyte-derived macrophages recruited during inflammation. We hypothesized that Lyve-1+ and Lyve-1− macrophages differentially contribute to aortic aneurysm. Approach and results: Angiotensin-2 and β-aminopropionitrile (AT2/BAPN) were administered to induce AAA in C57BL/6J mice. Using immunohistochemistry (IHC), we demonstrated primarily adventitial accumulation of aortic macrophages, and in association with areas of elastin fragmentation and aortic dissection. Compared with controls, AAA was associated with a relative percent depletion of Lyve-1+ resident aortic macrophages and accumulation of Lyve-1− macrophages. Using CD45.1/CD45.2 parabiosis, we demonstrated aortic macrophage recruitment in AAA. Depletion of aortic macrophages in CCR2−/− mice was associated with reduced aortic dilatation indicating the functional role of recruitment from the bone marrow. Depletion of aortic macrophages using anti-macrophage colony-stimulating factor 1 receptor (MCSF1R)-neutralizing antibody (Ab) reduced the incidence of AAA. Conditional depletion of Lyve-1+ aortic macrophages was achieved by generating Lyve-1wt/cre Csf1rfl/fl mice. Selective depletion of Lyve-1+ aortic macrophages had no protective effects following AT2/BAPN administration and resulted in increased aortic dilatation in the suprarenal aorta. Conclusions: Aortic macrophage accumulation in AAA derives from adventitial recruitment of Lyve-1− macrophages, with relative percent depletion of Lyve-1+ macrophages. Selective targeting of macrophage subtypes represents a potential novel therapeutic avenue for the medical treatment of AAA.
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Hamrick, Terri S., Edward A. Havell, John R. Horton, and Paul E. Orndorff. "Host and Bacterial Factors Involved in the Innate Ability of Mouse Macrophages To Eliminate Internalized UnopsonizedEscherichia coli." Infection and Immunity 68, no. 1 (January 1, 2000): 125–32. http://dx.doi.org/10.1128/iai.68.1.125-132.2000.
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ABSTRACT In an effort to better understand genetic and cellular factors that influence innate immunity, we examined host and bacterial factors involved in the nonopsonic phagocytosis and killing ofEscherichia coli K-12 by mouse macrophages. Unelicited (resident) peritoneal macrophages from five different mouse strains, BALB/c, C57BL/6, CD-1, C3H/HeJ, and C3H/HeN, were employed. Additional macrophage populations were obtained from CD-1 mice (bone marrow-derived macrophages). Also, for BALB/c and C57BL/6 mice, peritoneal macrophages elicited with either thioglycolate or proteose peptone, bone marrow-derived macrophages, and macrophage-like cell lines derived from the two strains were employed. Two E. coli K-12 strains that differed specifically in their abilities to produce type 1 pili containing the adhesive protein FimH were examined. The parameters used to assess macrophage bacteriocidal activity were (i) the killing of internalized (gentamicin-protected)E. coli during the approximately 4-h assay and (ii) the initial rate at which internalized E. coli were eliminated. Data on these parameters allowed the following conclusions: (i) unelicited or proteose peptone-elicited peritoneal macrophages were significantly better at eliminating internalized bacteria than thioglycolate-elicited peritoneal macrophages, bone marrow-derived macrophages, or macrophage cell lines; (ii) the host genetic background had no significant effect upon the ability of unelicited peritoneal macrophages to kill E. coli (even though the mouse strains differ widely in their in vivo susceptibilities to bacterial infection); and (iii) the FimH phenotype had no significant effect uponE. coli survival once the bacterium was inside a macrophage. Additionally, there was no correlation between the bacteriocidal effectiveness of a macrophage population and the number of bacteria bound per macrophage. However, macrophage populations that were the least bacteriocidal tended to bind higher ratios of FimH+ to FimH− E. coli. The effect of gamma interferon, fetal calf serum, and the recombination proficiency of E. coli were examined as factors predicted to influence intracellular bacterial killing. These had no effect upon the rate of E. coli elimination by unelicited peritoneal macrophages.
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Singh, Gyanesh, U. C. Pachouri, Chirag Chopra, Preeti Bajaj, and Pushplata Singh. "Macrophage Gene Therapy: opening novel therapeutic avenues for immune disorders." F1000Research 4 (August 6, 2015): 495. http://dx.doi.org/10.12688/f1000research.6817.1.
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Macrophages are probably the most important cells of the mammalian immune system, and compromised macrophage function is known to cause several diseases. Their involvement in arthritis, cancer, infections, atherosclerosis, diabetes, and autoimmune disorders is well known. There has been a constantly growing need to transfer therapeutic genes into macrophages. Like most non-macrophage gene therapies,in vitrogene transfer has been attempted much more frequently in case of macrophages. However, primary macrophages are still somewhat recalcitrant to transfection. Macrophage-specific synthetic promoters, which were recently used successfully, can have up to 100-fold higher activity than that of native promoters. Adenovirus, lentivirus, and adeno-associated virus are commonly used for macrophage gene therapy. A number of non-viral methods are also popular for the transfer of exogenous DNA into macrophages. Gene transfer to macrophages using naked DNA has also been successful in a few cases. Macrophages have specific mechanisms to recognize and respond to bacterial DNA because of the presence of unmethylated CpG dinucleotides, which are rare in eukaryotic DNA. With interesting developments in this area, macrophage gene therapy appears to have great potential for immune therapies.
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Boutilier, Ava J., and Sherine F. Elsawa. "Macrophage Polarization States in the Tumor Microenvironment." International Journal of Molecular Sciences 22, no. 13 (June 29, 2021): 6995. http://dx.doi.org/10.3390/ijms22136995.
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The M1/M2 macrophage paradigm plays a key role in tumor progression. M1 macrophages are historically regarded as anti-tumor, while M2-polarized macrophages, commonly deemed tumor-associated macrophages (TAMs), are contributors to many pro-tumorigenic outcomes in cancer through angiogenic and lymphangiogenic regulation, immune suppression, hypoxia induction, tumor cell proliferation, and metastasis. The tumor microenvironment (TME) can influence macrophage recruitment and polarization, giving way to these pro-tumorigenic outcomes. Investigating TME-induced macrophage polarization is critical for further understanding of TAM-related pro-tumor outcomes and potential development of new therapeutic approaches. This review explores the current understanding of TME-induced macrophage polarization and the role of M2-polarized macrophages in promoting tumor progression.
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Bauerle, Kevin Thomas, Jisu Oh, Amy Elizabeth Riek, Adriana Dusso, Anabel L. Castro-Grattoni, R. Ariel Gomez, Maria L. Sequeira-Lopez, and Carlos Bernal-Mizrachi. "Vitamin D Deficiency Induces Macrophage Pro-Inflammatory Phenotype via ER Stress-Mediated Activation of Renin-Angiotensin System." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A304—A305. http://dx.doi.org/10.1210/jendso/bvab048.620.
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Abstract Chronic inflammation and local activation of the renin-angiotensin-aldosterone system (RAAS) play a pivotal role in the pathogenesis and progression of diabetic complications. In patients with type 2 diabetes (T2DM), the prevalence of vitamin D deficiency is almost twice that of non-diabetics, and vitamin d deficiency nearly doubles the risk of developing hypertension and cardiovascular complications compared to diabetics with normal vitamin D levels. Interestingly, mice lacking the vitamin D receptor (VDR) in macrophages (KODMAC) develop renin-dependent hypertension, insulin resistance, and inflammation via up-regulation of macrophage ER stress. Macrophages also express all major components of the RAAS system. However, little is known about the regulation of macrophage-generated renin and its role in modulating the sequelae of VDR signaling in macrophage function and cytokine production. This study found that KODMAC macrophages and vitamin D-deficient macrophages have increased expression and secretion of renin, angiotensin II, ACE, and AT1 receptor and that adhesion, migration, and cytokine release were also increased. Inhibition of ER stress in KODMAC macrophages and vitamin D-deficient macrophages with 4-Phenylbutyric acid (PBA) reduced RAS gene expression and macrophage pro-inflammatory phenotype. Renin 1c gene deletion decreased macrophage adhesion, migration, and cytokine release compared to macrophages with disrupted VDR signaling. Notably, disruption of VDR signaling induced peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) expression in macrophages, and upregulation of renin expression in response to vitamin D deficiency was blunted in PCG1α-deficient macrophages. In conclusion, our findings delineate a mechanism by which impaired VDR signaling induces ER stress to drive PGC1α-dependent expression of renin and RAAS hyperactivation, thereby altering macrophage function and cytokine production. These data implicate RAAS as an essential mediator of VDR-mediated macrophage function and support ongoing investigations of VDR and RAAS modulation as therapeutic approaches in the management of T2DM and its complications.
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Song, Lili, Do-sung Kim, Wenyu Gou, Jingjing Wang, Ping Wang, Zhiguo Wei, Bei Liu, Zihai Li, Kemian Gou, and Hongjun Wang. "GRP94 regulates M1 macrophage polarization and insulin resistance." American Journal of Physiology-Endocrinology and Metabolism 318, no. 6 (June 1, 2020): E1004—E1013. http://dx.doi.org/10.1152/ajpendo.00542.2019.
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Macrophage polarization contributes to obesity-induced insulin resistance. Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER) chaperone specialized for folding and quality control of secreted and membrane proteins. To determine the role of GRP94 in macrophage polarization and insulin resistance, macrophage-specific GRP94 conditional knockout (KO) mice were challenged with a high-fat diet (HFD). Glucose tolerance, insulin sensitivity, and macrophage composition were compared with control mice. KO mice showed better glucose tolerance and increased insulin sensitivity. Adipose tissues from HFD-KO mice contained lower numbers of M1 macrophages, with lower expression of M1 macrophage markers, than wild-type (WT) mice. In vitro, WT adipocytes cocultured with KO macrophages retained insulin sensitivity, whereas those cultured with WT macrophages did not. In addition, compared with WT bone marrow-derived macrophages (BMDMs), BMDMs from GRP94 KO mice exhibited lower expression of M1 macrophage marker genes following stimulation with LPS or IFN-γ, and exhibited partially increased expression of M2 macrophage marker genes following stimulation with interleukin-4. These findings identify GRP94 as a novel regulator of M1 macrophage polarization and insulin resistance and inflammation.
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Pagan, Antonio, Chao-Tsung Yang, Laura Swaim, and Lalita Ramakrishnan. "Replenishment of granuloma macrophages promotes mycobacterial resistance by preventing extracellular bacterial growth (INC7P.410)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 186.11. http://dx.doi.org/10.4049/jimmunol.192.supp.186.11.
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Abstract Pathogenic mycobacteria exploit the early tuberculous granuloma for their expansion by inducing infected macrophage apoptosis and accelerating uninfected macrophage recruitment and infection upon engulfing the dying macrophages. Whether sustained macrophage recruitment to established granulomas is also host-detrimental is unclear. We addressed this question in the zebrafish model of tuberculosis by manipulating the macrophage colony stimulation factor 1 (CSF-1) pathway, which promotes macrophage development. Early granuloma formation was normal in CSF-1 receptor-deficient fish in spite of having fewer macrophages. However, they became hypersusceptible upon depleting their macrophages, leading to the sudden loss of new recruits that would normally engulf the infected dead cells. The unphagocytosed infected macrophages underwent necrosis, releasing mycobacteria into the extracellular milieu that promotes exuberant growth. Partial macrophage depletion with lipo-clodranate produced the same effects in wild-type fish. Conversely, overexpression of CSF-1 in wild-type fish increased macrophage numbers and reduced susceptibility to infection. These results suggest that granuloma kinetics must be nuanced to promote resistance - while delaying granuloma formation is host-beneficial, abolishing macrophage recruitment to established granulomas is detrimental. These results might also explain why monocytopenias confer susceptibility to mycobacterial infections in humans.
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Tekin, Cansu, Hella L. Aberson, Cynthia Waasdorp, Gerrit K. J. Hooijer, Onno J. de Boer, Frederike Dijk, Maarten F. Bijlsma, and C. Arnold Spek. "Macrophage-secreted MMP9 induces mesenchymal transition in pancreatic cancer cells via PAR1 activation." Cellular Oncology 43, no. 6 (August 18, 2020): 1161–74. http://dx.doi.org/10.1007/s13402-020-00549-x.
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Abstract Purpose Targeting tumor-infiltrating macrophages limits progression and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma (PDAC). Protease-activated receptor (PAR)1 drives monocyte/macrophage recruitment, and stromal ablation of PAR1 limits cancer growth and enhances gemcitabine sensitivity in experimental PDAC. However, the functional interplay between PAR1, macrophages and tumor cells remains unexplored. Here we address the PAR1-macrophage-tumor cell crosstalk and assess its contributions to tumor progression. Methods PAR1 expression and macrophage infiltration were correlated in primary PDAC biopsies using gene expression datasets and tissue microarrays. Medium transfer experiments were used to evaluate the functional consequences of macrophage-tumor cell crosstalk and to assess the contribution of PAR1 to the observed responses. PAR1 cleavage assays were used to identify a macrophage-secreted PAR1 agonist, and the effects of candidate proteases were assessed in medium transfer experiments with specific inhibitors and/or recombinant agonist. Results PAR1 expression correlates with macrophage infiltration in primary PDACs, and macrophages induce mesenchymal transition of PDAC cells through PAR1 activation. Protease profiling identified macrophage-secreted matrix metalloprotease 9 (MMP9) as the relevant PAR1 agonist in PDAC. PAR1 and/or MMP9 inhibition limited macrophage-driven mesenchymal transition. Likewise, preventing mesenchymal transition by silencing ZEB1 or by pharmacological inhibition of the MMP9/PAR1 axis significantly reduced the ability of tumor cells to survive the anti-tumor activities of macrophages. Conclusion Macrophages secrete MMP9, which acts upon PDAC cell PAR1 to induce mesenchymal transition. This macrophage-induced mesenchymal transition supports the tumor-promoting role of macrophage influx, explaining the dichotomous contributions of these immune cells to tumor growth.
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Pervin, Munmun, Mohammad Rabiul Karim, Mizuki Kuramochi, Takeshi Izawa, Mitsuru Kuwamura, and Jyoji Yamate. "Macrophage Populations and Expression of Regulatory Inflammatory Factors in Hepatic Macrophage-depleted Rat Livers under Lipopolysaccharide (LPS) Treatment." Toxicologic Pathology 46, no. 5 (June 24, 2018): 540–52. http://dx.doi.org/10.1177/0192623318776898.
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To investigate the significance of the appearance of hepatic macrophages and expression of inflammatory factors in normal and macrophage-depleted livers, hepatic macrophages were depleted with liposome (Lipo)-encapsulated clodronate (CLD; 50 mg/kg, i.v.) followed by lipopolysaccharide (LPS) administration (0.1 mg/kg, i.p.) in F344 rats (CLD + LPS). Vehicle control rats (Lipo + LPS) received empty-Lipo before LPS. The low dose of LPS did not result in microscopic changes in the liver in either treatment group but did modulate M1 and M2 macrophage activity in Lipo + LPS rats without altering repopulating hepatic macrophages in CLD + LPS rats. LPS treatment in Lipo + LPS rats dramatically increased the M1 (IL-1β, IL-6, TNF-α, and MCP-1) but not M2 macrophage-related factors (IL-4 and CSF-1) compared to CLD + LPS rats. In the CLD + LPS rats, the M2 macrophage-related factors IL-4 and CSF-1 were elevated. In conclusion, low-dose LPS activated hepatic macrophages in rat livers without causing liver injury or stimulating repopulating hepatic macrophages. These data suggest that LPS may alter the liver microenvironment by modulating M1 or M2 macrophage-related inflammatory mediators and macrophage-based hepatotoxicity.
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Cho, Sun Wook, Young A. Kim, Hyun Jin Sun, Ye An Kim, Byung-Chul Oh, Ka Hee Yi, Do Joon Park, and Young Joo Park. "CXCL16 signaling mediated macrophage effects on tumor invasion of papillary thyroid carcinoma." Endocrine-Related Cancer 23, no. 2 (November 11, 2015): 113–24. http://dx.doi.org/10.1530/erc-15-0196.
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Macrophages in tumor microenvironment have pivotal roles in tumor growth, metastasis, and angiogenesis. We investigated the interacting mechanism of macrophage actions in human papillary thyroid cancer (PTC). Co-cultures of macrophage/PTC significantly increased the cancer cell migration potentials, compared with the PTC culture alone. Treatment of conditioned medium (CM) of macrophage/PTC co-cultures enhanced cell invasions in 3D invasion assay. Cytokine array analysis demonstrated that CM of macrophage/PTC co-cultures contained a high level of CXCL16, while it was not found in CM of PTC culture alone. Treatment with CXCL16 enhanced the cell migration potentials in PTC cells, and blocking CXCL16 signaling using anti-CXCL16 antibody or metalloproteinase inhibitor (TAPI2) attenuated macrophage-mediated enhancement of PTC cell migration potentials. In PTC cells, CXCL16 treatment or co-cultures with macrophages increased Akt phosphorylation, and these macrophage-dependent increases of Akt phosphorylation was inhibited by anti-CXCL16 antibody. Moreover, Akt inhibitor attenuated macrophage-mediated increases of PTC cell migration potential. In macrophages, treatment of macrophage/PTC co-cultured CMs up-regulated CD163, Il10, and CD206, which were attenuated by anti-CXCL16 antibody treatment. Finally, CXCR6 and CXCL16 expressions were evaluated by immunohistochemical staining with a thyroid tissue microarray including 136 PTC. CXCR6 expressions showed positive correlation with the density of CD163+ macrophages and associated with lymph node metastasis. In conclusion, CXCL16 signaling partly mediated macrophage actions on PTC tumor cell invasion and also changed the macrophage phenotypes into M2-macrophages in PTC tumor microenvironment. These data suggested that CXCL16 signaling, a bidirectional player in macrophage-associated tumor microenvironment, might be a potential therapeutic target of human PTC.
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Song, Lige, Garyfallia Papaioannou, Hengguang Zhao, Hilary F. Luderer, Christine Miller, Claudia Dall’Osso, Rosalynn M. Nazarian, Amy J. Wagers, and Marie B. Demay. "The Vitamin D Receptor Regulates Tissue Resident Macrophage Response to Injury." Endocrinology 157, no. 10 (August 15, 2016): 4066–75. http://dx.doi.org/10.1210/en.2016-1474.
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Ligand-dependent actions of the vitamin D receptor (VDR) play a pleiotropic role in the regulation of innate and adaptive immunity. The liganded VDR is required for recruitment of macrophages during the inflammatory phase of cutaneous wound healing. Although the number of macrophages in the granulation tissue 2 days after wounding is markedly reduced in VDR knockout (KO) compared with wild-type mice, VDR ablation does not alter macrophage polarization. Parabiosis studies demonstrate that circulatory chimerism with wild-type mice is unable to rescue the macrophage defect in the wounds of VDR KO mice and reveal that wound macrophages are of local origin, regardless of VDR status. Wound cytokine analyses demonstrated a decrease in macrophage colony-stimulating factor (M-CSF) protein levels in VDR KO mice. Consistent with this, induction of M-CSF gene expression by TGFβ and 1,25-dihydroxyvitamin D was impaired in dermal fibroblasts isolated from VDR KO mice. Because M-CSF is important for macrophage self-renewal, studies were performed to evaluate the response of tissue resident macrophages to this cytokine. A decrease in M-CSF induced proliferation and cyclin D1 expression was observed in peritoneal resident macrophages isolated from VDR KO mice, suggesting an intrinsic macrophage abnormality. Consistent with this, wound-healing assays in mice with macrophage-specific VDR ablation demonstrate that a normal wound microenvironment cannot compensate for the absence of the VDR in macrophages and thus confirm a critical role for the macrophage VDR in the inflammatory response to injury.
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Rosa, L. F. B. P. Costa, Y. Cury, and R. Curi. "Hormonal control of macrophage function and glutamine metabolism." Biochemistry and Cell Biology 69, no. 4 (April 1, 1991): 309–12. http://dx.doi.org/10.1139/o91-047.
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Murine macrophages have been reported to utilize glutamine at high rates. However, the role of glutamine in macrophage function is still unknown. In the present study, the maximum glutaminase activity of macrophages was investigated under several endocrine dysfunctions that are known to cause alterations in macrophage function. The results obtained suggest that glutamine might play an important role in the onset of phagocytosis in inflammatory macrophages. Moreover, the studies show that insulin, glucocorticoids, and thyroid hormones may be responsible for the regulation of glutamine metabolism and, consequently, of macrophage function.Key words: macrophage, glutamine, insulin, glucocorticoids, thyroid hormones, catecholamines.
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Li, Wei, Yaomei Wang, Huizhi Zhao, Huan Zhang, Yuanlin Xu, Shihui Wang, Xinhua Guo, et al. "Identification, Isolation and Transcriptome Analyses of Mouse, Rat and Man Erythroblastic Island Central Macrophages." Blood 132, Supplement 1 (November 29, 2018): 841. http://dx.doi.org/10.1182/blood-2018-99-114188.
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Abstract Erythroblastic island (EBI), composed of a central macrophage and surrounding erythroid cells, is the first hematopoietic niche discovered for erythropoiesis. Yet, the identity of the central macrophage has so far remained elusive. Based on the previous findings that F4/80, VCAM1 and CD169 are potential mouse central macrophage markers, we first calculated the number of F4/80+VCAM1+CD169+ mouse macrophages in the mouse bone marrow and compared it to the number of Ter119+ erythroblasts. We found that the ratio of F4/80+VCAM1+CD169+ macrophage and erythroblasts is about 1:2. Given the fact that one central macrophage is surrounded by multiple erythroblasts, the above finding suggests that it is unlikely that all the F4/80+VCAM1+CD169+ macrophages are central macrophages. Erythropoietin (Epo) is essential for erythropoiesis. It has been reported that the Epo receptor (Epor) is expressed in peritoneal macrophages. These findings promoted us to speculate that EBI central macrophages may express Epor so that Epo acts on both erythroid cells and the central macrophages simultaneously in the niche to ensure efficient and optimal red cell production. To test this notion, we first examined whether mouse bone marrow and fetal liver macrophages express Epor using the Epor-GFPcre knockin mouse model. We found that ~5% of bone marrow F4/80+ macrophages and ~35% of fetal liver F4/80+ macrophages express Epor-GFP. As negative control, no Epor-GFP macrophages are noted in wild type F4/80+ macrophages. Importantly, ImageStream analyses revealed the native EBIs in bone marrow and fetal liver are formed by Epor+ but not Epor- macrophages. Bioinformatics analyses of RNA-seq data on the sorted Epor+ and Epor- macrophage populations revealed that molecules involved in central macrophage-erythroblast association such as VCAM1, CD169, and molecules known to be important for central macrophage function such as Dnase2a, ferroportin, are highly expressed in Epor+ macrophages. In marked contrast, highly expressed pathways in Epor- macrophages are associated with immune responses including antigen process and presentation. Intriguingly, the immune related pathways are dramatically downregulated in the Epor+ macrophages, suggesting that the Epor+ macrophages in bone marrow and fetal liver have evolved a specialized function in supporting erythropoiesis. To examine whether expression of Epor in EBI central macrophages is a conserved feature across species, we generated Epor-GFPcre knockin rat using the CRISP/Cas9 technology. Using CD163 as rat macrophage marker, we found that a subpopulation of rat bone marrow CD163+ macrophages expresses Epor-GFP. As a negative control, no Epor-GFP macrophages are noted in wild type CD163+ macrophages. To examine whether EPOR is expressed in human EBI central macrophages, antibody specificity for human EPOR is critical. To this end, we employed CRISP/Cas9 approach to knock out EPOR in K562 and Hela cell lines and validated the specificity of a commercially available anti-human EPOR antibody. Using CD163, CD169 as human macrophage markers, we found that EPOR is also expressed in a subpopulation of human macrophages. Moreover, in vitro EBI formation assay revealed that human EPOR+ but not EPOR- macrophages form EBIs with erythroid cells and that the EBI formation is enhanced by EPO. In summary, we for the first time, after discovery of the EBIs 60 years ago, have identified Epor+ macrophages in mouse bone marrow and fetal liver as EBI central macrophages. Our findings provide solid foundation for studying the mechanisms by which erythropoieis is supported EBI central macrophages. A better understanding of such mechanisms will provide extensive new knowledge on basic biology of erythropoiesis. It is also important to understand the pathology of erythropoietic disorders as well as to improve ex vivo erythrocyte production. Disclosures No relevant conflicts of interest to declare.
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Schwamb, Janine, Nina Reinart, Daniela Vorholt, Thomas Ulas, Vangica Ristovska, Christian J. Braun, Michael T. Hemann, Joachim Schultze, Michael Hallek, and Christian P. Pallasch. "Phagocytic Function of Macrophages Is Impaired By Chronic Lymphocytic Leukemia and high–grade Lymphoma Progression and Can be Highly Effectively Restored for Chemo-Immunotherapy." Blood 124, no. 21 (December 6, 2014): 2727. http://dx.doi.org/10.1182/blood.v124.21.2727.2727.
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Abstract Macrophage polarity has recently been shown to play a pivotal role in progression and prognosis of human malignancies. In CLL the high dependence of the malignant cell to the tumor microenvironment has revealed macrophages as major mediators of leukemia cell survival. In contrast, macrophage activation also offers novel therapeutic strategies for leukemia cell targeting. Here we analyze the reciprocal relationship of leukemia cells and macrophages and the specific functional impact of phagocytosis in leukemia progression and therapy. We employed the humanized hMB-Lymphoma and the Eµ-TCL1 CLL mouse model. Thioglycollate-induced macrophages, bone marrow derived murine macrophages and human monocyte derived macrophages were used for in vitroevaluation of phagocytosis either by bead based approaches or by ADCC. Applying gene-expression profiling of macrophages in Eµ-TCL1 mice we could identify profound transcriptional alterations indicating a re-programming during leukemogenesis. Functional genomic analysis particularly revealed impaired phagocytic function induced during leukemia onset. In vivo and ex vivo phagocytosis assays of primary macrophages showed a significant reduced phagocytic activity during CLL progression. Human macrophages in co-culture with CLL cells in vitro compared to healthy B-cells similarly showed defects in phagocytosis. In the humanized leukemia model we similarly observed impaired phagocytosis resulting in resistance towards therapeutic antibody/macrophage mediated therapy. Resistance was actively induced by increasing leukemia cell infiltration in the bone marrow. Impaired macrophage function could be identified being mediated by secretory crosstalk such as release of PGE2 by leukemia cells and Cholecalciferol. We could restore phagocytic function by combination regimens involving therapeutic antibodies and chemotherapy. Specifically, an acute secretory activating phenotype (ASAP), releasing cytokines from leukemia cells induces macrophage infiltration and phagocytic activity in the bone marrow. Thus, malignant cells can be effectively targeted by modulation of macrophage polarization and function. In conclusion, we have identified decreased phagocytic activity of macrophages as key functional aspect in leukemia and lymphoma associated macrophages. Inversely, enhancing phagocytosis rendered essential for the re-sensitization of refractory niches treatment towards monoclonal antibodies defined by macrophage polarity. Overall macrophage function represents a key therapeutic target in CLL and other B-cell malignancies. Disclosures No relevant conflicts of interest to declare.
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Chen, Peiwen, Hao Zuo, Hu Xiong, Matthew J. Kolar, Qian Chu, Alan Saghatelian, Daniel J. Siegwart, and Yihong Wan. "Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis." Proceedings of the National Academy of Sciences 114, no. 3 (January 3, 2017): 580–85. http://dx.doi.org/10.1073/pnas.1614035114.
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Macrophages are prominent immune cells in the tumor microenvironment that exert potent effects on cancer metastasis. However, the signals and receivers for the tumor–macrophage communication remain enigmatic. Here, we show that G protein-coupled receptor 132 (Gpr132) functions as a key macrophage sensor of the rising lactate in the acidic tumor milieu to mediate the reciprocal interaction between cancer cells and macrophages during breast cancer metastasis. Lactate activates macrophage Gpr132 to promote the alternatively activated macrophage (M2)-like phenotype, which, in turn, facilitates cancer cell adhesion, migration, and invasion. Consequently, Gpr132 deletion reduces M2 macrophages and impedes breast cancer lung metastasis in mice. Clinically, Gpr132 expression positively correlates with M2 macrophages, metastasis, and poor prognosis in patients with breast cancer. These findings uncover the lactate-Gpr132 axis as a driver of breast cancer metastasis by stimulating tumor–macrophage interplay, and reveal potential new therapeutic targets for breast cancer treatment.
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Mass, Elvira, Ivan Ballesteros, Matthias Farlik, Florian Halbritter, Johanna Klughammer, Christoph Bock, and Frederic Geissmann. "Establishment of tissue-resident macrophage core and tissue specific programs during embryogenesis." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 52.14. http://dx.doi.org/10.4049/jimmunol.196.supp.52.14.
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Abstract Tissue resident macrophages develop during embryogenesis, are maintained independently of hematopoietic stem cells during adulthood, and display tissue-specific functions and phenotypes. To understand the genetic program that drives macrophage differentiation from distinct progenitors and their tissue-specific identity, we performed a systematic spatio-temporal analysis of macrophage development in mice. Transcriptional and in situ analyses revealed that a core macrophage program is established very early and within a short time window and is conserved throughout fetal development and in adult macrophages. A new genetic mouse model supports the transcriptional data as it allows to specifically label differentiating macrophages, and therefore targets adult macrophages in all tissues. Interestingly, immediately after colonization of the target tissue, we could identify tissue-specific macrophage programs that are maintained until adulthood. Additionally, we identified a novel transcriptional regulator, which is expressed in early fetal liver macrophages, and whose inactivation results in an impaired Kupffer cell development. In summary, we present a macrophage developmental atlas, identify novel tissue-specific markers and transcriptional regulators, and show that tissue specialization is mainly influenced by ontogenetic gene expression programs.
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Xu, Rong, Hong-Fan Sun, David W. Williams, Adam V. Jones, Ali Al-Hussaini, Bing Song, and Xiao-Qing Wei. "IL-34 SuppressesCandida albicansInduced TNFαProduction in M1 Macrophages by Downregulating Expression of Dectin-1 and TLR2." Journal of Immunology Research 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/328146.
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Candida albicansis a fungus that is an opportunistic pathogen of humans. Normally,C. albicansexists as a harmless commensal and does not trigger inflammatory responses by resident macrophages in skin mucosa, which may be caused by a tolerance of skin macrophage toC. albicans. IL-34 is a recently discovered cytokine, constitutively expressed by keratinocytes in the skin. IL-34 binds to the receptor of M-CSF, thereby stimulating tissue macrophage maturation and differentiation. Resident macrophages exhibit phenotypic plasticity and may transform into inflammatory M1 macrophages for immunity or anti-inflammatory M2 macrophages for tissue repair. M1 macrophages produce higher levels of inflammatory cytokines such as TNFαin response toC. albicansstimulation. In this study, it was demonstrated that IL-34 attenuated TNFαproduction by M1 macrophages challenged with heat killed Candida (HKC). The molecular mechanism of IL-34 mediated suppression of HKC induced TNFαproduction by M1 macrophages was by the inhibition of M1 macrophage expression of keyC. albicanspattern recognition receptors (PPRs), namely, Toll-like receptor (TLR) 2 and Dectin-1. The results of this study indicated that constitutive IL-34 expressed by skin keratinocytes might suppress resident macrophage responses toC. albicanscolonisation by maintaining low levels TLR2 and Dectin-1 expression by macrophages.
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Unuvar Purcu, Duygu, Asli Korkmaz, Sinem Gunalp, Derya Goksu Helvaci, Yonca Erdal, Yavuz Dogan, Asli Suner, Gerhard Wingender, and Duygu Sag. "Effect of stimulation time on the expression of human macrophage polarization markers." PLOS ONE 17, no. 3 (March 14, 2022): e0265196. http://dx.doi.org/10.1371/journal.pone.0265196.
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Macrophages are highly plastic cells that can polarize into functionally distinct subsets in vivo and in vitro in response to environmental signals. The development of protocols to model macrophage polarization in vitro greatly contributes to our understanding of macrophage biology. Macrophages are divided into two main groups: Pro-inflammatory M1 macrophages (classically activated) and anti-inflammatory M2 macrophages (alternatively activated), based on several key surface markers and the production of inflammatory mediators. However, the expression of these common macrophage polarization markers is greatly affected by the stimulation time used. Unfortunately, there is no consensus yet regarding the optimal stimulation times for particular macrophage polarization markers in in vitro experiments. This situation is problematic, (i) as analysing a particular marker at a suboptimal time point can lead to false-negative results, and (ii) as it clearly impedes the comparison of different studies. Using human monocyte-derived macrophages (MDMs) in vitro, we analysed how the expression of the main polarization markers for M1 (CD64, CD86, CXCL9, CXCL10, HLA-DR, IDO1, IL1β, IL12, TNF), M2a (CD200R, CD206, CCL17, CCL22, IL-10, TGM2), and M2c (CD163, IL-10, TGFβ) macrophages changes over time at mRNA and protein levels. Our data establish the most appropriate stimulation time for the analysis of the expression of human macrophage polarization markers in vitro. Providing such a reference guide will likely facilitate the investigation of macrophage polarization and its reproducibility.
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Li, Xue, Deana Mikhalkova, Erhe Gao, Jin Zhang, Valerie Myers, Carmen Zincarelli, Yonghong Lei, et al. "Myocardial injury after ischemia-reperfusion in mice deficient in Akt2 is associated with increased cardiac macrophage density." American Journal of Physiology-Heart and Circulatory Physiology 301, no. 5 (November 2011): H1932—H1940. http://dx.doi.org/10.1152/ajpheart.00755.2010.
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Akt2 protein kinase has been shown to promote cell migration and actin polymerization in several cell types, including macrophages. Because migrating macrophages constitute an important inflammatory response after myocardial ischemia, we determined cardiac macrophage expression after ischemia-reperfusion (I/R) injury and cryo-injury in mice lacking Akt2 (Akt2-KO). At 7 days post-I/R, Akt2-KO cardiac tissues showed an increase in immunohistochemical staining for macrophage markers (Galectin 3 and F4/80) compared with wild-type (WT) mice, indicating macrophage density was increased in the injured Akt2-KO myocardium. This change was time dependent because macrophage density was similar between WT and Akt2-KO myocardium at 3 days post-I/R, but by 7 and 14 days post-I/R, macrophage density was significantly increased in Akt2-KO myocardium. Concomitantly, infarct size was larger and cardiac function was reduced in Akt2-KO mice subjected to I/R. However, when cryo-infarction produced similar infarct sizes in the anterior wall in both WT and Akt2-KO mice, macrophage density remained higher in Akt2-KO mouse myocardium, suggesting Akt2 regulates myocardial macrophage density independent of infarct size. Consistently, bone marrow from Akt2-KO mice enhanced myocardial macrophage density in both C57/B6 WT and Akt2-KO recipient mice. Finally, reciprocal ex-vivo coculturing of macrophages and cardiac myocytes showed that activated Akt2-KO peritoneal macrophages had reduced mobility and adhesion when compared with WT littermate controls. Thus, although Akt-2 KO mice did not affect the initial inflammation response after injury and Akt2 deficiency has been shown to impair cell migration or motility in macrophages, our data suggested a novel mechanism in which increasing retention of Akt2-KO macrophages resulted in increasing cardiac Akt2-KO macrophage density in the myocardial space.
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Snarski, Patricia, Sergiy Sukhanov, Tadashi Yoshida, Yusuke Higashi, Svitlana Danchuk, Bysani Chandrasekar, Di Tian, Vikara Rivera-Lopez, and Patrick Delafontaine. "Macrophage-Specific IGF-1 Overexpression Reduces CXCL12 Chemokine Levels and Suppresses Atherosclerotic Burden in Apoe-Deficient Mice." Arteriosclerosis, Thrombosis, and Vascular Biology 42, no. 2 (February 2022): 113–26. http://dx.doi.org/10.1161/atvbaha.121.316090.
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Objective: IGF-1 (insulin-like growth factor 1) exerts pleiotropic effects including promotion of cellular growth, differentiation, survival, and anabolism. We have shown that systemic IGF-1 administration reduced atherosclerosis in Apoe −/ − (apolipoprotein E deficient) mice, and this effect was associated with a reduction in lesional macrophages and a decreased number of foam cells in the plaque. Almost all cell types secrete IGF-1, but the effect of macrophage-derived IGF-1 on the pathogenesis of atherosclerosis is poorly understood. We hypothesized that macrophage-derived IGF-1 will reduce atherosclerosis. Approach and Results: We created macrophage-specific IGF-1 overexpressing mice on an Apoe − / − background. Macrophage-specific IGF-1 overexpression reduced plaque macrophages, foam cells, and atherosclerotic burden and promoted features of stable atherosclerotic plaque. Macrophage-specific IGF1 mice had a reduction in monocyte infiltration into plaque, decreased expression of CXCL12 (CXC chemokine ligand 12), and upregulation of ABCA1 (ATP-binding cassette transporter 1), a cholesterol efflux regulator, in atherosclerotic plaque and in peritoneal macrophages. IGF-1 prevented oxidized lipid-induced CXCL12 upregulation and foam cell formation in cultured THP-1 macrophages and increased lipid efflux. We also found an increase in cholesterol efflux in macrophage-specific IGF1–derived peritoneal macrophages. Conclusions: Macrophage IGF-1 overexpression reduced atherosclerotic burden and increased features of plaque stability, likely via a reduction in CXCL12-mediated monocyte recruitment and an increase in ABCA1-dependent macrophage lipid efflux.
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Tian, Ying, Sheri E. Kelemen, and Michael V. Autieri. "Inhibition of AIF-1 expression by constitutive siRNA expression reduces macrophage migration, proliferation, and signal transduction initiated by atherogenic stimuli." American Journal of Physiology-Cell Physiology 290, no. 4 (April 2006): C1083—C1091. http://dx.doi.org/10.1152/ajpcell.00381.2005.
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Allograft inflammatory factor-1 (AIF-1) is a cytoplasmic, calcium-binding, inflammation-responsive scaffold protein. Several studies have reported increased AIF-1 expression in activated macrophages and have implicated AIF-1 as a marker of activated macrophages. However, the function of AIF-1 in macrophages and the mechanism whereby it participates in macrophage activation are unknown at this time. Immunohistochemical analysis colocalized AIF-1 expression with CD68-positive macrophages in atherosclerotic human coronary arteries. Subsequent experiments were designed to determine a role for AIF-1 in macrophage activation in response to atherogenic stimuli. Stimulation of human and murine macrophages with oxidized LDL significantly increased AIF-1 expression above basal levels. Stable transfection of AIF-1 small interfering RNA (siRNA) in macrophages reduced AIF-1 protein expression by 79% and reduced macrophage proliferation by 52% ( P < 0.01). Inhibition of proliferation was not due to induction of apoptosis. Sequences that did not knock down AIF-1 expression had no effect on proliferation. AIF-1 siRNA expression reduced macrophage migration by 60% ( P < 0.01). Both proliferation and migration of siRNA-expressing macrophages could be restored by adenoviral expression of AIF-1 ( P < 0.001 and 0.005, respectively), suggesting a tight association between AIF-1 expression and macrophage activation. Phosphorylation of Akt, p44/42 MAPK, and p38 kinase were significantly reduced in siRNA macrophages challenged with oxidized LDL ( P < 0.05). Phosphorylation of p38 kinase was significantly inhibited in siRNA macrophages stimulated with T lymphocyte conditioned medium ( P < 0.05). These data indicate that AIF-1 mediates atherogenesis-initiated signaling and activation of macrophages.
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Gong, Manyu, Xuewen Yang, Yaqi Wang, Yanying Wang, Dongping Liu, Haodong Li, Yunmeng Qu, et al. "Growth differentiation factor 11 promotes macrophage polarization towards M2 to attenuate myocardial infarction via inhibiting Notch1 signaling pathway." Frigid Zone Medicine 3, no. 1 (January 25, 2023): 53–64. http://dx.doi.org/10.2478/fzm-2023-0008.
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Abstract Background Myocardial infarctions (MI) is a major threat to human health especially in people exposed to cold environment. The polarization of macrophages towards different functional phenotypes (M1 macrophages and M2 macrophages) is closely related to MI repairment. The growth differentiation factor 11 (GDF11) has been reported to play a momentous role in inflammatory associated diseases. In this study, we examined the regulatory role of GDF11 in macrophage polarization and elucidated the underlying mechanisms in MI. Methods In vivo, the mice model of MI was induced by permanent ligation of the left anterior descending coronary artery (LAD), and mice were randomly divided into the sham group, MI group, and MI+GDF11 group. The protective effect of GDF11 on myocardial infarction and its effect on macrophage polarization were verified by echocardiography, triphenyl tetrazolium chloride staining and immunofluorescence staining of heart tissue. In vitro, based on the RAW264.7 cell line, the effect of GDF11 in promoting macrophage polarization toward the M2 type by inhibiting the Notch1 Signaling pathway was validated by qRT-PCR, Western blot, and flow cytometry. Results We found that GDF11 was significantly downregulated in the cardiac tissue of MI mice. And GDF11 supplementation can improve the cardiac function. Moreover, GDF11 could reduce the proportion of M1 macrophages and increase the accumulation of M2 macrophages in the heart tissue of MI mice. Furthermore, the cardioprotective effect of GDF11 on MI mice was weakened after macrophage clearance. At the cellular level, application of GDF11 could inhibit the expression of M1 macrophage (classically activated macrophage) markers iNOS, interleukin (IL)-1β, and IL-6 in a dose-dependent manner. In contrast, GDF11 significantly increased the level of M2 macrophage markers including IL-10, CD206, arginase 1 (Arg1), and vascular endothelial growth factor (VEGF). Interestingly, GDF11 could promote M1 macrophages polarizing to M2 macrophages. At the molecular level, GDF11 significantly down-regulated the Notch1 signaling pathway, the activation of which has been demonstrated to promote M1 polarization in macrophages. Conclusions GDF11 promoted macrophage polarization towards M2 to attenuate myocardial infarction via inhibiting Notch1 signaling pathway.
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Mouton, Alan J., Xuan Li, Michael E. Hall, and John E. Hall. "Obesity, Hypertension, and Cardiac Dysfunction." Circulation Research 126, no. 6 (March 13, 2020): 789–806. http://dx.doi.org/10.1161/circresaha.119.312321.
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Obesity and hypertension, which often coexist, are major risk factors for heart failure and are characterized by chronic, low-grade inflammation, which promotes adverse cardiac remodeling. While macrophages play a key role in cardiac remodeling, dysregulation of macrophage polarization between the proinflammatory M1 and anti-inflammatory M2 phenotypes promotes excessive inflammation and cardiac injury. Metabolic shifting between glycolysis and mitochondrial oxidative phosphorylation has been implicated in macrophage polarization. M1 macrophages primarily rely on glycolysis, whereas M2 macrophages rely on the tricarboxylic acid cycle and oxidative phosphorylation; thus, factors that affect macrophage metabolism may disrupt M1/M2 homeostasis and exacerbate inflammation. The mechanisms by which obesity and hypertension may synergistically induce macrophage metabolic dysfunction, particularly during cardiac remodeling, are not fully understood. We propose that obesity and hypertension induce M1 macrophage polarization via mechanisms that directly target macrophage metabolism, including changes in circulating glucose and fatty acid substrates, lipotoxicity, and tissue hypoxia. We discuss canonical and novel proinflammatory roles of macrophages during obesity-hypertension–induced cardiac injury, including diastolic dysfunction and impaired calcium handling. Finally, we discuss the current status of potential therapies to target macrophage metabolism during heart failure, including antidiabetic therapies, anti-inflammatory therapies, and novel immunometabolic agents.
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Wang, Jianjun, Yongliang Yao, Jing Xiong, Jianhong Wu, Xin Tang, and Guangxin Li. "Evaluation of the Inflammatory Response in Macrophages Stimulated with Exosomes Secreted byMycobacterium avium-Infected Macrophages." BioMed Research International 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/658421.
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Exosomes secreted fromMycobacterium avium-infected macrophages contain numerous antigens of bothM. aviumand the host cell and are involved in the induction and expression of the inflammatory responses in macrophages. The interaction between exosomes secreted fromM. avium-infected macrophages and macrophage phagocytosis, cytokine secretion, immunostimulation, and apoptosis was analyzed. Upon stimulation with exosomes secreted fromM. avium-infected macrophages, the phagocytosis of dextran by treated macrophages was increased. Furthermore, the expression of CD40, CD80, CD81, CD86, HLA-DR, and most notably CD195 was enhanced. Additionally, the secretion of IL-6, IL-8, IL-10, IFN-γ, and TNF-αwas increased by stimulated macrophages. Exosome stimulation did not induce macrophage apoptosis when compared with macrophages infected withM. avium. Caspase expression, including that of caspases 3, 6, and 8, was also not altered in exosome stimulated macrophages. Thus exosomes trigger the inflammatory response in macrophages owing to the presence of bacterial antigens but have no effect on macrophage viability.
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Lu, Chunxia, P. Anil Kumar, Yong Fan, Mark A. Sperling, and Ram K. Menon. "A Novel Effect of Growth Hormone on Macrophage Modulates Macrophage-Dependent Adipocyte Differentiation." Endocrinology 151, no. 5 (February 25, 2010): 2189–99. http://dx.doi.org/10.1210/en.2009-1194.
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The GH receptor (GHR) is expressed on macrophages. However, the precise role of GH in regulation of macrophage function is unclear. We hypothesized that soluble factors including cytokines produced by macrophages in a GH-dependent manner regulate adipogenesis. We confirmed expression and functional integrity of the GHR in the J774A.1 macrophage cells. Conditioned medium (CM) from macrophages inhibited adipogenesis in a 3T3-L1 adipogenesis assay. CM from GH-treated macrophages decreased the inhibitory effect of CM from macrophages on adipogenesis. This effect on preadipocyte differentiation was active only during the first (early) phase of adipocyte differentiation. CM from stromal vascular compartment macrophages of mice with macrophage-specific deletion of the GHR exhibited more inhibitory effect on 3T3-L1 preadipocyte differentiation compared with CM from stromal vascular compartment macrophages of control mice, indicating that intact GH action in primary macrophages also increases preadipocyte differentiation. GH did not increase IGF-1 expression in macrophages. PCR array analysis identified IL-1β as a candidate cytokine whose expression was altered by GH in macrophages. Levels of IL-1β mRNA and protein were significantly decreased in GH-treated J774A.1 macrophages. Nuclear factor-κB stimulates IL-1β gene expression, and GH induced a significant decrease in the levels of phosphorylated nuclear factor-κB in macrophages. IL-1β is a known inhibitor of adipogenesis, and these results support GH-dependent down-regulation of macrophage IL-1β expression as one mechanism for the observed increase in adipogenesis with CM from GH-treated macrophages. We conclude that GH decreases secretion of IL-1β by the macrophage and thus in a paracrine manner increases adipocyte differentiation. These results provide a novel mechanism for GH’s actions in the control of adipogenesis.
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Shaw, Maureen A., Zhen Gao, and Eric S. Mullins. "Plasmin(ogen) Mediates Macrophage Migration in a Fibrin(ogen) Dependent Mechanism." Blood 128, no. 22 (December 2, 2016): 18. http://dx.doi.org/10.1182/blood.v128.22.18.18.
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Abstract Mounting evidence ties both fibrin(ogen) and plasmin(ogen) to inflammatory diseases. Indeed, both fibrin(ogen) and plasmin(ogen) have been linked to critical macrophage functions in multiple disease processes. Migration of macrophages to sites of sterile inflammation is, at least partially, dependent on plasmin(ogen). Mice lacking plasminogen, when challenged with sterile thioglycollate-induced peritonitis, have both diminished overall leukocyte migration and decreased macrophage migration. Additionally, macrophage migration defects have been identified in both mice lacking plasminogen and plasminogen receptors. Plasmin has many targets that may play a role in supporting macrophage migration. In addition to proteolysis of fibrin(ogen), plasmin activates matrix metalloprotease (MMP) 2 and MMP9 and cleaves collagen and laminin. Indeed, mice that lack MMP9 have a migration defect similar to mice that lack plasminogen, suggesting that MMP9 is a biologically relevant proteolytic target in this context. To further examine the targets of plasmin that regulate macrophage migration, we challenged animals that have individual and combined genetic deficiencies in fibrinogen and plasminogen with thioglycollate-induced peritonitis. We have found that mice that lack fibrinogen alone have a significantly increased migration of macrophages to the peritoneal cavity. Mice with lack of plasminogen alone demonstrated the expected diminution in macrophage migration to the peritoneal cavity. However, mice that were deficient in both plasminogen and fibrinogen demonstrated macrophage migration that was indistinguishable from wildtype. These data suggest that fibrin(ogen) impedes macrophage migration to the peritoneal cavity. To further confirm this mechanism, we examined macrophage migration in a transwell assay in vitro, in response to macrophage chemoattractant protein-1 (MCP-1). Here, a macrophage cell line (RAW 264.7) migration was examined in the absence and presence of fibrin matrices. Macrophages, in the absence of plasminogen, did demonstrate a modest, but statistically significant, increase in migration across the transwell membrane in the absence of fibrinogen. When a fibrin matrix was generated on the transwell membrane, macrophages were essentially unable to cross in the absence of plasminogen. These data further support the concept that macrophages require plasmin(ogen) to cross fibrin matrices. To further explore the plasmin(ogen)-fibrin(ogen) interaction in macrophage migration, we assessed the migration of macrophages to fibrin degradation products (FDPs). First, we examined macrophage transwell migration in response to MCP-1 in the presence of FDPs to assess if FDPs impede macrophage migration. Instead of impeding macrophage migration, FDPs significantly increased macrophage migration across the transwell membrane. Indeed FDPs initiated macrophage migration even in the absence of MCP-1. To confirm that this was FDP induced migration, and not direct plasmin signaling on macrophages, we examined macrophage migration to FDPs in the presence of an irreversible plasmin inhibitor. We again found that plasmin degradation of fibrin was needed for migration, however, further plasmin activity was not required. Taken together, these data suggest that macrophages require plasmin(ogen) to navigate fibrin matrices and that the by-product of this degradation (FDPs) is a signal for additional macrophage migration to sites of fibrin deposition. Disclosures Mullins: Baxalta (now part of Shire): Honoraria; US WorldMeds: Membership on an entity's Board of Directors or advisory committees.
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Arai, Fumio, Takeshi Miyamoto, Osamu Ohneda, Tomohisa Inada, Tetsuo Sudo, Kenneth Brasel, Takashi Miyata, Dirk M. Anderson, and Toshio Suda. "Commitment and Differentiation of Osteoclast Precursor Cells by the Sequential Expression of C-Fms and Receptor Activator of Nuclear Factor κb (Rank) Receptors." Journal of Experimental Medicine 190, no. 12 (December 20, 1999): 1741–54. http://dx.doi.org/10.1084/jem.190.12.1741.
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Osteoclasts are terminally differentiated cells derived from hematopoietic stem cells. However, how their precursor cells diverge from macrophagic lineages is not known. We have identified early and late stages of osteoclastogenesis, in which precursor cells sequentially express c-Fms followed by receptor activator of nuclear factor κB (RANK), and have demonstrated that RANK expression in early-stage of precursor cells (c-Fms+RANK−) was stimulated by macrophage colony-stimulating factor (M-CSF). Although M-CSF and RANKL (ligand) induced commitment of late-stage precursor cells (c-Fms+RANK+) into osteoclasts, even late-stage precursors have the potential to differentiate into macrophages without RANKL. Pretreatment of precursors with M-CSF and delayed addition of RANKL showed that timing of RANK expression and subsequent binding of RANKL are critical for osteoclastogenesis. Thus, the RANK–RANKL system determines the osteoclast differentiation of bipotential precursors in the default pathway of macrophagic differentiation.