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Liu, Yunfeng, Fangmiao Jing, Woelsung Yi, Avital Mendelson, Patricia Shi, Ronald Walsh, David F. Friedman, et al. "HO-1hi patrolling monocytes protect against vaso-occlusion in sickle cell disease." Blood 131, no. 14 (April 5, 2018): 1600–1610. http://dx.doi.org/10.1182/blood-2017-12-819870.
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Key Points SCD patients with a recent VOC episode have lower frequencies and numbers of HO-1hi patrolling monocytes. Heme-driven SCD vaso-occlusion is exacerbated in mice lacking patrolling monocytes and reversed following patrolling monocyte transfer.
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Finsterbusch, Michaela, Pam Hall, Anqi Li, Sapna Devi, Clare L. V. Westhorpe, A. Richard Kitching, and Michael J. Hickey. "Patrolling monocytes promote intravascular neutrophil activation and glomerular injury in the acutely inflamed glomerulus." Proceedings of the National Academy of Sciences 113, no. 35 (August 15, 2016): E5172—E5181. http://dx.doi.org/10.1073/pnas.1606253113.
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Nonclassical monocytes undergo intravascular patrolling in blood vessels, positioning them ideally to coordinate responses to inflammatory stimuli. Under some circumstances, the actions of monocytes have been shown to involve promotion of neutrophil recruitment. However, the mechanisms whereby patrolling monocytes control the actions of neutrophils in the circulation are unclear. Here, we examined the contributions of monocytes to antibody- and neutrophil-dependent inflammation in a model of in situ immune complex-mediated glomerulonephritis. Multiphoton and spinning disk confocal intravital microscopy revealed that monocytes patrol both uninflamed and inflamed glomeruli using β2 and α4 integrins and CX3CR1. Monocyte depletion reduced glomerular injury, demonstrating that these cells promote inappropriate inflammation in this setting. Monocyte depletion also resulted in reductions in neutrophil recruitment and dwell time in glomerular capillaries and in reactive oxygen species (ROS) generation by neutrophils, suggesting a role for cross-talk between monocytes and neutrophils in induction of glomerulonephritis. Consistent with this hypothesis, patrolling monocytes and neutrophils underwent prolonged interactions in glomerular capillaries, with the duration of these interactions increasing during inflammation. Moreover, neutrophils that interacted with monocytes showed increased retention and a greater propensity for ROS generation in the glomerulus. Also, renal patrolling monocytes, but not neutrophils, produced TNF during inflammation, and TNF inhibition reduced neutrophil dwell time and ROS production, as well as renal injury. These findings show that monocytes and neutrophils undergo interactions within the glomerular microvasculature. Moreover, evidence indicates that, in response to an inflammatory stimulus, these interactions allow monocytes to promote neutrophil recruitment and activation within the glomerular microvasculature, leading to neutrophil-dependent tissue injury.
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Liu, Yunfeng, Fangmiao Jing, Woelsung Yi, Avital Mendelson, Patricia Shi, Ronald Walsh, David F. Friedman, et al. "Protective Role of HO-1 Expressing CD16+ Patrolling Monocytes Against Hemolysis-Induced Endothelial Damage and Vaso-Occlusive Crisis in Sickle Cell Disease." Blood 130, Suppl_1 (December 7, 2017): 767. http://dx.doi.org/10.1182/blood.v130.suppl_1.767.767.
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Abstract Causing leukocyte activation and upregulation of adhesion molecules on endothelial cells. CD16+ monocytes, also known as endothelial patrolling monocytes, normally scavenge the damaged cells and debris from the vasculature. As compared to other monocyte subsets or immune cell types, the CD16+monocyte subset expresses higher levels of the anti-inflammatory heme oxygenase 1 (HO-1), a heme degrading enzyme. Given the role of CD16+ monocytes as scavengers of debris on endothelial cells, we tested the hypothesis that this subset may protect SCD vasculature from the ongoing hemolytic insult through expression of high levels of HO-1. We found roughly 35% of circulating CD16+ monocytes from SCD patients expressed very high levels of HO-1 as compared to 5% in healthy controls. The HO-1hi SCD monocytes expressed significantly (30%) less TNF-a compared to HO-1lo monocytes following stimulation, consistent with anti-inflammatory effects of HO-1. We hypothesized that uptake of free hemoglobin/heme was responsible for high HO-1 expression levels in SCD CD16+ monocytes. To test this, healthy donors (HDs) or SCD patient monocytes were treated with different doses of free heme or hemolysed RBCs. We found dose-dependent HO-1 induction (five-fold at 20mM heme) in purified CD16- monocytes, but surprisingly none in CD16+ subset. However, upon co-culture with human umbilical vein endothelial cells (HUVEC), continuous or prior exposure to heme induced HO-1hi expression exclusively in CD16+ monocytes (5 fold in HD and further two fold in SCD compared to non-heme treated cocultures, p<0.001). Using imagining flow cytometric analysis, we found marked increase in uptake of heme-exposed endothelial cell-derived material by CD16+ monocytes (HD: 2% to 13% ± 3%; in SCD: 20% ± 3% to 30% ± 4%, p< 0.001) but none by CD16- monocytes. Our transwell studies demonstrated that cell-cell contact between CD16+ monocytes and heme-exposed HUVEC was required for HO-1hi expression. We found roughly 4-fold increase in expression of phosphatidylserine (PS, annexin V+), ICAM-1 and vCAM-1 on heme-treated HUVEC cells. Antibody blocking studies identified PS moieties as well as ICAM-1 as key molecules involved in monocyte-HUVEC interactions that mediated HO-1hi induction, suggesting that high levels of HO-1 expression in SCD CD16+ monocytes is in part the result of attachment to and engulfment of apoptotic, activated endothelial cells damaged by heme. SCD patients suffer from vaso-occlusive crisis (VOC), resulting from increased attachment of SCD RBCs to damaged and activated endothelium. We hypothesized that inadequate numbers or lower HO-1hi levels in CD16+ monocyte will predispose SCD patients to episodes of VOC due to decreased removal by CD16+ monocytes of damaged endothelial and sickle RBCs. Amongst SCD patients receiving chronic transfusions, we found a two-fold lower frequency of circulating CD16+ monocytes and half the numbers of CD16+HO-1hi monocytes in patients with a recent history of VOC episode as compared to those without VOC (p< 0.01); the former group also expressed higher levels of circulating sVCAM-1 (997 ± 210 vs 765 ± 236 ng/m, p=0.02), a marker of endothelial activation. To formally test the role of patrolling monocytes in endothelial damage induced by SCD RBCs and heme, we injected RBCs from Townes SCD mice alone or after 24hrs with heme into Nr4a1-knockout mice which have a selective loss of patrolling monocytes. Immunofluorescence analysis of liver vasculature showed a 3 fold increase in the activated endothelial marker, ICAM-1 within 24hrs following injection of sickle RBCs and two-fold increase in circulating sVCAM-1 levels in mice treated with sickle RBC plus heme (p <0.001). Transfer of HO-1+ patrolling monocytes (LY6Clo), but not a classical monocyte subset (LY6C+) reversed activated endothelial phenotype, indicating that patrolling monocytes can inhibit SCD-induced endothelial activation. Altogether, these data suggest that SCD patrolling monocytes remove hemolysis-damaged endothelial cells, resulting in HO-1 upregulation and dampening of vascular inflammation. Perturbations in CD16+ monocyte numbers resulting in lower local HO-1 levels can predispose SCD patients to VOC, thus identifying HO-1+ patrolling monocytes as key players in VOC pathophysiology and as therapeutic targets. Disclosures No relevant conflicts of interest to declare.
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Marcovecchio, Paola M., Graham D. Thomas, Zbigniew Mikulski, Erik Ehinger, Karin A. L. Mueller, Amy Blatchley, Runpei Wu, et al. "Scavenger Receptor CD36 Directs Nonclassical Monocyte Patrolling Along the Endothelium During Early Atherogenesis." Arteriosclerosis, Thrombosis, and Vascular Biology 37, no. 11 (November 2017): 2043–52. http://dx.doi.org/10.1161/atvbaha.117.309123.
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Objective— Nonclassical monocytes (NCM) function to maintain vascular homeostasis by crawling or patrolling along the vessel wall. This subset of monocytes responds to viruses, tumor cells, and other pathogens to aid in protection of the host. In this study, we wished to determine how early atherogenesis impacts NCM patrolling in the vasculature. Approach and Results— To study the role of NCM in early atherogenesis, we quantified the patrolling behaviors of NCM in ApoE −/− (apolipoprotein E) and C57BL/6J mice fed a Western diet. Using intravital imaging, we found that NCM from Western diet–fed mice display a 4-fold increase in patrolling activity within large peripheral blood vessels. Both human and mouse NCM preferentially engulfed OxLDL (oxidized low-density lipoprotein) in the vasculature, and we observed that OxLDL selectively induced NCM patrolling in vivo. Induction of patrolling during early atherogenesis required scavenger receptor CD36, as CD36 −/− mice revealed a significant reduction in patrolling activity along the femoral vasculature. Mechanistically, we found that CD36-regulated patrolling was mediated by a SFK (src family kinase) through DAP12 (DNAX activating protein of 12KDa) adaptor protein. Conclusions— Our studies show a novel pathway for induction of NCM patrolling along the vascular wall during early atherogenesis. Mice fed a Western diet showed increased NCM patrolling activity with a concurrent increase in SFK phosphorylation. This patrolling activity was lost in the absence of either CD36 or DAP12. These data suggest that NCM function in an atheroprotective manner through sensing and responding to oxidized lipoprotein moieties via scavenger receptor engagement during early atherogenesis.
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Thomas, Graham, Robert Tacke, Catherine C. Hedrick, and Richard N. Hanna. "Nonclassical Patrolling Monocyte Function in the Vasculature." Arteriosclerosis, Thrombosis, and Vascular Biology 35, no. 6 (June 2015): 1306–16. http://dx.doi.org/10.1161/atvbaha.114.304650.
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Contreras, Cristina F., Sabina Kaczanowska, and Rosandra N. Kaplan. "Function of circulating myeloid cells in healthy donors and patients with metastatic solid tumors." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 101.03. http://dx.doi.org/10.4049/jimmunol.206.supp.101.03.
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Abstract Monocytes are a heterogeneous group of mononuclear innate immune cells that have diverse inflammatory responses. In the context of cancer, monocytes and monocyte-derived cells have been evaluated for their pro- and anti-tumoral effects in the tumor microenvironment. These functions range from induction of tumor cell death to suppression of T cells, promotion of angiogenesis and remodeling of the extracellular matrix. Outside of the primary tumor, monocytes in circulation maintain their dichotomous role in cancer immunosurveillance. Specifically, patrolling non-classical CD14−CD16+ monocytes have been found to play a role in the prevention of metastasis. In contrast, CD14+ monocyte-derived cells from patients with solid tumors have been shown to promote tumor progression. Therefore, understanding this monocytic heterogeneity as well as other unexplored roles (i.e. monocyte-mediated phagocytosis of tumor cells) is crucially important for malignancies with high rates of metastasis. Yet, the phenotypic and functional diversity of circulating monocytes in patients with metastatic solid malignancies is still largely unknown. In this study, we sought to characterize and compare peripheral blood monocytes obtained from healthy donors and patients with advanced stage solid tumors. Through flow cytometric analysis and functional assays, we determined the subpopulation distributions as well as the phagocytic and suppressive activities of the monocytic compartment in patients with advanced cancer and healthy controls. Providing new insights into their cancer-related functions, we highlight the need for consideration of circulating monocytes into immune-targeting approaches in metastatic solid malignancies.
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Contreras, Cristina F., Sabina Kaczanowska, and Rosandra N. Kaplan. "Transcriptomic and epigenetic profiling of tumor-associated monocyte function." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 179.07. http://dx.doi.org/10.4049/jimmunol.208.supp.179.07.
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Abstract Monocytes are innate immune cells recognized for their ability to play both tumor permissive and surveillant roles in cancer. Circulating classical monocytes (CD14+CD16−) can home to the tumor and suppress other immune cells through various mechanisms, including the production of arginase and the release of reactive oxygen species (ROS). Conversely, patrolling nonclassical monocytes (CD14−CD16+) have been shown to employ processes such as phagocytosis and presentation of tumor antigens to prevent metastasis. This heterogeneous monocyte function is influenced by tumor-derived factors that are released during cancer development and progression. Phenotypic and transcriptional alterations in circulating monocytes and other myeloid cells in patients with solid tumors have been reported and associated with poor clinical outcomes. However, perturbations of specific monocyte functions in the setting of solid tumors have not been well explored. Here we present a characterization of monocytes by coupling flow cytometry-based functional assays with sequencing (Func-seq). Healthy donor primary monocytes and monocytic cell lines were used to examine the production of ROS and arginase in response to osteosarcoma-conditioned media and monocyte-mediated phagocytosis of osteosarcoma cells. Bulk RNA-seq and ATAC-seq were performed on FACS-sorted populations to compare differentially expressed genes and establish transcriptomic and epigenetic signatures associated with monocyte-mediated immunosuppression and tumor-cell phagocytosis. The incorporation of functional selection into -omic characterization provides insights into monocyte behavior and potential therapeutic targets to alter their activity in solid tumors. Funding: US National Institutes of Health grants ZIA BC 011332 and ZIA BC 011855 and NCI cancer moonshot.
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O’Connor, Kevin W., Tiantian Liu, Sunkyung Kim, Theresa Murphy, and Kenneth M. Murphy. "Notch2, Bcl6, and IRF2 govern differentiation and survival of murine nonclassical monocytes." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 163.20. http://dx.doi.org/10.4049/jimmunol.208.supp.163.20.
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Abstract Nonclassical (patrolling) monocytes are a population of monocytes which monitor the vasculature and participate in tissue repair. Though nonclassical monocytes are thought to be developmentally derived from classical monocytes, the mechanisms that control the differentiation of classical monocytes into nonclassical monocytes are still not completely understood. Signaling through the Notch2 receptor appears to trigger development of nonclassical monocytes. Also, the transcription factors C/EBPβ and Nur77 (Nr4a1) are required for nonclassical monocyte development in vivo. We have now identified additional transcription factor requirements for the differentiation and/or survival of nonclassical monocytes in vivo. We find that mice with conditional deletion of Bcl6 in myeloid cells or germline IRF2 deficiency show a severe loss of nonclassical monocytes. Both Bcl6 and IRF2 are induced during the transition from classical to nonclassical monocyte. In vitro culture of myeloid progenitors on stromal cells expressing DLL1, a Notch2 ligand, recapitulates aspects of nonclassical monocyte development seen in vivo, confirming Notch signaling as a key initiating event in the development of nonclassical monocytes. This system allows for the identification of the downstream targets of Notch2 signaling that drive nonclassical monocyte development, as well as the analysis of the impact of other transcription factors on the differentiation and survival of these cells in vivo. We present a model of the steps required for development of murine nonclassical monocytes. Supported by NIH (RO1 AI150297, RO1 CA248919)
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França, Carolina N., Maria C. O. Izar, Marinella N. S. Hortêncio, Jônatas B. do Amaral, Carlos E. S. Ferreira, Izabela D. Tuleta, and Francisco A. H. Fonseca. "Monocyte subtypes and the CCR2 chemokine receptor in cardiovascular disease." Clinical Science 131, no. 12 (May 31, 2017): 1215–24. http://dx.doi.org/10.1042/cs20170009.
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Monocytes circulate in the blood and migrate to inflammatory tissues, but their functions can be either detrimental or beneficial, depending on their phenotypes. In humans, classical monocytes are inflammatory cluster of differentiation (CD)14++CD16−CCR2++ cells originated from the bone marrow or spleen reservoirs and comprise ≥92% of monocytes. Intermediate monocytes (CD14++CD16+CCR2+) are involved in the production of anti-inflammatory cytokines [such as interleukin (IL)-10], reactive oxygen species (ROS), and proinflammatory mediators [such as tumor necrosis factor-α (TNF-α) and IL-1β). Nonclassical monocytes (CD14+CD16++CCR2−) are patrolling cells involved in tissue repair and debris removal from the vasculature. Many studies in both humans and animals have shown the importance of monocyte chemoattractant protein-1 (MCP-1) and its receptor [chemokine receptor of MCP-1 (CCR2)] in pathologies, such as atherosclerosis and myocardial infarction (MI). This review presents the importance of these monocyte subsets in cardiovascular diseases (CVDs), and sheds light on new strategies for the blocking of the MCP-1/CCR2 axis as a therapeutic goal for treating vascular disorders.
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Regal-McDonald, Kellie, Brittney Xu, Jarrod W. Barnes, and Rakesh P. Patel. "High-mannose intercellular adhesion molecule-1 enhances CD16+ monocyte adhesion to the endothelium." American Journal of Physiology-Heart and Circulatory Physiology 317, no. 5 (November 1, 2019): H1028—H1038. http://dx.doi.org/10.1152/ajpheart.00306.2019.
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Human monocytes have been classified into three distinct groups, classical (anti-inflammatory; CD14+/CD16−), nonclassical (patrolling; CD14+/CD16++), and intermediate (proinflammatory; CD14++/CD16+). Adhesion of nonclassical/intermediate monocytes with the endothelium is important for innate immunity, and also vascular inflammatory disease. However, there is an incomplete understanding of the mechanisms that regulate CD16+ versus CD16− monocyte adhesion to the inflamed endothelium. Here, we tested the hypothesis that a high-mannose (HM) N-glycoform of intercellular adhesion molecule-1 (ICAM-1) on the endothelium mediates the selective recruitment of CD16+ monocytes. Using TNF-α treatment of human umbilical vein endothelial cells (HUVECs), and using proximity ligation assay for detecting proximity of specific N-glycans and ICAM-1, we show that TNF-α induces HM-ICAM-1 formation on the endothelial surface in a time-dependent manner. We next measured CD16− or CD16+ monocyte rolling and adhesion to TNF-α-treated HUVECs in which HM- or hybrid ICAM-1 N-glycoforms were generated using the α-mannosidase class I and II inhibitors, kifunensine and swainsonine, respectively. Expression of HM-ICAM-1 selectively enhanced CD16+ monocyte adhesion under flow with no effect on CD16− monocytes noted. CD16+ monocyte adhesion was abrogated by blocking either HM epitopes or ICAM-1. A critical role for HM-ICAM-1 in mediating CD16+ monocyte rolling and adhesion was confirmed using COS-1 cells engineered to express HM or complex ICAM-1 N-glycoforms. These data suggest that HM-ICAM-1 selectively recruits nonclassical/intermediate CD16+ monocytes to the activated endothelium. NEW & NOTEWORTHY Monocyte subsets have been associated with cardiovascular disease, yet it is unknown how different subsets are recruited to the endothelium. This study demonstrates the formation of distinct ICAM-1 N-glycoforms in the activated endothelium and reveals a key role for high mannose ICAM-1 in mediating proinflammatory CD16+ monocyte adhesion. Presented data identify roles for endothelial N-glycans in recruiting specific monocyte subsets during inflammation.
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Sato, Ryota, Tatjana Reuter, Ryosuke Hiranuma, Takuma Shibata, Ryutaro Fukui, Yuji Motoi, Yusuke Murakami, et al. "The impact of cell maturation and tissue microenvironments on the expression of endosomal Toll-like receptors in monocytes and macrophages." International Immunology 32, no. 12 (August 25, 2020): 785–98. http://dx.doi.org/10.1093/intimm/dxaa055.
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Abstract Toll-like receptors (TLRs) impact myeloid cell responsiveness to environmental cues such as pathogen components and metabolites. Although TLR protein expression in monocytes and tissue macrophages is thought to be optimized for microenvironments in each tissue, a comprehensive study has not been reported. We here examined protein expression of endogenous TLRs in tissue-resident myeloid cells. Neutrophils in peripheral blood, spleen, liver and lung expressed TLR2, TLR4 and TLR5 in all tissues. Ly6C+ MHC II‒ classical monocytes mature into Ly6C‒ MHC II+ monocyte-derived dendritic cells (moDCs) or Ly6C‒ MHC II‒ patrolling monocytes. These subsets were found in all the tissues studied. TLR2 and TLR4 were displayed on all of these subsets, regardless of location. In contrast, expression of endosomal TLRs did vary with tissues and subsets. moDCs expressed TLR9, but much less TLR7. In contrast, TLR7, not TLR3 or TLR9, was highly expressed in classical and patrolling monocytes. Tissue macrophages such as red pulp macrophages in the spleen, Kupffer cells in the liver, microglia in the brain, alveolar macrophages in the lung and adipose tissue macrophages all expressed TLR2, TLR4 and TLR3. TLR7 was also expressed in these tissue macrophages except Kupffer cells in the liver. TLR9 expression in tissue macrophages was much lower or hard to detect. These results suggest that expression of endosomal TLRs in myeloid cells is influenced by their differentiation status and tissue-specific microenvironments.
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Laurance, Sandrine, Francois-Rene Bertin, Talin Ebrahimian, Stephanie Lehoux, Catherine A. Lemarie, and Mark D. Blostein. "Gas6 Promotes Pro-Inflammatory (Ly6Chi) Monocyte Recruitment in Venous Thrombosis." Blood 124, no. 21 (December 6, 2014): 1533. http://dx.doi.org/10.1182/blood.v124.21.1533.1533.
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Abstract Recent studies have demonstrated that innate immune cells, i.e. neutrophils and monocytes, provide the initiating stimulus for venous thrombus development. Gas6 was found to promote inflammation by inducing interactions between the endothelium and innate immune cells. In addition, we recently showed that Gas6 was involved in venous thrombosis by inducing tissue factor expression in the endothelium. Since Gas6 is expressed in monocytes, we hypothesize that Gas6 may be involved in monocyte recruitment during venous thrombosis. Venous thrombosis was induced in the inferior vena cava of wild type (WT) and Gas6 deficient (-/-) mice using 5% FeCl3. Using ultrasonography, we found that global monocyte depletion by clodronate resulted in the formation of smaller thrombi. Selective depletion of the pro-inflammatory (Ly6Chi) monocyte subset, using an anti-CCR2 antibody, also induced the formation of smaller clots. In addition, MOMA-2 (monocyte-macrophage marker) staining showed a reduced number of monocytes in thrombi from Gas6-/- mice. More importantly, immunofluorescent staining revealed that fewer Ly6Chi monocytes were recruited to the thrombi of Gas6-/- mice compared to WT. However, Ly6Clow (patrolling) monocytes were equivalently recruited between Gas6-/- and WT mice. In vitro, mRNA expression of CCR2 was increased by thrombin in WT but not in Gas6-/- monocytes. The mRNA and protein expression of the CCR2 ligand, CCL2, was also increased by thrombin in WT but not in Gas6-/- endothelial cells. CCL2 secretion, as demonstrate by ELISA, was induced by thrombin treatment in WT but not in Gas6-/- endothelial cells. Conditioned media from WT or Gas6-/- endothelial treated by thrombin was used for monocyte migration experiments. The conditioned media from WT endothelial cells treated with thrombin increased migration of WT monocytes compared to media from untreated or Gas6-/- endothelial cells. Our results demonstrate an important role for Ly6Chi monocytes in thrombus formation and that Gas6 is specifically involved in the recruitment of these monocytes through the expression of CCL2 and CCR2. Disclosures No relevant conflicts of interest to declare.
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Singhal, Rashi, Deepak K. Rathore, Teena Bhakuni, Tulika Seth, and Prasenjit Guchhait. "Absence of Nonclassical Monocytes in Hemolytic Patients: Free Hb and NO-Mediated Mechanism." Journal of Immunology Research 2019 (March 27, 2019): 1–11. http://dx.doi.org/10.1155/2019/1409383.
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In a recent work, we have described the kinetics among the monocyte subsets in the peripheral blood of hemolytic patients including paroxysmal nocturnal hemoglobinuria (PNH) and sickle cell disease (SCD). After engulfing Hb-activated platelets, classical monocytes (CD14+CD16-) significantly transformed into highly inflammatory (CD14+CD16hi) subsets in vitro. An estimated 40% of total circulating monocytes in PNH and 70% in SCD patients existed as CD14+CD16hi subsets. In this study, we show that the nonclassical (CD14dimCD16+) monocyte subsets are nearly absent in patients with PNH or SCD, compared to 10-12% cells in healthy individuals. In mechanism, we have described the unique role of both free Hb and nitric oxide (NO) in reducing number of nonclassical subsets more than classical monocytes. After engulfing Hb-activated platelets, the monocytes including nonclassical subsets acquired rapid cell death within 12 h in vitro. Further, the treatment to monocytes either with the secretome of Hb-activated platelets containing NO and free Hb or purified free Hb along with GSNO (a physiological NO donor) enhanced rapid cell death. Besides, our data from both PNH and SCD patients exhibited a direct correlation between intracellular NO and cell death marker 7AAD in monocytes from the peripheral blood. Our data together suggest that due to the immune surveillance nature, the nonclassical or patrolling monocytes are encountered frequently by Hb-activated platelets, free Hb, and NO in the circulation of hemolytic patients and are predisposed to die rapidly.
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de Castro-Amarante, Maria Fernanda, Cynthia A. Pise-Masison, Katherine McKinnon, Robyn Washington Parks, Veronica Galli, Maria Omsland, Vibeke Andresen, et al. "Human T Cell Leukemia Virus Type 1 Infection of the Three Monocyte Subsets Contributes to Viral Burden in Humans." Journal of Virology 90, no. 5 (November 25, 2015): 2195–207. http://dx.doi.org/10.1128/jvi.02735-15.
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ABSTRACTBecause the viral DNA burden correlates with disease development, we investigated the contribution of monocyte subsets (classical, intermediate, and nonclassical monocytes) to the total viral burden in 22 human T cell leukemia virus type 1 (HTLV-1)-infected individuals by assessing their infectivity status, frequency, as well as chemotactic and phagocytic functions. All three monocyte subsets sorted from HTLV-1-infected individuals were positive for viral DNA, and the frequency of classical monocytes was lower in the blood of HTLV-1-infected individuals than in that of uninfected individuals, while the expression levels of the chemokine receptors CCR5, CXCR3, and CX3CR1 in classical monocytes were higher in HTLV-1-infected individuals than uninfected individuals; the percentage of intermediate monocytes and their levels of chemokine receptor expression did not differ between HTLV-1-infected and uninfected individuals. However, the capacity of intermediate monocytes to migrate to CCL5, the ligand for CCR5, was higher, and a higher proportion of nonclassical monocytes expressed CCR1, CXCR3, and CX3CR1. The level of viral DNA in the monocyte subsets correlated with the capacity to migrate to CCL2, CCL5, and CX3CL1 for classical monocytes, with lower levels of phagocytosis for intermediate monocytes, and with the level of viral DNA in CD8+and CD4+T cells for nonclassical monocytes. These data suggest a model whereby HTLV-1 infection augments the number of classical monocytes that migrate to tissues and become infected and the number of infected nonclassical monocytes that transmit virus to CD4+and CD8+T cells. These results, together with prior findings in a macaque model of HTLV-1 infection, support the notion that infection of monocytes by HTLV-1 is likely a requisite for viral persistence in humans.IMPORTANCEMonocytes have been implicated in immune regulation and disease progression in patients with HTLV-1-associated inflammatory diseases. We detected HTLV-1 DNA in all three monocyte subsets and found that infection impacts surface receptor expression, migratory function, and subset frequency. The frequency of nonclassical patrolling monocytes is increased in HTLV-1-infected individuals, and they have increased expression of CCR1, CXCR3, and CX3CR1. The viral DNA level in nonclassical monocytes correlated with the viral DNA level in CD4+and CD8+T cells. Altogether, these data suggest an increased recruitment of classical monocytes to inflammation sites that may result in virus acquisition and, in turn, facilitate virus dissemination and viral persistence. Our findings thus provide new insight into the importance of monocyte infection in viral spread and suggest targeting of monocytes for therapeutic intervention.
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Quintar, Amado, Sara McArdle, Dennis Wolf, Alex Marki, Erik Ehinger, Melanie Vassallo, Jacqueline Miller, Zbigniew Mikulski, Klaus Ley, and Konrad Buscher. "Endothelial Protective Monocyte Patrolling in Large Arteries Intensified by Western Diet and Atherosclerosis." Circulation Research 120, no. 11 (May 26, 2017): 1789–99. http://dx.doi.org/10.1161/circresaha.117.310739.
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Schneider, Christine A., Dario X. Figueroa Velez, Ricardo Azevedo, Evelyn M. Hoover, Cuong J. Tran, Chelsie Lo, Omid Vadpey, Sunil P. Gandhi, and Melissa B. Lodoen. "Imaging the dynamic recruitment of monocytes to the blood–brain barrier and specific brain regions during Toxoplasma gondii infection." Proceedings of the National Academy of Sciences 116, no. 49 (November 14, 2019): 24796–807. http://dx.doi.org/10.1073/pnas.1915778116.
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Brain infection by the parasite Toxoplasma gondii in mice is thought to generate vulnerability to predation by mechanisms that remain elusive. Monocytes play a key role in host defense and inflammation and are critical for controlling T. gondii. However, the dynamic and regional relationship between brain-infiltrating monocytes and parasites is unknown. We report the mobilization of inflammatory (CCR2+Ly6Chi) and patrolling (CX3CR1+Ly6Clo) monocytes into the blood and brain during T. gondii infection of C57BL/6J and CCR2RFP/+CX3CR1GFP/+ mice. Longitudinal analysis of mice using 2-photon intravital imaging of the brain through cranial windows revealed that CCR2-RFP monocytes were recruited to the blood–brain barrier (BBB) within 2 wk of T. gondii infection, exhibited distinct rolling and crawling behavior, and accumulated within the vessel lumen before entering the parenchyma. Optical clearing of intact T. gondii-infected brains using iDISCO+ and light-sheet microscopy enabled global 3D detection of monocytes. Clusters of T. gondii and individual monocytes across the brain were identified using an automated cell segmentation pipeline, and monocytes were found to be significantly correlated with sites of T. gondii clusters. Computational alignment of brains to the Allen annotated reference atlas [E. S. Lein et al., Nature 445:168–176 (2007)] indicated a consistent pattern of monocyte infiltration during T. gondii infection to the olfactory tubercle, in contrast to LPS treatment of mice, which resulted in a diffuse distribution of monocytes across multiple brain regions. These data provide insights into the dynamics of monocyte recruitment to the BBB and the highly regionalized localization of monocytes in the brain during T. gondii CNS infection.
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Nanda, Sambit Kumar, Tsvetana Petrova, Francesco Marchesi, Marek Gierlinski, Momchil Razsolkov, Katherine L. Lee, Stephen W. Wright, Vikram R. Rao, Philip Cohen, and J. Simon C. Arthur. "Distinct signals and immune cells drive liver pathology and glomerulonephritis in ABIN1[D485N] mice." Life Science Alliance 2, no. 6 (November 6, 2019): e201900533. http://dx.doi.org/10.26508/lsa.201900533.
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We report that TLR7, IL-6, and the adaptive immune system are essential for autoimmunity and glomerulonephritis but not for liver pathology in mice expressing the ubiquitin-binding–defective ABIN1[D485N] mutant. The blood and organs of ABIN1[D485N] mice have exceptionally high numbers of patrolling monocytes (pMo), which develop independently of IL-6 and the adaptive immune system. They are detectable in the blood months before autoimmunity and organ pathology are seen and may have diagnostic potential. The splenic pMo, inflammatory monocytes (iMo), and neutrophils of ABIN1[D485N] mice expressed high levels of mRNAs encoding proteins released during NETosis, which together with the high numbers of monocyte-derived dendritic cells (MoDCs) may drive the liver pathology in ABIN1[D485N] mice, and contribute to the pathology of other organs. The splenic iMo of ABIN1[D485N] mice displayed high expression of mRNAs encoding proteins controlling cell division and were actively dividing; this may underlie the increased pMo and MoDC numbers, which are derived from iMo. An orally active IRAK4 inhibitor suppressed all facets of the disease phenotype and prevented the increase in pMo numbers.
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Collison, Joanna, Leo Carlin, Frederic Geissmann, and Mark Peakman. "Migratory behavior of human CD14dimCD16+ monocytes on human macro- and micro-vascular endothelia: an in vitro approach (P5144)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 58.26. http://dx.doi.org/10.4049/jimmunol.190.supp.58.26.
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Abstract In the mouse, much work has been done to characterize the function of Ly6c- “patrolling” monocytes by utilising intravital microscopy. However, this technique cannot be used outside of animal models, and therefore relatively little is known about the behaviour of their human counterpart, CD14dimCD16+ monocytes. To address this, we developed a re-circulating pump system to grow human endothelial cells under shear flow for 72h before adding human CD14dimCD16+ monocytes to the circulating media and performing live cell time-lapse imaging with a Nikon TiE fluorescence microscope. Using this approach we observed CD14dimCD16+ monocytes adhere and crawl on both macro-vascular HUVEC and micro-vascular HDMEC. The tracks of CD14dimCD16+ monocytes were twice as long when crawling on HDMEC compared with HUVEC under the same shear flow rate and 3 times fewer cells detached and re-entered the flow, indicating a preference for crawling on micro-vascular endothelium. HDMEC show higher levels of CD31, ICAM-1, E-selectin and VEGFR2, and lower levels of VCAM-1 and NRP-1 in a resting state, suggesting that the former represent ligands preferentially used for CD14dimCD16+ monocyte migration on micro-vascular cells, a role that will require further elucidation by studying migration under blocking conditions.
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Yazdanparast, Haniyeh, Bola Hanna, Philipp Rößner, Franziska Haderk, Helene Haegel, Peter Lichter, and Martina Seiffert. "Modulation of the myeloid tumor microenvironment in chronic lymphocytic leukemia by targeting CSF-1R." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 73.22. http://dx.doi.org/10.4049/jimmunol.196.supp.73.22.
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Abstract Chronic lymphocytic leukemia (CLL) is highly dependent on the tumor microenvironment, which comprises monocyte-derived nurse-like cells (NLCs) as key players that possess tumor-supportive properties and resemble tumor-associated macrophages. Our main goal is to understand and target the tumor supportive properties of myeloid cells in CLL. CSF-1R is known to be important for proliferation, differentiation, and survival of myeloid cells. Targeting CSF-1R has revealed clinical relevance in solid tumors. However, its role in hematological malignancies has not been assessed so far. Therefore, we tested a unique novel monoclonal antibody, TG3003 (Transgene S.A.), against this receptor in cocultures of primary CLL cells and NLCs and observed a significant decrease in CLL cell survival as well as a change in the concentration of inflammatory factors such as CCL2 and IL-6 in the cell culture supernatant. Moreover, we found that these changes were connected to a decrease in NLC numbers. Therefore, we aimed at exploring the in vivo activity of TG3003 in a well-established mouse model of CLL, that is the adoptive transfer of malignant splenocytes from leukemic Eμ-TCL1 mice into syngeneic recipient animals. Targeting CSF-1R in these mice resulted in a significant decrease of splenic monocytes but not macrophages and dendritic cells, indicating that monocytes are the main target of the antibody. More detailed investigations of monocyte subsets revealed that the previously described CLL-associated enrichment of patrolling monocytes was significantly but incompletely reversed. As TG3003 treatment had no effect on tumor development in this model, our future work will focus on combination approaches including other immunomodulatory drugs.
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McArdle, Sara, Grzegorz Chodaczek, Nilanjan Ray, and Klaus Ley. "Intravital live cell triggered imaging system reveals monocyte patrolling and macrophage migration in atherosclerotic arteries." Journal of Biomedical Optics 20, no. 02 (February 24, 2015): 1. http://dx.doi.org/10.1117/1.jbo.20.2.026005.
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Zare, Fatemeh. "Controlling role of Ly6Chigh Monocytes in breast cancer and C26 colon carcinoma." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 211.13. http://dx.doi.org/10.4049/jimmunol.196.supp.211.13.
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Abstract Tumor microenvironment encompasses a wide variety of immune cells, which macrophages comprise the most dominant portion of them and thus are the major players in the connection between inflammation and cancer. These tumor-associated macrophages (TAMs) are derived from blood monocyte precursors and subsequently acquire distinct characteristics as a result of tumor micro-environmental cues. Monocytes are a heterogeneous population in the blood with an enormous plasticity whose fate and functions are dictated by the microenvironment. Therefore, the roles of specific Monocytes subsets in tumor progression and the molecular mechanisms for their impacts need to be elucidated. Ly6Chigh and Ly6Clow are two main different types of murine monocytes subsets that have been defined by distinct phenotypes and immunoregulatory functions. Recent data demonstrates that Ly6Chigh monocytes can recruit to inflammation loci while Ly6Clow monocytes are patrolling cells. We have developed a method to produce large number of Ly6Chigh monocytes in vitro. In our study we observed that, injection of these cells affects tumor progression in breast cancer and C26 colon carcinoma animal models. Activation of Ly6Clow monocytes by pro- or anti-inflammatory cytokines, results in displaying a genetic expression profile, corresponding to pro- or anti-inflammatory genes, respectively. Injection of pre- activated Ly6Clow monocytes toward pro- or anti-inflammatory polarization in C26 colon carcinoma showed that anti-inflammatory activated monocytes are more beneficial in delaying cancer cachexia. Increased knowledge of monocytes improves the chances to find therapies against a broad spectrum of diseases including cancer.
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Ciaglia, Elena, Francesco Montella, Anna Maciag, Pasqualina Scala, Anna Ferrario, Carlotta Banco, Albino Carrizzo, et al. "Longevity-Associated Variant of BPIFB4 Mitigates Monocyte-Mediated Acquired Immune Response." Journals of Gerontology: Series A 74, Supplement_1 (May 10, 2019): S38—S44. http://dx.doi.org/10.1093/gerona/glz036.
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Abstract One of the basis of exceptional longevity is the maintaining of the balance between inflammatory and anti-inflammatory networks. The monocyte-macrophages activation plays a major role in tuning the immune responses, by oscillating between patrolling-protective to inflammatory status. Longevity-associated variant (LAV) of bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) activates calcium, PKC-alpha, and eNOS, rescuing endothelial dysfunction in aged mice and inducing revascularization. The BPIFB4’s increment in serum of healthy long-living individuals (LLIs) compared to nonhealthy ones, its therapeutic potential in improving vascular homeostasis, which depends on immune system, together with its expression in bone marrow myeloid cells, suggests that LAV-BPIFB4 may improve immune regulation. Here we show that human monocytes exposed to LAV-BPIFB4 protein increased co-stimulatory molecules in resting state and reduced pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) after activating stimuli. Accordingly, a low percentage of CD69+ activated lymphocytes are found among LAV-BPIFB4-treated peripheral blood mononuclear cells (PBMCs). Moreover, human monocyte-derived dendritic cells (DCs) generated in presence of LAV-BPIFB4 secreted higher anti-(IL-10 and TGF-β) and lower pro-inflammatory (TNF-α and IL-1β) cytokines. Accordingly, LLIs’ plasma showed higher levels of circulating IL-10 and of neutralizing IL-1 receptor antagonist (IL-1RA) compared to controls. Thus, LAV-BPIFB4 effects on myeloid compartment could represent one example of a genetic predisposition carried by LLIs to protect from immunological dysfunctions.
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Wang, Rikang, Weili Bao, Mouli Pal, Yunfeng Liu, Karina Yazdanbakhsh, and Hui Zhong. "Intermediate monocytes induced by IFN-γ inhibit cancer metastasis by promoting NK cell activation through FOXO1 and interleukin-27." Journal for ImmunoTherapy of Cancer 10, no. 1 (January 2022): e003539. http://dx.doi.org/10.1136/jitc-2021-003539.
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BackgroundCirculating monocytes are functionally heterogeneous and can be divided into classical (CMo), intermediate (IMo), and non-CMo/patrolling monocyte (PMo) subsets. CMo can differentiate into PMo through IMo. PMos have been shown to inhibit cancer metastasis but the role of IMo is unclear. To date, no strategy has been developed to inhibit cancer metastasis through enhancing PMo/IMo differentiation.MethodsWe screened multiple inflammatory cytokines/chemokines activity of modulating PMo/IMo associated cell markers expression using human monocyte in vitro culture system. We tested our candidate cytokine activity in vivo using multiple mice models. We identified critical key factors and cytokines for our candidate cytokine activity by using gene-knockout mice and neutralization antibodies.ResultsWe identified IFN-γ as a candidate inflammatory cytokine in the regulation of human IMo/PMo marker expression. Our in vivo data demonstrated that IMo expansion was induced by short-term (3 days) IFN-γ treatment through increasing CMo-IMo differentiation and blocking IMo-PMo differentiation. The IMo induced by IFN-γ (IFN-IMo), but not IFN-γ activated CMo (IFN-CMo), inhibited cancer metastasis by 90%. Surprizing, the effect of IFN-γ is greater in PMo deficiency mice, indicating the effect of IFN-IMo is not mediated through further differentiation into PMo. We also found that IFN-IMos induced by short-term IFN-γ treatment robustly boosted NK cell expansion for threefold and promoted NK differentiation and function through IL-27 and CXCL9. Furthermore, we identified that FOXO1, a key molecule controlling cellular energy metabolism, mediated the effect of IFN-γ induced IL-27 expression, and that NR4A1, a key molecule controlling PMo differentiation and inhibiting cancer metastasis, inhibited the pro-NK cell and anti-metastasis activity of IFN-IMo by suppressing CXCL9 expression.ConclusionsWe have discovered the antimetastasis and pro-NK cell activity of IFN-IMo, identified FOXO1 as a key molecule for IFN-γ driven monocyte differentiation and function, and found NR4A1 as an inhibitory molecule for IFN-IMo activity. Our study has not only shown novel mechanisms for a classical antitumor cytokine but also provided potential target for developing superior monocytic cell therapy against cancer metastasis.
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Tamura, Akihiro, Hideyo Hirai, Asumi Yokota, Atsushi Sato, Hisayuki Yao, Masaki Iwasa, Aya Fujishiro, Yasuo Miura, and Taira Maekawa. "Essential Roles of C/EBPβ in Survival of Ly6C– monocytes." Blood 124, no. 21 (December 6, 2014): 224. http://dx.doi.org/10.1182/blood.v124.21.224.224.
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Abstract Accumulating evidences have shown that mouse monocytes can be divided into two subsets, based on the expression of a surface marker Ly6C. Although distinct functions of Ly6C+ monocytes (also called classical or inflammatory monocytes) and Ly6C– monocytes (also known as patrolling monocytes) have been gradually uncovered, molecular mechanisms which govern development of these monocytes remain largely unknown. We have previously reported the requirement of CCAAT Enhancer Binding Protein β (C/EBPβ), a leucine zipper transcription factor, for ‘emergency’ granulopoiesis (Nat Immunol, 2006, J Immunol, 2012, Leukemia 2013). C/EBPβ is also known to play roles in the differentiation and function of macrophages. However, involvement of C/EBPβ in monocyte development has not been fully investigated. The aim of this study is to elucidate the roles of C/EBPβ in monopoiesis. First, we measured C/EBPβ mRNA expression in purified hematopoietic stem cells, myeloid progenitors and monocyte subsets, and found that monocytes, especially Ly6C– monocytes, expressed C/EBPβ mRNA at extremely higher level than any of other cell types examined. When we analyzed peripheral blood, the frequencies of total monocytes (CD11b+ CD115+ cells) in C/EBPβ–/– mice was significantly lower than those in wild type (WT) mice (4.24±2.71% in WT mice vs. 0.72±0.50% in C/EBPβ–/– mice, p<0.001). Of note, Ly6C– monocytes were almost absent in peripheral blood of C/EBPβ–/– mice (0.67±0.57% in WT mice vs. 0.017±0.021% in C/EBPβ–/– mice). In order to clarify whether the defects in C/EBPβ–/– monopoiesis were cell-intrinsic or cell-extrinsic, we generated mixed bone marrow (BM) chimeras by reconstituting lethally irradiated mice (CD45.1+) with BM cells from WT (CD45.1+) mice together with the equal number of BM cells from either WT or C/EBPβ–/– (CD45.2+) mice. Six weeks after reconstitution, we confirmed that C/EBPβ–/– BM-derived Ly6C– monocytes were absent in peripheral blood of the recipient mice, suggesting that monopoiesis in C/EBPβ–/– mice is impaired in a cell-intrinsic manner. A recent report revealed that MX1-Cre transgenic system can be used for monocyte specific deletion of genes of interest, as MX1 is highly expressed by monocytes (Hashimoto D et al. Immunity 2013). In MX1-Cre+ C/EBPβfloxed/floxed mice, the number of monocytes were decreased to the level similar to C/EBPβ–/– mice, suggesting that C/EBPβ is specifically required in monocytes rather than other progenitors during monopoiesis. As cell cycle status of myeloid progenitors and monocytes did not differ between WT mice and C/EBPβ–/– mice, we evaluated apoptosis by flow cytometry. The frequencies of late apoptotic/dead cells within Ly6C– monocytes in peripheral blood of C/EBPβ–/– mice were significantly higher than those in peripheral blood of WT mice (5.84±2.90% in WT mice vs. 50.4±22.4% in C/EBPβ–/– mice, p<0.001). These enhanced apoptosis of C/EBPβ–/– Ly6C– monocyte was partially reversed by retroviral transduction of Bcl2 gene. Previous reports have shown that Nr4a1, CX3CR1 and S1PR5 are required for survival or BM egress of Ly6C– monocytes. We found that mRNA expressions of these factors are severely reduced in C/EBPβ–/– Ly6C– monocytes. These results suggested that C/EBPβ maintains survival of Ly6C– monocytes through direct or indirect association of these molecules. Collectively, our data strongly indicate that C/EBPβ is essential for survival of Ly6C– monocytes. We are currently investigating the molecular mechanisms involved in the enhanced apoptosis of of Ly6C– monocytes in C/EBPβ–/– mice. Disclosures No relevant conflicts of interest to declare.
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Trompette, Aurélien, Eva S. Gollwitzer, Céline Pattaroni, Isabel C. Lopez-Mejia, Erika Riva, Julie Pernot, Niki Ubags, Lluis Fajas, Laurent P. Nicod, and Benjamin J. Marsland. "Dietary Fiber Confers Protection against Flu by Shaping Ly6c− Patrolling Monocyte Hematopoiesis and CD8+ T Cell Metabolism." Immunity 48, no. 5 (May 2018): 992–1005. http://dx.doi.org/10.1016/j.immuni.2018.04.022.
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Yotsumoto Fertrin, Kleber, Dulcinéia Martins Albuquerque, Carolina Lanaro, Carla Fernanda Franco-Penteado, Flavia Rubia Pallis, Sara T. Olalla Saad, and Fernando Ferreira Costa. "Monocyte Shift to a Non-Classical CD14dim/CD16+ Phenotype Correlates with Fetal Hemoglobin Levels in Sickle Cell Anemia Patients Treated with Hydroxyurea." Blood 120, no. 21 (November 16, 2012): 817. http://dx.doi.org/10.1182/blood.v120.21.817.817.
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Abstract Abstract 817 Vaso-occlusion in sickle cell anemia (SCA) involves inflammation and cell activation; fetal hemoglobin (HbF) elevation by hydroxyurea (HU) remains the mainstay of SCA treatment. Monocytes are activated in SCA, and their contribution to the chronic inflammatory state includes the production of cytokines and reactive oxygen species (ROS). Monocytes are a heterogeneous group of leukocytes subdivided into distinct subsets: classical monocytes comprise over 80% of circulating monocytes, are highly positive for CD14 (CD14bright) and typically CD16-negative, while CD16-positive monocytes have been further subdivided into intermediate CD14bright/CD16+, and non-classical CD14dim/CD16+ monocytes. Intermediate monocytes are recognized as the main monocytic producers of ROS and are increased in inflammatory conditions such as atherosclerosis and sepsis. The less characterized non-classical subset is believed to have a patrolling behavior in blood vessels, does not produce ROS and constitutively produces IL-1 receptor antagonist (IL1-RA). Another relevant subgroup of monocytes expresses angiopoietin-2 receptor TIE2, and the role of TIE2-expressing monocytes (TEMs) has been investigated in angiogenesis in neoplastic diseases. TEMs usually correspond to intermediate monocytes, but their importance in inflammation is still unclear. We hypothesized that monocyte subsets in SCA patients would differ from controls, and that treatment with HU might also influence monocyte phenotypes, thus shedding light on the possible role of these subsets in an inflammatory condition not previously studied. EDTA-anticoagulated peripheral blood samples were collected upon written informed consent from 21 healthy controls (CON, ages 21–63 years) and 34 SCA patients (18 on HU, ages 16–58 years) in steady state, with no transfusion or acute sickling episode in the previous three months. Monocytes were immunophenotyped by flow cytometry on a multicolor FACSCalibur cytometer. Medical history of SCA-associated complications, HbF levels and dosage of HU in mg/kg/day were obtained from medical charts. Statistical analysis was performed on GraphPad Prism 5.0 software. As expected, we found that relative percentage and absolute count of CD16-positive monocytes were higher in SCA patients than in controls. Surprisingly, a significantly higher percentage of non-classical CD14dim/CD16+ monocytes, rather than intermediate cells, was found in SCA patients on HU (SCA-HU) treatment (mean±SEM: CON 2.06±0.43%, SCA 2.91±0.50%, SCA-HU 6.42±0.80%, P<0.0001). TEMs were also increased in SCA patients compared to controls (CON 2.64±0.72%, SCA 20.48±5.40%, SCA-HU 32.97±5.92%, P<0.0001), but HU treatment did not significantly influence TEM counts. Mean TIE2 expression did not vary among the groups, and there was no correlation between TEMs and presence of SCA complications pathophysiologically associated with disturbed angiogenesis, such as pulmonary hypertension, osteonecrosis, leg ulcers and retinopathy. Higher percentages of non-classical monocytes in HU-treated patients were initially interpreted as a possible toxic effect of HU on monocytopoiesis, but the lack of correlation of monocytes subsets with the degree of relative monocytopenia made this hypothesis unlikely. Moreover, we found a significant positive correlation between percentages of non-classical monocytes and HbF levels (rS=0.4763, P=0.0068, see figure). This suggests that successful HU treatment with higher HbF could correlate with the expansion of this particular monocyte subset. During the study period, only one patient was available for comparison before and after HU, but the increase in HbF from 4.2% to 11.6% and in non-classical monocytes from 1.82% to 9.48%, in this case, corroborates that HU therapy may explain this phenotype shift in monocytes. Whether non-classical monocytes expansion represents yet another pleiotropic effect of HU, if these cells are less likely to take part in the vaso-occlusive process and have an antiinflammatory role or, furthermore, if a bone marrow counterpart of this monocyte subset could be involved in increasing HbF production, remains to be investigated. The correlation of the expansion of non-classical monocytes with HbF levels could prove to be an interesting biomarker of response to HU, and future studies may address its clinical usefulness. Disclosures: No relevant conflicts of interest to declare.
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Atehortúa, Laura, Mauricio Rojas, Gloria M. Vásquez, and Diana Castaño. "Endothelial Alterations in Systemic Lupus Erythematosus and Rheumatoid Arthritis: Potential Effect of Monocyte Interaction." Mediators of Inflammation 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/9680729.
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Patients with systemic autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are prone to develop atherosclerosis and cardiovascular diseases five times more often than the general population; this increase in frequency could be partially explained by an increase in the macrovasculature endothelial damage. In these autoimmune diseases, a microvascular endothelial injury has also been reported in different organs and tissues, especially in sites where ultrafiltration processes occur. Different components that are characteristic to the immunopathology of RA and SLE could be involved in the endothelial cell activation, permeability increase, functional alteration, and vascular injury. Circulating immune complexes (IC) detected in SLE and RA have been proposed to participate in the endothelial injury. In the vascular environment, IC can generate different responses that could be mediated by monocytes, because these cells have patrolling and monitoring functions on the endothelium. However, with certain stimuli such as TLR ligands, the monocytes are retained in the lumen, releasing proinflammatory mediators that participate in the endothelial damage. This paper aims to review some aspects about the endothelial activation and dysfunction in the context of SLE and RA, as well as the potential role that monocytes apparently play in this process.
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Tacke, Robert, Heba Nowyhed, Amy Wu, and Catherine Hedrick. "Nr4a1 regulates thymic resident macrophage development and function (P4468)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 52.51. http://dx.doi.org/10.4049/jimmunol.190.supp.52.51.
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Abstract Mononuclear phagocytes, including monocytes, macrophages, and dendritic cells, function in tissue homeostasis, and also regulate immune responses. Tissue resident macrophages in a variety of tissues arise from the yolk sac, and are generated independently of hematopoietic stem cells. However, the origin of thymic macrophages remains poorly understood. Nr4a1 is an orphan nuclear receptor that limits pro-inflammatory cytokine production in macrophages, and functions as the master regulator of Ly6C- patrolling monocyte development. Here, we report a significant defect in the development of thymic resident macrophages in Nr4a1-deficient animals. Thymic macrophage levels were reduced over two-fold compared with wild-type controls. However, Nr4a1 does not globally regulate the development of tissue macrophages, as macrophages resident in the spleen, lung, brain, pancreas, and peritoneum from Nr4a1-deficient mice develop normally. Moreover, Nr4a1-deficient thymic macrophages fail to clear apoptotic thymocytes in vivo, and express reduced levels of genes important for apoptotic cell engulfment, including engulfment receptors Mertk, and Axl. Defective thymic macrophage development likely impairs proper T cell selection, thus altering the immune system as a whole. Together, these data show that Nr4a1 regulates the development and functional capacity of tissue resident macrophages in the thymus, and provide a novel mechanism for maintenance of thymic homeostasis.
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Tamura, Akihiro, Hideyo Hirai, Asumi Yokota, Naoka Kamio, Atsushi Sato, Tsukimi Shoji, Takahiro Kashiwagi, et al. "C/EBPβ Is Required for Survival of Ly6C- Monocytes after Committment to Monocyte Lineage through Upregulation of Csf1r." Blood 128, no. 22 (December 2, 2016): 1325. http://dx.doi.org/10.1182/blood.v128.22.1325.1325.
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Abstract Monopoiesis is the process in which hematopoietic stem cells (HSCs) continuously give rise to monocytes. Accumulating evidence has identified cellular constituents of monopoiesis. Common myeloid progenitors (CMPs), granulocyte-macrophage progenitors (GMPs), macrophage-dendritic cell precursors (MDPs) and common monocyte progenitors (cMoPs) are the intermediates during the differentiation of HSCs into mature monocytes. In mice, CD11b+ CD115+ monocytes are further divided into two subsets based on the expression of Ly6C. Classical monocytes express Ly6C on their surface. By contrast, Ly6C− patrolling monocytes have been recently identified, and the molecular mechanisms which regulate the development and homeostasis of Ly6C−monocytes still remain elusive. C/EBPβ is a leucine zipper transcription factor which regulates stress-induced granulopoiesis (Hirai et al. Nat Immunol, 2006, Hayashi et al. Leukemia 2013). We have recently found that peripheral blood (PB) monocytes are significantly reduced in steady-state Cebpb−/− mice (Tamura et al. Biochem Biophys Res Commun, 2015). In addition, last year at this meeting, we have reported that cell death of Ly6C− monocytes was accelerated through reduced expression of Csf1r (encoding a receptor for M-CSF) in Cebpb−/− mice. Here in this study, we determined the precise developmental stage where C/EBPβ is mandatory for survival of Ly6C− monocytes, and investigated the mechanism of Csf1r regulation by C/EBPβ. A recent publication demonstrated that Mx1 is preferentially expressed by monocytes and a Mx1 promoter-mediated conditional system targets monocytes without inoculation of polyI:C (Hashimoto et al. Immunity, 2013), suggesting that Mx1-Cre Cebpbf/f mouse is ideal to evaluate the monocyte-specific requirement for C/EBPβ. We confirmed that upregulation of Cebpb mRNA during monopoiesis was significantly impaired after cMoP stage in Mx1-Cre+Cebpbf/f mice. In order to exclude the possible involvement of Cebpβ deficient microenvironment, bone marrow (BM) cells of Mx1-Cre+Cebpβf/f mice (CD45.2+) were transplanted into lethally irradiated CD45.1+ wild type mice. The frequencies of Ly6C− monocytes in the recipients of Mx1-Cre+Cebpbf/f BM cells were significantly reduced when compared to mice that received Mx1-Cre−Cebpbf/f BM cells (Figure). These results strongly suggest that C/EBPβ is specifically required after commitment to monocytes. In order to investigate the molecular mechanisms involved in the regulation of Csf1r by C/EBPβ, we utilized a combination of a promoter and an enhancer region located in the first intron of Csf1r gene (Fms intronic regulatory element: FIRE) for reporter assay (Pridans et al. Mol Ther Methods Clin Dev, 2014). These regulatory elements contain at least 2 consensus binding sites for C/EBPβ (one in the promoter and the other in the enhancer). C/EBPβ significantly enhanced the reporter activity of the regulatory elements in a dose-dependent manner, and introduction of mutations into either of the consensus binding sites abrogated the reporter activity. Next, we engineered EML cells, a mouse HSC line, to express C/EBPβ-estrogen receptor (ER) fusion protein or ER alone. Nuclear translocation of C/EBPβ-ER in the presence of tamoxifen resulted in significant increase of Csf1r mRNA and protein. Using these cells, we performed chromatin immunoprecipitation PCR. Upon treatment with tamoxifen, significant enrichment of C/EBPβ at the promoter region and the FIRE region was observed. These data indicated that C/EBPβ regulates Csf1r through direct binding to these regulatory elements. Collectively, these results demonstrate that C/EBPβ supports survival of Ly6C− monocytes after commitment to monocyte lineage through direct regulation of Csf1r, which is critical for survival and differentiation of monocytes. Figure Figure. Disclosures Hirai: Kyowa Hakko Kirin: Research Funding; Novartis Pharma: Research Funding. Maekawa:Bristol-Myers K.K.: Research Funding.
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Bloch, Olga, Alex Blatt, Michael Y. Appel, Gilad Ben Yehudah, Dror Cantrell, Michael Goldberg, Itamar Love, Haitham Abu Khadija, and Micha J. Rapoport. "Coronary atherosclerosis severity is closely associated with decreased GLP-1R positivity among CD16+ pro-inflammatory and patrolling monocyte subsets." Atherosclerosis Plus 46 (December 2021): 15–19. http://dx.doi.org/10.1016/j.athplu.2021.10.001.
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Mumau, Melanie, Sophia Golec, Ashley Vanderbeck, Elizabeth Lynch, Jennifer A. Punt, and Stephen Emerson. "The role of the orphan nuclear receptor NR4A1 in erythro-myelopoiesis." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 190.3. http://dx.doi.org/10.4049/jimmunol.196.supp.190.3.
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Abstract Studies of hematopoietic stem cells (HSCs) have advanced our understanding of the intracellular signals and microenvironmental interactions that influence HSC fate. Our lab is interested in the role of orphan nuclear receptor NR4A1, an immediate response gene sensitive to external stimuli, in HSC development. NR4A1 regulates the development of specific, mature hematopoietic cell lineages from both the innate and adaptive immune system including patrolling monocytes, a mature myeloid cell subset. More recently, we have shown that NR4A1 expression also identifies a subpopulation of myeloid-biased long-term HSCs in the bone marrow. Given that NR4A1 directs both immature and differentiated cell types, we investigated its role in myeloid cell maturation. Within the bone marrow and spleen progenitor cell compartments, we find that NR4A1 is exclusively expressed by myeloid progenitors and not by more restricted megakaryocyte, erythroid, or common monocyte progenitors. Nr4a1−/−mice exhibit skewed myeloid progenitor cell populations, exhibiting a 2-fold increase in CD105+CD150− erythroid progenitors and cKit+Ter119+CD71+ pro-erythroblasts in the spleen but not in the bone marrow. In vitro cultures of Nr4a1−/−splenic myeloid progenitors also show that NR4A1 restricts the frequency of erythroid cells, yet bone marrow transplant studies show similar erythroid progenitor reconstitution from both WT and Nr4a1−/− donors. Taken together, our data reveal a new role for NR4A1 as both a direct and indirect modulator of erythropoiesis.
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Zhong, Hui, Weili Bao, Yunfeng Liu, and Karina Yazdanbakhsh. "Inflammation Response Cytokines IFN-γ and IL-10 Regulate Monocyte Subset Differentiation." Blood 134, Supplement_1 (November 13, 2019): 3586. http://dx.doi.org/10.1182/blood-2019-129515.
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Circulating monocytes comprise of a heterogeneous and functionally-diverse cell population which based on surface markers can be divided into three subsets: classical (CMo), intermediate (IMo), and non-classical monocytes/patrolling monocytes (PMo). The frequency/number, gene expression profile and activity of IMo and PMo significantly change in a variety of inflammatory diseases with the changes associated with disease risk and severity as well as response to treatment. While it is believed that CMo differentiate into IMo and that IMo further differentiate into PMo, there is paucity of data on the mechanisms that alter CMo to IMo/PMo differentiation profiles in these conditions. In addition, factors which induce human and mouse IMo and PMo differentiation have yet to be identified. To screen cytokine/chemokine candidates affecting IMo/PMo differentiation, human monocytes were isolated from healthy donors (HD) and cultured with candidates (22 cytokines/chemokines) for 3 days. On day 3, IMo/PMo marker expression was examined by flow cytometry focusing on candidate molecules that led to increased expression of markers (CD16, CX3CR1, CD11c, HO-1, HLA-DR) whose levels are normally found to be higher in IMo/PMo and to decrease in expression of markers (CD14, CD36, CCR2) which are expressed at higher level in CMo as measured by mean fluorescence intension (MFI). We found that of all molecules tested, only two , IFN-γ and IL-10, had significant effects: IFN-γ (10ng/ml) increased expression of CX3CR1 (20 fold), CD16 (60%), HLADR (15%) and inhibited CD36 (42% inhibition) and CD14 expression (45% inhibition) while IL-10 (10ng/ml) increased CD16 (3.3 fold), CD11c (45%), HO-1 (59%) and CX3CR1 (6 fold) expression and inhibited CCR2 (60% inhibition) expression. These data suggest that IFN-γ and IL-10, two key cytokines involved in sterile and infectious inflammation, induce IMo and PMo differentiation. To test whether the effect of IFN-γ and IL-10 in human in vitro cultures can be replicated in vivo, wildtype B6 mice were I.V. injected with IFN-γ or IL-10 for 3 days: IFN-γ, IL-10, or the same volume of PBS. The frequencies of monocyte subsets in blood (gated on CD45+Ly6G-CD11bhighCD115+ for total monocyte population and CMo/IMo/PMo based on Ly6C expression level) on day 4 were analyzed by flow cytometry. We found that IFN-γ (2.5μg/injection/mice twice/day) significantly increased IMo frequencies (from 12% to 35%) but decreased PMo frequencies (from 38% to 26%) while IL-10 (0.25μg/injection/mice twice/day) significantly induced PMo differentiation (from 38% to 63%) without effect on IMo frequencies. The data suggest that IFN-γ increases IMo frequency by simultaneously inducing CMo differentiation into IMo and inhibiting IMo differentiation into PMo. We have previously reported lower PMo frequency in patients with sickle cell disease (SCD), considered an inflammatory disease with altered immune profiles. To test whether altered differentiation programming of IMo/PMo may contribute to reduced PMo frequency in SCD, we analyzed the frequency of CMo/IMo/PMo at baseline and after IFN-γ or IL-10 injection to mimic an inflammatory response in AA mice (expressing normal human hemoglobin) and SS mice (expressing human SCD hemoglobin). We found significantly lower IMo frequency before treatment (AA vs SS:15.0% vs 9.2%) but also lower induction of IMo following IFN-γ treatment in SS mice (18%) relative to AA mice (35%), suggesting that IFN-γ inhibition of IMo differentiation into PMo in SCD is impaired. Furthermore, IL-10 was less effective in inducing PMo in SS as compared to AA mice (SS vs AA: 40% vs 60%). These data suggest that IFN-γ or IL-10-mediated monocyte differentiation in SCD is altered. Altogether, these data have unraveled a novel role for IFN-γ or IL-10, two key cytokines known to be induced during an inflammatory response, in monocyte differentiation, and suggest that IMo/PMo differentiation in a chronic inflammatory disease such as SCD may be defective due to altered response to IFN-γ and IL-10, opening up the potential for identification of novel therapeutic targets for IMo/PMo associated diseases including SCD. Disclosures No relevant conflicts of interest to declare.
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Hanna, Bola, Fabienne McClanahan, Nadja Zaborsky, Claudia Dürr, Verena Kalter, Alexander Egle, John G. Gribben, Peter Lichter, and Martina Seiffert. "Targeting Dysfunctional Myeloid Cells Delays Disease Development and Improves Immune Function in a CLL Mouse Model." Blood 124, no. 21 (December 6, 2014): 3298. http://dx.doi.org/10.1182/blood.v124.21.3298.3298.
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Abstract Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells that is characterized by apoptosis resistance and dysfunctional immune system. The chronic nature and slow development of the disease indicates a contribution of CLL-induced inflammation in the disease course. Previous reports suggested a potential role of myeloid cells in mediating these defects. However, the composition and function of CLL-associated myeloid cells have not been thoroughly investigated in an in vivo system. Here, we used the well-established CLL mouse model, Eµ-TCL1 mice (TCL1), to characterize changes within myeloid cell populations along with CLL development and the influence of their depletion on disease progression and immune dysfunction. We have recently shown that CLL development in TCL1 mice is associated with massive changes within myeloid cell populations. In the peritoneal cavity (PC) of leukemic mice we observed an infiltration of monocytes and an M2-like skewing of macrophages according to phenotypical and signaling signatures. Along this line, monocytes infiltrated the spleens of leukemic animals, both in primary CLL and adoptive transfer models, which is most likely due to high CCL2 serum levels. These monocytes lost the inflammatory Ly6Chi subset and were severely skewed towards Ly6Clow patrolling monocytes, accompanied by high expression of adhesion and angiogenic molecules like ICAM1, PECAM1 and MMP14. Gene expression profiling of splenic myeloid cells from TCL1 mice revealed an enrichment of various genes involved in dendritic cell (DC) maturation and MHC-II-mediated antigen presentation. However, the numbers of MHC-IIhi mature DCs and macrophages were significantly decreased, suggesting a monocyte differentiation arrest leading to impaired anti-tumor immune response. The observed transcriptional upregulation of multiple inflammatory cytokines like TNF-α, CXCL9, CXCL10 and CXCL16 in monocytes was confirmed by serum cytokine arrays, and is likely due to the overexpression of the pro-inflammatory regulator TREM-1. In addition, TCL1 monocytes upregulated the expression of several inhibitory molecules like PD-L1, IL-10, IL1ra and IL4i1 suggesting an impaired immune function. While CLL-induced immune dysfunction is a well-established phenomenon, the contribution of myeloid cells in this context was not clear. We therefore sought to determine the in vivo effects of myeloid cell depletion on CLL development and its associated immune defects. For that purpose we used liposomal clodronate to selectively ablate macrophages and monocytes from young wild-type mice adoptively transferred with murine CLL. Our data clearly show control of CLL development in clodronate-treated mice relative to control liposomes as demonstrated by decreased spleen weight (1.09 vs. 0.54 g, p < 0.0001) and a significant drop in tumor load, defined as CD5+CD19+ cells, in spleen (60.58% vs. 42.25%), peripheral blood (43% vs 11.8%), PC (66.2% vs 3.1%), lymph nodes (4.9% vs 1.2%) and bone marrow (1.9% vs 0.8%). In addition, we observed changes in immune effector cells in response to myeloid cell depletion suggesting better immune status in treated mice. Interestingly, the loss of macrophages/monocytes was compensated by increased splenic monocyte proliferation as shown by EdU incorporation in vivo. In contrast to control mice, the repopulating monocytes upon clodronate treatment were largely inflammatory Ly6Chi monocytes. In summary, our data show that skewing of myeloid cells actively contributes to CLL development via; 1) enhancing the survival of leukemic cells, and 2) suppressing anti-tumor immune functions. In the absence of monocytes and macrophages, disease development is delayed in mice adoptively transferred with murine CLL. Therefore, we suggest that targeting non-malignant myeloid cells in CLL might serve as a novel strategy for CLL immunotherapy. Disclosures No relevant conflicts of interest to declare.
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Tamura, Akihiro, Hideyo Hirai, Asumi Yokota, Atsushi Sato, Tsukimi Shoji, Takahiro Kashiwagi, Masaki Iwasa, Aya Fujishiro, Yasuo Miura, and Taira Maekawa. "Csf1r Is a Downstream Target of C/EBPβ in Ly6C¯ Monocytes." Blood 126, no. 23 (December 3, 2015): 994. http://dx.doi.org/10.1182/blood.v126.23.994.994.
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Abstract Currently, monocytes are classified into at least two subsets. Classical monocytes, also known as inflammatory monocytes (a Ly6C+ subset in mice and a CD14+ CD16− subset in human), are involved in innate immune responses. On the other hand, patrolling monocytes (a Ly6C− subset in mice and a CD14− CD16+ subset in human) have been recently identified. Ly6C− monocytes are found attached on the luminal side of endothelium and scavenge microparticles. Developmentally, Ly6C+ and Ly6C− monocytes share common monocyte progenitors (cMoPs), or Ly6C− monocytes might be converted from Ly6C+ monocytes. Although involvement of Ly6C− monocytes in various kinds of diseases has been reported, molecular mechanisms which regulate the homeostasis of Ly6C− monocytes are largely unknown. CCAAT/Enhancer Binding Protein β (C/EBPβ) is a leucine zipper type transcription factor. We and others have previously shown that C/EBPβ is required for stress-induced granulopoiesis (Hirai et al. Nat Immunol, 2006, Satake et al. J Immunol, 2012, Hayashi et al. Leukemia 2013). However, its roles in steady state hematopoiesis remain relatively unknown. We have recently found that peripheral blood monocytes are significantly reduced in Cebpb−/− mice (Tamura et al. Biochem Biophys Res Commun, 2015). In addition, last year in this meeting, we have reported that Cebpb mRNA is highly upregulated during differentiation from myeloid progenitors or Ly6C+ monocytes to Ly6C− monocytes, and that Ly6C− monocytes are almost completely absent in Cebpb−/− mice due to enhanced cell death [Abstract #224]. Here, we further investigated the molecular mechanisms underlying C/EBPβ-dependent survival of Ly6C− monocytes. In this study, we focused on the regulation of Csf1r (also known as M-CSF receptor). Csf1r is an essential molecule for the development and survival of monocytes. To determine the developmental stages at which Csf1r plays critical roles, we measured the expressions of Csf1r mRNA in hematopoietic stem/progenitor cells and monocyte subsets obtained from wild-type (WT) mice. Csf1r mRNA was expressed at at low levels in hematopoietic stem/progenitors including macrophage dendritic precursors (MDPs) and cMoPs. Csf1r mRNA started to be upregulated in Ly6C+ monocytes, followed by a drastic increase in Ly6C− monocytes. These expression patterns were quite similar to those of Cebpb, suggesting the close relationship between Csf1r and C/EBPβ. Interestingly, such drastic increase of Csf1r mRNA in Ly6C− monocytes was blunted in Cebpb−/− mice, and protein levels of Csf1r in Cebpb−/− Ly6C− monocytes were significantly lower than those in WT Ly6C− monocytes. In order to evaluate the effect of C/EBPβ overexpression on Csf1r expression, EML cells, a mouse hematopoietic stem cell line, were engineered to express C/EBPβ-estrogen receptor (ER) fusion protein or ER alone. Nuclear translocation of C/EBPβ-ER in the presence of tamoxifen resulted in significantly increased levels of Csf1r mRNA and protein when compared to nuclear translocation of ER alone. Previous reports have demonstrated that a combination of a promoter sequence and an enhancer region located in the first intron of Csf1r gene (Fms intronic regulatory element: FIRE) is enough to recapitulate the endogenous Csf1r expression and that these elements contained consensus binding sites for C/EBP transcription factors. Then, we hypothesized that C/EBPβ binds to these sites, activates transcription of Csf1r gene and promotes survival of Ly6C- monocytes. To evaluate this hypothesis, we utilized an expression vector, in which green fluorescent protein (GFP) is driven by a combination of the Csf1r promoter and FIRE sequences (Csf1r-EGFP-FIRE) (a kind gift from Drs Clare P and David A Hume, University of Edinburgh). When a C/EBPβexpression vector was co-transfected with the vector containing Csf1r-EGFP-FIRE into HEK293 cells, the frequencies of GFP positive cells were significantly higher when compared to a control vector (C/EBPβ vs control; 4.6±0.6 vs 1.6±1.0, p=0.01), suggesting that C/EBPβ regulates Csf1r expression through these elements. We are currently evaluating the significance of C/EBP consensus binding sites in the promoter and the enhancer. ChIP PCR is also in progress to further verify our hypothesis. Collectively, these results suggest that Csf1r is a critical downstream target of C/EBPβ in Ly6C- monocytes. Disclosures No relevant conflicts of interest to declare.
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Grivas, A., M. Grigoriou, P. Katsimpri, P. Verginis, and D. Boumpas. "POS0413 COMPREHENSIVE IMMUNE PROFILING OF PERIPHERAL BLOOD IN PSORIATIC ARTHRITIS (PsA) PATIENTS: EXPANSION OF INTERMEDIATE MONOCYTES AND DECREASED T REG AND CD8 T CELLS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 436.1–436. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3540.
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Background:Psoriatic arthritis (PsA) is a heterogeneous inflammatory arthritis that develops in a subset of patients with psoriasis. According to the current paradigm, cells of the innate and adaptive immunity interact with resident tissue fibroblasts mounting an inflammatory response via complex cytokine networks in the skin and joints in which type 1 and type 17 T cells play a dominant role. The abundance and relative contribution of other peripheral blood immune cells to disease pathogenesis as well the molecular signature of peripheral blood mononuclear cells and tissue fibroblasts remain ill defined.Objectives:To comprehensively characterize immune cell subsets driving inflammation in the peripheral blood of patients with active PsA and their impact on psoriatic skin fibroblasts.Methods:Peripheral blood was collected from PsA patients (n=31) and age-/sex-matched healthy individuals (HI) (n=9), after informed consent. Psoriatic skin biopsies were acquired from a subset of 5 patients and 3 HI. All patients fulfilled the CASPAR criteria for the diagnosis and displayed peripheral polyarthritis of moderate- to high-disease activity. Patients’ demographic and clinical data were recorded at time of sampling. Disease activity was assessed using the Disease Activity Index for Psoriatic arthritis (DAPSA) score. Skin psoriasis activity indices, enthesitis and dactylitis were also recorded. Peripheral blood mononuclear cells (PBMCs) were isolated by ficoll density gradient centrifugation. Flow cytometry was performed using a BD FACS-Aria-III and analyzed using FlowJo software. The antibody staining panel utilized aimed at the identification of the following immune cell subsets: Monocyte subsets (HLA-DR+ CD14+/- CD16+/-), Plasmacytoid dendritic cells (HLA- DR+ CD123+), T helper (CD4+), cytotoxic T (CD8+), regulatory T (CD4+ CD25+ CD127-) and B cells (CD19+). Statistical analyses were performed using GraphPad Prism software. Differences between groups were compared using unpaired T test for parametric data; Mann-Whitney and Kruskal Wallis tests for non-parametric data. The level of significance was set at P<0.05.Results:9 males and 22 females PsA patients are included (mean age 50 years and the mean disease duration 19.2 years for skin disease and 5.9 years for arthritis). The mean DAPSA score was 43.4, suggestive of high disease activity, while 8 (26%) patients displayed clinical enthesitis at time of sampling. Flow cytometry analysis revealed aberrancies in peripheral blood immune cell populations. More specifically, PsA patients displayed a significant increase in intermediate monocyte subset (HLA-DR+ CD14+ CD16+) compared to HI with patients with clinical enthesitis demonstrating a more exaggerated expansion of intermediate monocytes compared to patients without enthesitis. A trend towards increased patrolling monocytes (HLA-DR+ CD14- CD16+) was also noted although this did not reach statistical significance. In contrast, both regulatory T cells and cytotoxic CD8+ T cells were significantly decreased probably due to their selective migration at the sites of inflammation. RNA-seq from whole blood and skin fibroblasts from affected skin are in progress.Conclusion:These data demonstrate significant expansion of intermediate monocytes -more pronounced in the enthesitis affected individuals- and decrease in T regulatory cells and T cytotoxic cells in PsA peripheral blood. Increased antigen presentation and co-stimulation mediated via intermediate monocytes in combination with their proangiogenic properties may contribute to disease pathogenesisReferences:[1]Veale, D. J. & Fearon, U. The pathogenesis of psoriatic arthritis. The Lancet (2018) doi:10.1016/S0140-6736(18)30830-4.Disclosure of Interests:None declared
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Lin, Gene, Jennifer C. Yu, Joshua J. Field, David G. Nathan, and Joel Linden. "Human Sickle Cell Disease Increases Numbers and Activation Of Peripheral Blood Myeloid Dendritic Cells, Monocytes, and Neutrophils." Blood 122, no. 21 (November 15, 2013): 1033. http://dx.doi.org/10.1182/blood.v122.21.1033.1033.
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Abstract Sickle cell disease (SCD) is characterized by widespread vaso-occlusion in venules that is initiated by the polymerization of deoxy-hemoglobin in sickle RBCs and exacerbated by leukocyte activation and endothelial injury. In the course of the disease, episodic flare-ups result in painful vaso-occlusive crises (pVOC) and acute chest syndrome that over time result in chronic tissue injury. We have previously shown that pVOC in SCD is associated with activation of a small subset of CD1d restricted T lymphocytes known as invariant NKT (iNKT) cells that release large amounts of pro-inflammatory cytokines and propagate an inflammatory cascade. Antigen presenting cells (APCs) stimulate the activation of iNKT cells by presenting lipid antigens on CD1d and by releasing co-activating cytokines such as IL-12 and IL-18. Cytokines released by activated iNKT cells such as IFN-γ further propagate inflammation by stimulating chemotaxis of and activation of additonal leukocytes. In mice, the cytokines that are released by activated iNKT cells trans-activate monocytes and neutrophils. In this study we investigated for the first time the effect of pVOC in patients on the activation of myeloid (CD11c+/CD123-) dendritic cells (DCs) (CD45+/Lin1-/HLA-DR+), monocytes (CD3-/CD19-/CD15-/CD66b-/CD14+), and neutrophils (CD3-/CD19-/CD15+/CD66b+). Our findings indicate that like iNKT cells, myeloid DCs, monocytes, and neutrophils are increased in peripheral blood of SCD subjects relative to non-SCD controls. Plasmacytoid DCs (CD11c-/CD123+) were little affected. This increase in cell numbers is enhanced during pVOC except for myeloid DCs which decrease, possibly due to extravasation out of the blood stream. In addition, CD1d+ myeloid DCs from SCD individuals express higher levels of the activation marker, CD86, and this is further increased during pVOC. Similarly, neutrophils and monocyte subsets including classical monocytes (CD14+/CD16-) and patrolling monocytes (CD14dim/CD16+) express higher levels of activated adhesion molecules, LFA-1 (detected with KIM127 antibody) and Mac-1 (detected with CBRM1/5 antibody that recognizes active CD11b), in SCD subjects during pVOC as compared to controls and steady-state SCD patients. Taken together, these findings strongly suggest that the severity of vaso-occlusion during the clinical course of SCD correlates with an increased pro-inflammatory state reflected by increased circulating activated leukocytes. These findings are also consistent with previous murine studies showing that iNKT cells are necessary, but not sufficient for initiating and amplification of tissue inflammation and damage. The activation of CD1d+ APCs during pVOC is likely to facilitate iNKT cell activation due to the expression of co-stimulatory molecules (CD86), inflammatory cytokines, and possibly lipid antigens. Moreover, the activation of adhesion molecules on monocytes and neutrophils may enhance their propensity to contribute to vaso-occlusion. Disclosures: Field: NKT Therapeutics: Consultancy.
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Tesio, Melania. "Patrolling Monocytes Watch Over Relapse." HemaSphere 4, no. 4 (July 21, 2020): e451. http://dx.doi.org/10.1097/hs9.0000000000000451.
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Collison, Joanna. "Patrolling monocytes promote kidney disease." Nature Reviews Rheumatology 15, no. 7 (May 20, 2019): 385. http://dx.doi.org/10.1038/s41584-019-0239-1.
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Williams, Jesse W., Gwendalyn J. Randolph, and Bernd H. Zinselmeyer. "A Polecat’s View of Patrolling Monocytes." Circulation Research 120, no. 11 (May 26, 2017): 1699–701. http://dx.doi.org/10.1161/circresaha.117.311021.
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Cassetta, Luca, and Jeffrey W. Pollard. "Cancer immunosurveillance: role of patrolling monocytes." Cell Research 26, no. 1 (December 4, 2015): 3–4. http://dx.doi.org/10.1038/cr.2015.144.
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Michaud, Jean-Philippe, Pedro Moreno Pimentel-Coelho, Yannick Tremblay, and Serge Rivest. "The Impact of Ly6Clow Monocytes after Cerebral Hypoxia-Ischemia in Adult Mice." Journal of Cerebral Blood Flow & Metabolism 34, no. 7 (April 30, 2014): e1-e9. http://dx.doi.org/10.1038/jcbfm.2014.80.
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After an ischemic stroke, mononuclear phagocytic cells such as microglia, macrophages, and monocytes migrate to the lesion site and coordinate an immune response. Monocytes, which are recruited from the bloodstream after ischemic brain injury, can be categorized into two subsets in mice: inflammatory and patrolling monocytes. Although inflammatory monocytes (Ly6Chi) seem to have a protective role in stroke progression, the impact of patrolling monocytes (Ly6Clow) is unknown. To address the role of Ly6Clow monocytes in stroke, we generated bone marrow chimeric mice in which their hematopoietic system was replaced by Nr4a1−/− cells, allowing the complete and permanent ablation of Ly6Clow monocytes without affecting the Ly6Chi subset. We then subjected adult mice to cerebral hypoxia-ischemia using the Levine/Vannucci model. Functional outcomes after stroke such as body weight change, neurologic score, motor functions and spatial learning were not affected. Moreover, depletion in Ly6Clow monocytes did not change significantly the total infarct size, cell loss, atrophy, the number, or the activation state of microglia/macrophages at the lesion site. These data suggest that Ly6Clow patrolling monocytes are redundant in the progression and recovery of ischemic stroke.
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Hanna, Richard, Cagler Cekic, Manesh Chittezhath, Erica Herrley, Grzegorz Chodaczek, Subhra Biswas, and Catherine Hedrick. "NR4A1 (Nur77) dependent monocytes patrol the lung vasculature and inhibit tumor cell invasion (P5068)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 180.17. http://dx.doi.org/10.4049/jimmunol.190.supp.180.17.
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Abstract The nuclear receptor NR4A1 (Nur77) is expressed in monocytes and macrophages, yet its function in regulating inflammation associated with cancer is uncertain. Our previous studies identified that Nur77 regulates the development of patrolling Ly6C- monocytes and is involved in the resolution of inflammation. In the current study, we sought to determine how absence of Nur77 in hematopoietic cells impacts tumor growth and metastasis. Mice deficient in Nur77 showed a significant increase in growth and lung metastasis of syngeneic B16F10 melanoma. Increased tumor seeding of the lung was visible after only 4 days post IV tumor transfer, and appears to be specific to the lung. In vivo imaging reveals that Nur77-defficient mice have a drastic reduction in cells patrolling the lung vasculature, and that these patrolling monocytes establish early immune interactions with tumor cells and granulocytes in the lung. Furthermore, over-expression of Nur77 in human monocytes inhibited angiogenesis and invasion of human tumor cells in co-culture assays. We conclude that the absence of Nur77-regulated patrolling monocytes in combination with polarization of myeloid cells towards a pro-inflammatory and pro-angiogenic phenotype contributes to early tumor cell invasion of the vasculature and growth in the lung. These studies indicate that Nur77 is a novel target for modulating the inflammatory phenotype of monocytes and macrophages in inflammatory diseases, including cancers.
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Liu, Y., H. Zhong, F. Vinchi, A. Mendelson, and K. Yazdanbakhsh. "Patrolling monocytes in sickle cell hemolytic conditions." Transfusion Clinique et Biologique 26, no. 2 (May 2019): 128–29. http://dx.doi.org/10.1016/j.tracli.2019.02.004.
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Carlin, Leo M., Cedric Auffray, Takeshi Satoh, Kevin Woollard, and Frederic Geissmann. "Functions and molecular mechanisms of patrolling monocytes." Vascular Pharmacology 56, no. 5-6 (May 2012): 328. http://dx.doi.org/10.1016/j.vph.2011.08.066.
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Imhof, Beat A., Stephane Jemelin, Romain Ballet, Christian Vesin, Marc Schapira, Melis Karaca, and Yalin Emre. "CCN1/CYR61-mediated meticulous patrolling by Ly6Clow monocytes fuels vascular inflammation." Proceedings of the National Academy of Sciences 113, no. 33 (August 1, 2016): E4847—E4856. http://dx.doi.org/10.1073/pnas.1607710113.
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Inflammation is characterized by the recruitment of leukocytes from the bloodstream. The rapid arrival of neutrophils is followed by a wave of inflammatory lymphocyte antigen 6 complex (Ly6C)-positive monocytes. In contrast Ly6Clow monocytes survey the endothelium in the steady state, but their role in inflammation is still unclear. Here, using confocal intravital microscopy, we show that upon Toll-like receptor 7/8 (TLR7/8)-mediated inflammation of mesenteric veins, platelet activation drives the rapid mobilization of Ly6Clow monocytes to the luminal side of the endothelium. After repeatedly interacting with platelets, Ly6Clow monocytes commit to a meticulous patrolling of the endothelial wall and orchestrate the subsequent arrival and extravasation of neutrophils through the production of proinflammatory cytokines and chemokines. At a molecular level, we show that cysteine-rich protein 61 (CYR61)/CYR61 connective tissue growth factor nephroblastoma overexpressed 1 (CCN1) protein is released by activated platelets and enables the recruitment of Ly6Clow monocytes upon vascular inflammation. In addition endothelium-bound CCN1 sustains the adequate patrolling of Ly6Clow monocytes both in the steady state and under inflammatory conditions. Blocking CCN1 or platelets with specific antibodies impaired the early arrival of Ly6Clow monocytes and abolished the recruitment of neutrophils. These results refine the leukocyte recruitment cascade model by introducing endothelium-bound CCN1 as an inflammation mediator and by demonstrating a role for platelets and patrolling Ly6Clow monocytes in acute vascular inflammation.
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Hubbeling, Harper, Jonathan Maltzman, Amy Moran, Kristin Hogquist, Nicole Cunningham, and Jenni A. Punt. "Patrolling Murine Monocytes Are Defined by Their Expression of the Orphan Nuclear Receptor, Nur77 (nr4a1)." Blood 116, no. 21 (November 19, 2010): 4723. http://dx.doi.org/10.1182/blood.v116.21.4723.4723.
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Abstract Abstract 4723 ‘Resident’ or ‘patrolling’ monocytes have recently been described as a unique subset of myeloid cells that differ in phenotype and function from classic inflammatory monocytes. Resident monocytes are distinguished by their ‘crawling’ migration on endothelial surfaces, their immunosuppressive activity, and their unique pattern of surface protein expression: Ly6Clo, CX3CR1hi, CCR2-, LFA-1+, and PDL-1+. Using a Nur77-eGFP reporter mouse, we show that all murine patrolling monocytes, but not conventional monocytes express Nur77+ (also known as NR4A1), a member of the Nur orphan nuclear receptor family that regulates cell fate decisions several cell types and inhibits leukemogenesis. Nur77 is an immediate early response gene, and we have recently determined that it is a sensitive indicator of antigen receptor signaling among T cells. We therefore propose that its expression among patrolling monocytes is an indication that these cells are actively receiving signals, perhaps via interactions with the endothelium. We are currently working to identify these signals and our preliminary data suggest that adhesion molecules play an influential role. We thank the Arnold and Mabel Beckman Foundation (HH), and NSF (MCB-0744570 (JP and NC)) for their support for this work. Disclosures: No relevant conflicts of interest to declare.
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Hanna, R. N., C. Cekic, D. Sag, R. Tacke, G. D. Thomas, H. Nowyhed, E. Herrley, et al. "Patrolling monocytes control tumor metastasis to the lung." Science 350, no. 6263 (October 22, 2015): 985–90. http://dx.doi.org/10.1126/science.aac9407.
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Conejo‐Garcia, Jose R., and Paulo C. Rodriguez. "Kindlin‐3 gives patrolling monocytes a strong grip." Journal of Leukocyte Biology 107, no. 6 (June 2020): 879–81. http://dx.doi.org/10.1002/jlb.3ce0320-168.
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Talayeva, T. V., O. M. Parkhomenko, I. V. Tretyak, O. V. Dovhan, and O. V. Shumakov. "Relationship between dynamic changes in subpopulations of blood monocytes and the development of complications in patients with acute myocardial infarction." Ukrainian Journal of Cardiology 27, no. 4 (October 1, 2020): 9–17. http://dx.doi.org/10.31928/1608-635x-2020.4.917.
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The aim – to determine the extent of different subpopulations of blood monocytes in acute myocardial infarction (AMI) with ST-segment elevation patients on day 1 and 7 and to evaluate the relationship between their content and the dynamics of changes and the risk of complications after AMI.Materials and methods. The composition of individual subpopulations of monocytes in the peripheral venous blood (and general clinical and biochemical blood tests) was evaluated in 50 pts with STEMI (who were admitted within 6 hours after the onset of the disease) at admission (before primary PCI) and on day 7. All patients received standard recommended therapy. Dynamic heart echocardiography was also performed on the 1st and 7th day. All patients were divided into 2 groups depending on the dynamical increase (1 group – 21 pts) or decrease (2 group – 29 pts) of classical monocytes (CD14hiCD16–) subpopulation during 7 days of follow-up. The control group included 15 healthy subjects with no signs of coronary heart disease and 23 pts with chronic coronary heart disease without AMI.Results and discussion. In subgroup 1, the percentage of the «classical» fraction of monocytes during the observation increased to 89.0±1.2 %, which was 4.2 % more than on the 1st day and 12.5 % more than in the control group (р<0.05), while the absolute amount of classic monocytes on day 7 increased by 48 % compared to initial value (р<0.01). The percentage of «intermediate» (CD14hiCD16+) blood monocytes in patients of this subgroup on the 1st day of hospitalization was 70 % higher than in the control group, and 42 % higher than in the 2nd subgroup of patients (р<0,001), however, on the 7th day it decreased by 30 % compared to baseline, although it remained by 8 % more than in the control group (the absolute number of «intermediate» monocytes did not change). The activation index (IA) of the «intermediate» monocytes on the first day did not differ between subgroups and was 40 % higher than in the control group (р<0.001). However, in the dynamics of observation, in patients of subgroup 1, this figure did not change, while in subgroup 2 IA decreased by 60 % (р<0.001). Despite the fact that the absolute number of anti-inflammatory («patrolling») (CD14+lowCD16++) monocytes did not change until the 7th day of observation (and their percentage decreased slightly), their IA was significantly lower than in the control group (95 %) and in patients of subgroup 2 (92 %, р<0,001). In patients of subgroup 2, the decrease of the percentage of «classic» monocytes was –7.7 % (from 90.4±0.8 to 83.4±1.2 %). Despite the fact that the number and percentage of intermediate monocytes increased in dynamics, their IA decreased almost 2 times, which may indicate a decrease in the pro-inflammatory ability these monocytes. The percentage and number of «patrolling» monocytes increased in dynamics by 37.4 % (р<0.0001) and by 268.3 % (р<0.01), respectively. IA of patrolling monocytes was almost 12 and 7 times higher than in patients of subgroup 1 on the 1st and 7th day of observation, respectively, which may indicate a significant activation of anti-inflammatory activity of patrolling monocytes. Intracardiac thrombosis was 3.3 times more common in patients of subgroup 1, in this subgroup was also more often noted (compared to the subgroup 2): dilatation of the left ventricle (almost 8 times), reduction of left ventricular ejection fraction (4 times), and pathological post-infarction remodeling of the left ventricle (almost 7 times).Conclusions. The results of the study indicate the important role of different subpopulations of blood monocytes in the processes of myocardial damage and recovery (in particular, the pro-inflammatory role of increasing the number of classical monocytes and increasing the activity of intermediate monocytes, as well as the anti-inflammatory role of increasing the number, percentage and activity of patrolling monocytes) in patients with AMI and can be the basis for developing new approaches to the diagnosis and prevention of complications of this disease.
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Debien, Emilie, Katia Mayol, Vincent Biajoux, Cécile Daussy, Mercedes Gomez De Aguero, Morgan Taillardet, Nicolas Dagany, et al. "S1PR5 is pivotal for the homeostasis of patrolling monocytes." European Journal of Immunology 43, no. 6 (April 30, 2013): 1667–75. http://dx.doi.org/10.1002/eji.201343312.
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