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1
Cavallaro, Elena C., Kar-Kate Liang, Kevin D. Forsyth, and Dani-Louise Dixon. "Neutrophil polarization in the airways of infants with bronchiolitis." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 55.30. http://dx.doi.org/10.4049/jimmunol.198.supp.55.30.
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Abstract Pulmonary neutrophilia is observed in pediatric patients with viral-induced bronchiolitis. Despite an alleviation in clinical symptoms, our findings suggest that airway neutrophil infiltration and activation does not appear to resolve by discharge in hospitalized infants. The recent identification of neutrophil plasticity and polarization into distinct phenotypic pro-inflammatory (N1) and immunosuppressive (N2) subsets provides an unexplored avenue for regulation of the neutrophilic inflammatory response in bronchiolitis. Admission nasopharyngeal aspirate (NPA) samples were assessed from twelve bronchiolitic infants presenting to Flinders Medical Centre, Adelaide, Australia in 2013. An overall strong positive correlation between N2 soluble mediator TGF-β1 and the percentage of neutrophils stained for N2 marker MMP-9 was observed; with no correlation observed between TGF-β1 and neutrophils positive for N1 marker ICAM-1. In 2015 and 2016, eleven bronchiolitic infants provided consecutive NPAs across hospitalization. In both cohorts, concentrations of active TGF-β1 detected were comparable to levels previously identified to significantly suppress neutrophil activity in vitro (>1 pg/mL). Temporal assessment of neutrophil polarization is underway. The detection of pre-established neutrophil polarizing mediators, and the correlation of these mediators with different neutrophilic subsets within NPAs indicates a potential N1/N2 paradigm occurring within the airways of bronchiolitic infants. Further investigation is merited, with analyses over disease trajectory and by disease severity required to assess biological significance.
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Forlow, S. Bradley, Jill R. Schurr, Jay K. Kolls, Gregory J. Bagby, Paul O. Schwarzenberger, and Klaus Ley. "Increased granulopoiesis through interleukin-17 and granulocyte colony-stimulating factor in leukocyte adhesion molecule–deficient mice." Blood 98, no. 12 (December 1, 2001): 3309–14. http://dx.doi.org/10.1182/blood.v98.12.3309.
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Abstract Many mutant mice deficient in leukocyte adhesion molecules display altered hematopoiesis and neutrophilia. This study investigated whether peripheral blood neutrophil concentrations in these mice are elevated as a result of accumulation of neutrophils in the circulation or altered hematopoiesis mediated by a disrupted regulatory feedback loop. Chimeric mice were generated by transplanting various ratios of CD18+/+ and CD18−/− unfractionated bone marrow cells into lethally irradiated wild-type mice, resulting in approximately 0%, 10%, 50%, 90%, or 100% CD18 null neutrophils in the blood. The presence of only 10% CD18+/+ neutrophils was sufficient to prevent the severe neutrophilia seen in mice reconstituted with CD18−/− bone marrow cells. These data show that the neutrophilia in CD18−/− mice is not caused by enhanced neutrophil survival or the inability of neutrophils to leave the vascular compartment. In CD18−/−, CD18−/−E−/−, CD18−/−P−/−, EP−/−, and EPI−/− mice, levels of granulocyte colony-stimulating factor (G-CSF) and interleukin-17 (IL-17) were elevated in proportion to the neutrophilia seen in these mice, regardless of the underlying mutation. Antibiotic treatment or the propensity to develop skin lesions did not correlate with neutrophil counts. Blocking IL-17 or G-CSF function in vivo significantly reduced neutrophil counts in severely neutrophilic mice by approximately 50% (P < .05) or 70% (P < .01), respectively. These data show that peripheral blood neutrophil numbers are regulated by a feedback loop involving G-CSF and IL-17 and that this feedback loop is disrupted when neutrophils cannot migrate into peripheral tissues.
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Mizgerd, J. P., B. B. Meek, G. J. Kutkoski, D. C. Bullard, A. L. Beaudet, and C. M. Doerschuk. "Selectins and neutrophil traffic: margination and Streptococcus pneumoniae-induced emigration in murine lungs." Journal of Experimental Medicine 184, no. 2 (August 1, 1996): 639–45. http://dx.doi.org/10.1084/jem.184.2.639.
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The roles of selectins in the pulmonary margination and emigration of neutrophils were investigated by using mice genetically deficient in both E- and P-selectins (E/P mutants) and/or by intravenous injections of fucoidin (inhibiting both L- and P-selectins). E/P mutants were neutrophilic (14.7 +/- 4.9 x 10(6) vs. 0.8 +/- 0.1 x 10(6) neutrophils/ml). This neutrophilia was associated with increased margination of neutrophils within pulmonary capillaries (39.7 +/- 9.4 vs. 4.6 +/- 1.1 neutrophil profiles per 100 red blood cell profiles) but no change in margination within noncapillary pulmonary microvessels. After intratracheal instillation of Streptococcus pneumoniae, lungs of E/P mutants displayed increased neutrophil emigration (564 +/- 92 vs. 116 +/- 19 neutrophils per 100 alveolar profiles), edema (5.3 +/- 1.5 vs. 1.5 +/- 0.4 microliter/g body weight), and histologic evidence of lung injury compared with those in wild-type (WT). Fucoidin treatment did not affect neutrophil emigration during streptococcal pneumonia in WT or E/P mice. During pneumonia, the number of white blood cells (WBC) tethered to or spread upon the noncapillary vessel endothelium increased in both WT and E/P lungs. These are the first data demonstrating that neutrophil margination in uninfected pulmonary capillaries does not require E- and P-selectins; that streptococcal pneumonia induces an E- and P-selectin-independent increase in WBC interactions with noncapillary endothelium; and that migration of neutrophils to alveoli can occur despite deficiency or inhibition of all of the known selectins.
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Harvath, L., K. B. Yancey, and S. I. Katz. "Selective inhibition of human neutrophil chemotaxis to N-formyl-methionyl-leucyl-phenylalanine by sulfones." Journal of Immunology 137, no. 4 (August 15, 1986): 1305–11. http://dx.doi.org/10.4049/jimmunol.137.4.1305.
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Abstract The therapeutic efficacy of the sulfones, dapsone, and sulfoxone in neutrophilic dermatoses may be related to the effects of these drugs on neutrophil function. Therefore we determined whether neutrophil chemotactic migration to various chemoattractants could be inhibited by sulfones in vitro. The chemotactic responses of human neutrophils from healthy donors were tested by using N-formyl-methionyl-leucyl-phenylalanine (F-met-leu-phe), purified human C5a, and leukocyte-derived chemotactic factor (LDCF). Therapeutic concentrations of sulfones selectively inhibited neutrophil chemotaxis to F-met-leu-phe, but did not affect neutrophil chemotaxis to LDCF or C5a. Inhibition of neutrophil chemotaxis to F-met-leu-phe was induced by both dapsone and sulfoxone at a concentration of 10 micrograms/ml without affecting random migration, and the inhibition was reversed by washing the neutrophils. When dapsone- and sulfoxone-treated neutrophils (100 micrograms/ml) were stimulated with F-met-leu-phe, neutrophil superoxide generation was not inhibited. Sulfapyridine (10 micrograms/ml) also selectively inhibited neutrophil chemotaxis to F-met-leu-phe; however, sulfamethoxazole and sulfisoxazole did not affect chemotaxis. The inhibitory effects of dapsone, sulfoxone, and sulfapyridine could not be demonstrated with granulocytes from rabbits or guinea pigs nor with human monocytes. Experiments with radiolabeled dapsone showed rapid, nonspecific, and reversible binding of dapsone to human neutrophils. These data suggest that a mechanism of action of sulfones in neutrophilic dermatoses may be a selective inhibition of neutrophil migration to as yet undefined chemoattractants in the skin.
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Wang, Jun-Xia, and Peter Nigrovic. "CD177 participates in a novel mechanism for regulating neutrophil recruitment (P3093)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 43.9. http://dx.doi.org/10.4049/jimmunol.190.supp.43.9.
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Abstract Background: Neutrophils are the sine qua non of inflammatory arthritis, and contribute to pain, swelling, and tissue injury, rendering neutrophil migration to the joint a potential therapeutic target. We recently found that the murine neutrophil surface protein Ly6G modulates chemotaxis via interaction with β2 integrins. Whereas CD177 is a neutrophil-specific human protein in the same gene family, we sought to identify the role of CD177 in human neutrophil recruitment. Method: Flow cytometry was used to analyze the levels of cell surface proteins in circulating neutrophils and in neutrophils from inflamed joints. Fluorescence lifetime imaging microscopy/Fluorescence resonance energy transfer assay (FLIM/FRET) was used to quantify CD177-β2 integrin interactions. Result: In patients with rheumatoid arthritis, synovial neutrophils exhibit higher levels of surface CD177 expression comparing with blood neutrophils. Using FLIM/FRET, ~40% CD11a and ~20% CD11b β2 integrins interact with CD177 on surface of resting blood neutrophils. In vitro, a specific CD177 antibody inhibits LTB4-induced conformational activation of CD11b β2 integrin, which is correlated with an impaired neutrophil migration towards LTB4 in anti-CD177 treated cells in a transwell system. Conclusion: CD177 regulates neutrophil chemotaxis and may serve as a potential neutrophil-specific therapeutic target in neutrophilic inflammatory diseases such as arthritis.
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Wang, Guoshun, and Hang Pong Ng. "Myeloid CFTR Loss-of-function Causes Persistent Neutrophilic Inflammation in Cystic Fibrosis." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 187.33. http://dx.doi.org/10.4049/jimmunol.202.supp.187.33.
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Abstract Persistent neutrophilic inflammation is a hallmark manifestation of cystic fibrosis (CF). However, the mechanism underlying this phenomenal clinical symptom remains incompletely understood. Here we report a pivotal role of CFTR in myeloid immune cells in control of neutrophilic inflammation. Myeloid CFTR-Knockout (Mye-Cftr−/−) mice and Wild-type (WT) mice were challenged peritoneally with zymosan at different doses. The lethal-dose challenge resulted in significantly higher mortality in Mye-Cftr−/− mice, indicating an intrinsic defect in host protection against inflammation in CF. The sub-lethal-dose challenge demonstrated an impaired resolution of inflammation in Mye-Cftr−/− mice, reflected by persistent neutrophilic inflammation, and hyper-inflammation with significantly higher levels of pro-inflammatory cytokines, including the neutrophil-recruiting chemokines MIP-2 and KC, which led to excessive neutrophil recruitment in vivo. Pulmonary challenge with zymosan confirmed the peritoneal finding. To determine the major types of cells responsible for the over-recruitment of neutrophils, zymosan-elicited peritoneal neutrophils and macrophages from Mye-Cftr−/− and WT mice were FACS-sorted and cultured ex vivo. The CF neutrophils produced significantly more neutrophil chemokine MIP-2. Moreover, peripheral blood neutrophils and monocytes from Mye-Cftr−/− and WT mice were cultured and stimulated with zymosan in vitro. Similarly, the CF neutrophils produced significantly more MIP-2. These data altogether suggest that CFTR dysfunction in myeloid immune cells leads to excessive neutrophil recruitment, thus serving as a mechanism for the long-observed neutrophilic inflammation in CF.
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Gadjeva, Mihaela, Abirami Kugadas, Anastasia Petenkova, Jennifer Geddes-McAlister, Michael K. Mansour, and David Sykes. "Neutrophil maturation and their response to infectious pathogens are regulated by microbiota." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 127.22. http://dx.doi.org/10.4049/jimmunol.202.supp.127.22.
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Abstract It has long been considered that a neutrophil’s response to various infectious challenges is innately pre-determined. Here, we provide data that demonstrates that neutrophil proteomes are modulated by the microbiota. We found that the proteomic signatures of mature neutrophils derived from germ free (GF) and specific pathogen free (SPF) mice were significantly different. In the absence of microbiota, mature neutrophils lacked GM-CSF-driven priming. To identify molecular pathways, we set-up an in vitro system where neutrophil progenitors were transduced with lenti-guides to knock-down key microbiota-driven pathway gene targets. GF-serum exposed neutrophil progenitors did not mature efficiently and had compromised bactericidal properties when compared to progenitors matured in SPF-derived serum. To identify which of the microbiota-driven proteins directly impacted bactericidal functions of neutrophils, we knocked out 19 candidates and tested their killing efficacy. Among all tested clones, one demonstrated a superior inhibition of neutrophil’s bactericidal capacities. Excitingly, this protein had no previously identified function: the knock down of prenylcysteine oxidase-like 1 (pcyox 1l) protein reduced neutrophil’s ability to kill efficiently P. aeruginosa in vitro due to diminished ROS release. Hence, we identified a novel mechanism for microbiota-driven control of innate immunity. Cumulatively, the data support the concept that microbiota affects neutrophil maturation by defining not only the quantity, but also the quality of mature neutrophils. We predict that neutrophil responses can be specifically tailored to pathogens.
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Borges, Leandro, Tania Cristina Pithon-Curi, Rui Curi, and Elaine Hatanaka. "COVID-19 and Neutrophils: The Relationship between Hyperinflammation and Neutrophil Extracellular Traps." Mediators of Inflammation 2020 (December 2, 2020): 1–7. http://dx.doi.org/10.1155/2020/8829674.
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Coronavirus disease 2019 (COVID-19) is a virus-induced respiratory disease that may progress to acute respiratory distress syndrome (ARDS) and is triggered by immunopathological mechanisms that cause excessive inflammation and leukocyte dysfunction. Neutrophils play a critical function in the clearance of bacteria with specific mechanisms to combat viruses. The aim of this review is to highlight the current advances in the pathways of neutrophilic inflammation against viral infection over the past ten years, focusing on the production of neutrophil extracellular traps (NETs) and its impact on severe lung diseases, such as COVID-19. We focused on studies regarding hyperinflammation, cytokine storms, neutrophil function, and viral infections. We discuss how the neutrophil’s role could influence COVID-19 symptoms in the interaction between hyperinflammation (overproduction of NETs and cytokines) and the clearance function of neutrophils to eliminate the viral infection. We also propose a more in-depth investigation into the neutrophil response mechanism targeting NETosis in the different phases of COVID-19.
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Brinkworth, Jessica F., Kathrine Van Etten, Priya Bhatt, Keaton McClure, Negin Valizadegan, Minkyu Woo, Suvanthee Gunasekera, Yaravi Suarez, and Brian Aldridge. "Functional comparison of human and non-human primate neutrophil responses." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 73.21. http://dx.doi.org/10.4049/jimmunol.202.supp.73.21.
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Abstract Humans and apes are neutrophilic, maintaining high levels (50–70% of circulating leukocytes) of this short-lived, highly reactive cell type (neutrophils), while most primates maintain significantly lower proportions(20–40% circulating leukocytes). Neutrophils are key limiters of bacterial and parasitic infection, amplifying inflammation, phagocytosing and presenting, and trapping invading foreign material, as well as committing bystander tissue damage in these efforts. The comparative neutrophilia of humans, therefore, suggests alterations in neutrophil activities such that higher proportions are both required and tolerated in this species. To address this possibility, we analyzed transcriptomic, and cell physiological responses of neutrophils from humans, and two biomedically important primates, rhesus macaque and common marmoset. Cells were isolated via a density gradient and stimulated with 1ng-1ug of lipopolysaccarhide (LPS) from Escherichia coli K12 or the bacteria itself (MOI 10:1) for 1–3 hours. Transcriptomic responses were captured by RNAseq, and physiological responses [phagocytosis, apoptosis, extracellular trapping (NETing)] by fluorescent microscopy. The species differed strongly the expression of genes in innate immune and cell trafficking pathways. Overall, primates exhibited NETing and apoptosis sensitivity to even the lowest dose of LPS. Humans, however, displayed a unique complement of neutrophil antimicrobial responses - phagocytosing and apoptosising more, while NETing less than the other species. These results suggest inter-species differences in important neutrophil antimicrobial strategies that may impact interpretation of primate biomedical models.
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Shelite, Thomas R., Nicole L. Mendell, Donald H. Bouyer, David Hughes Walker, and Lynn Soong. "The role of neutrophils during Orientia infection." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 66.28. http://dx.doi.org/10.4049/jimmunol.196.supp.66.28.
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Abstract Scrub typhus is a seriously neglected disease with approximately one-third of the world’s population at risk of being infected with Orientia tsutsugamushi, and the occurrence of over one million scrub typhus cases annually illustrate its importance in global health. All scrub typhus case studies that report blood cell counts, describe neutrophilia during the course of infection. Patients with confirmed scrub typhus have significant increases in activated neutrophil proteins in serum, and the increase of neutrophil recruiting cytokines. We also observed neutrophilia as well as neutrophil recruitment to infected tissues in intravenously infected mice, suggesting key role for neutrophils in scrub typhus disease progression. To determine the role of neutrophils in this infection, female C57BL/6 mice were lethally challenged, and neutrophils were depleted one day prior to infection (D−1) or six (D+6) days post infection. The effects of neutrophil depletion were observed to be dependent on the time post infection. Animals depleted early (D-1) exhibited more severe pathology at an earlier time point and had disease progression similar to non-depleted animals but had greater survival. Animals depleted 6 dpi recovered weight, and signs of illness had resolved by 12 dpi. Histopathology demonstrated decreased cellular infiltrates when compared to infected, non-depleted animals. Depletion of neutrophils decreased mortality independent of when depleted, but only depletion 6 dpi resulted in amelioration of signs. These data suggest an important role of neutrophils in tissue pathology and disease progression during scrub typhus infection.
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Jondle, Christopher Ned, Bibhuti B. Mishra, and Jyotika Sharma. "Macrophage galactose-type lectin 1 (MGL-1) regulates neutrophil mobilization during pulmonary Gram negative pneumonia." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 131.2. http://dx.doi.org/10.4049/jimmunol.198.supp.131.2.
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Abstract Macrophage galactose-type lectin 1 (MGL-1) is a type 2 transmembrane C-type lectin receptor. We recently reported that MGL1-mediated responses are required to mitigate disease severity in Klebsiella pneumoniae (KPn) induced murine pneumosepsis. Here we investigated the role of MGL-1 in neutrophil development and homeostasis during KPn infection. We found that MGL-1−/− mice exhibit severe neutrophilia in their lungs upon KPn infection. Adaptive transfer experiments showed that MGL-1 deficiency on neutrophils significantly increased their capacity to infiltrate the lungs. Analysis of neutrophil numbers and their progenitors in various compartments showed that increased mobilization of mature neutrophils from bone marrow storage pools, but not the progenitor proliferation, accounted for the increased systemic neutrophil counts. This was correlated with elevated levels of neutrophil mobilizing factors G-CSF and MCP-2 in MGL-1−/− mice. Collectively, our findings demonstrate that MGL-1 has a profound role in neutrophil homeostasis during acute inflammatory condition.
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Panova, Veera, Mayuri Gogoi, Noe Rodriguez-Rodriguez, Meera Sivasubramaniam, Helen E. Jolin, Morgan W. D. Heycock, Jennifer A. Walker, et al. "Group-2 innate lymphoid cell-dependent regulation of tissue neutrophil migration by alternatively activated macrophage-secreted Ear11." Mucosal Immunology 14, no. 1 (May 26, 2020): 26–37. http://dx.doi.org/10.1038/s41385-020-0298-2.
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AbstractType-2 immunity is characterised by interleukin (IL)-4, IL-5 and IL-13, eosinophilia, mucus production, IgE, and alternatively activated macrophages (AAM). However, despite the lack of neutrophil chemoattractants such as CXCL1, neutrophils, a feature of type-1 immunity, are observed in type-2 responses. Consequently, alternative mechanisms must exist to ensure that neutrophils can contribute to type-2 immune reactions without escalation of deleterious inflammation. We now demonstrate that type-2 immune-associated neutrophil infiltration is regulated by the mouse RNase A homologue, eosinophil-associated ribonuclease 11 (Ear11), which is secreted by AAM downstream of IL-25-stimulated ILC2. Transgenic overexpression of Ear11 resulted in tissue neutrophilia, whereas Ear11-deficient mice have fewer resting tissue neutrophils, whilst other type-2 immune responses are not impaired. Notably, administration of recombinant mouse Ear11 increases neutrophil motility and recruitment. Thus, Ear11 helps maintain tissue neutrophils at homoeostasis and during type-2 reactions when chemokine-producing classically activated macrophages are infrequently elicited.
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Devi, Sapna, Yilin Wang, Weng Keong Chew, Ronald Lima, Noelia A-González, Citra N. Z. Mattar, Shu Zhen Chong, et al. "Neutrophil mobilization via plerixafor-mediated CXCR4 inhibition arises from lung demargination and blockade of neutrophil homing to the bone marrow." Journal of Experimental Medicine 210, no. 11 (September 30, 2013): 2321–36. http://dx.doi.org/10.1084/jem.20130056.
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Blood neutrophil homeostasis is essential for successful host defense against invading pathogens. Circulating neutrophil counts are positively regulated by CXCR2 signaling and negatively regulated by the CXCR4–CXCL12 axis. In particular, G-CSF, a known CXCR2 signaler, and plerixafor, a CXCR4 antagonist, have both been shown to correct neutropenia in human patients. G-CSF directly induces neutrophil mobilization from the bone marrow (BM) into the blood, but the mechanisms underlying plerixafor-induced neutrophilia remain poorly defined. Using a combination of intravital multiphoton microscopy, genetically modified mice and novel in vivo homing assays, we demonstrate that G-CSF and plerixafor work through distinct mechanisms. In contrast to G-CSF, CXCR4 inhibition via plerixafor does not result in neutrophil mobilization from the BM. Instead, plerixafor augments the frequency of circulating neutrophils through their release from the marginated pool present in the lung, while simultaneously preventing neutrophil return to the BM. Our study demonstrates for the first time that drastic changes in blood neutrophils can originate from alternative reservoirs other than the BM, while implicating a role for CXCR4–CXCL12 interactions in regulating lung neutrophil margination. Collectively, our data provides valuable insights into the fundamental regulation of neutrophil homeostasis, which may lead to the development of improved treatment regimens for neutropenic patients.
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White, Mitchell R., I.-Ni Hsieh, Xavier De Luna, and Kevan L. Hartshorn. "Effects of serum amyloid protein A on influenza A virus replication and viral interactions with neutrophils." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 168.11. http://dx.doi.org/10.4049/jimmunol.200.supp.168.11.
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Abstract Innate immunity is vital for the early control of influenza A virus (IAV) infection. Serum amyloid A (SAA1) is an acute phase reactant produced in the liver and lung that rises dramatically during IAV infection. SAA has been reported to directly activate neutrophils and to recruit them to the lung during infectious and inflammatory processes. In this study we characterized the interactions of several forms of SAA with IAV and with neutrophils. The complex of SAA with HDL had some neutralizing activity against IAV. Similarly purified SAA containing amino acids 19–94 prepared from human serum had some viral neutralizing activity. In contrast recombinant SAA containing amino acids 19–123 (rSAA) did not. SAA preparations, including rSAA, increased various responses of neutrophils to the virus. Neither serum nor rSAA directly stimulated neutrophil respiratory burst responses on their own; however, both preparations increased these responses to IAV. rSAA also increased neutrophil uptake of IAV. rSAA alone did trigger neutrophil IL-8 production but modestly increased the strong neutrophil IL-8 response triggered by IAV. rSAA alone did trigger a neutrophil intracellular calcium response and also increased the peak calcium response to IAV. Combining rSAA with surfactant protein D (a known lung inhibitor of IAV) resulted in potentiation of viral neutralizing and aggregating activity of IAV. We provide evidence that the effects of SAA on neutrophil responses to IAV were not mediated by formyl peptide receptor 2 but were in part mediated by TLR2. These results suggest that SAA produced in the lung may significantly modulate the early neutrophilic host response to IAV.
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Kwak, DongWook, Donghwan Park, Jae-Hyun Jang, and Jae-Hong Kim. "The leukotriene B4 receptors contributes to neutrophil-dominant asthmatic airway inflammation via IL-1β and IL-17 production." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 65.19. http://dx.doi.org/10.4049/jimmunol.204.supp.65.19.
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Abstract The leukotriene B4 is one of the chemo-attractant molecule for neutrophils, its receptors, BLT1/2 may contribute to neutrophil-dominant airway inflammation. Therefore, we investigated whether BLT1/2 signaling was associated with neutrophil-dominant severe asthma. The role of BLT1/2 as well as 5-/12-lipoxygenase in neutrophil-dominant airway inflammation was investigated using pharmacological inhibitors in murine model. Blockade of BLT1/2 significantly suppressed airway inflammation including thickness of airway wall, recruitment of immune cells and IL-17 production in neutrophil-dominant airway inflammation. 5-/12-LOX, upstream of LTB4 receptors was also critical for neutrophil-dominant airway inflammation and synthesis of IL-17. Furthermore, inhibition of 5-/12-LOX, BLT1/2, suppressed NF-κB activation, thus attenuating airway inflammation and production of IL-17, suggesting that NF-κB lies downstream of BLT1/2 in neutrophilic airway inflammation. Our results suggest that ‘5-/12-LOX-BLT1/2-NF-κB’ cascade significantly contributes to neutrophil-dominant airway inflammation through IL-17 synthesis. What is interesting is IL-1β also acts important role in the neutrophil-dominant asthmatic condition with IL-17 production. The high-expression level of IL-1β which is mainly produced by NLRP3 inflammasome activation already reported clinically in the sputum of neutrophilic asthma patients. Consequentially, our studies suggest that the cooperative mechanism of IL-1β and IL-17 considerably acts to neutrophil-dominant airway inflammation and the leukotriene B4 receptors have possibilities to control the severity via regulation effect of IL-1β and IL-17.
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Nwakoby, Izuchukwu E., Krishna Reddy, Puja Patel, Neena Shah, Saroj Sharma, Madhu Bhaskaran, Nora Gibbons, Aditi A. Kapasi, and Pravin C. Singhal. "Fas-Mediated Apoptosis of Neutrophils in Sera of Patients with Infection." Infection and Immunity 69, no. 5 (May 1, 2001): 3343–49. http://dx.doi.org/10.1128/iai.69.5.3343-3349.2001.
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ABSTRACT In the presence of infection, neutropenia is considered to be a marker of poor prognosis; conversely, neutrophilia may not be a determinant of a better prognosis. Since apoptotic neutrophils are compromised functionally, we evaluated the effect of infection on neutrophil apoptosis. The rate of apoptosis was greater for neutrophils isolated from patients with infection than for healthy controls.Escherichia coli did not directly modulate the rate of neutrophil apoptosis. However, sera from infected patients promoted (P < 0.001) neutrophil apoptosis. Interestingly, the sera of patients with different types of infection (gram negative, gram positive, or culture negative) exerted a more or less identical response on neutrophil apoptosis. Sera of infected patients showed a fivefold greater content of FasL compared to controls. Moreover, anti-FasL antibody partly attenuated the infected-serum-induced neutrophil apoptosis. In in vitro studies, E. coli enhanced monocyte FasL expression. Moreover, conditioned media prepared from activated macrophages from control mice showed enhanced apoptosis of human as well as mouse neutrophils. On the contrary, conditioned media prepared from activated macrophages isolated from FasL-deficient mice induced only a mild degree of neutrophil apoptosis. These results suggest that neutrophils in patients with infection undergo apoptosis at an accelerated rate. Infection not only promoted monocyte expression of FasL but also increased FasL content of the serum. Because the functional status of apoptotic cells is compromised, a significant number of neutrophils may not be participating in the body's defense. Since neutrophils play the most important role in innate immunity, their compromised status in the presence of infection may transfer the host defense burden from an innate response to acquired immunity. The present study provides some insight into the lack of correlation between neutrophilia and the outcome of infection.
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Dinh, Huy, Tobias Eggert, Melissa Meyer, Yanfang Zhu, Claire Olingy, Ryan Llewellyn, Runpei Wu, and Catherine C. Hedrick. "Identification of a CD117+CD71+ early neutrophil progenitor population in human bone marrow." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 63.6. http://dx.doi.org/10.4049/jimmunol.204.supp.63.6.
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Abstract Neutrophils play critical roles in health and disease. Due to their very short half-life in blood and tissue, neutrophils are constantly replenished by bone-marrow progenitors. Thus, a comprehensive understanding of bone marrow neutrophil development is of paramount importance to identify how neutrophil production is altered in disease. Recently, two novel human neutrophil progenitor populations were identified; ‘human neutrophil progenitor’ or ‘hNeP’ (Lin-CD66b+CD117+) and ‘neutrophil precursor’ or ‘preNeu’ (Lin-CD66b+CD15+CD49d+). How these subsets fit into the neutrophil lineage is unclear. By using mass and flow cytometry, we show that hNeP are a heterogenous population containing a homogeneous progenitor subset termed ‘early neutrophil progenitor’ or ‘eNeP’ (Lin-CD66b+CD117+CD71+). Surface marker and RNA expression, together with the ability to form colonies in vitro suggest that eNePs, which constitute only ~0.14% of bone marrow neutrophils, are upstream of preNeu (~5% of bone marrow neutrophils). Furthermore, we have identified novel neutrophil surface markers associated with distinct developmental stages, including CD71. Intriguingly, CD71+ characterizes proliferating neutrophils, which are expanded in the blood of melanoma and lung cancer patients and detectable in human lung tumors. Collectively, our findings i) identify CD117+CD71+ eNeP as an early neutrophil progenitor population, ii) introduce a unified model of human neutrophil bone marrow development, iii) identify novel surface markers for distinct neutrophil developmental stages and iv) provide evidence for neutrophil progenitor expansion in cancer.
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Kolios, Antonios, Victor Diaz, Cecilie Egholm, Cornelia Halin, Onur Boyman, and Alaz Özcan. "Clearance of skin-homing CCR7+ neutrophils by conventional type1 dendritic cells regulates cutaneous local autoimmunity and infection." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 111.08. http://dx.doi.org/10.4049/jimmunol.206.supp.111.08.
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Abstract A rapid neutrophil response is essential for immunity against infections, however impaired elimination or migration can inflict significant tissue damage by exacerbated inflammation. Here we show that neutrophils recruited to inflamed or infected skin are rapidly redirected to skin-draining lymph nodes (dLNs) and non-draining secondary lymphoid tissues. Using transgenic mouse models and bone marrow chimeras, cutaneous inflammation is induced with imiquimod, a TLR7-mediated psoriasis-like model, or skin infection is induced by Staphylococcus aureus. We show that neutrophils migrate to the dLNs through lymphatic vessels in a CC-motif chemokine receptor 7 (CCR7)-dependent manner and are phagocytosed by resident conventional type1 dendritic cells in the dLNs when entering the lymph node, a mechanism contributing to neutrophil clearance. Deficiency of CCR7 impairs neutrophil elimination in the dLNs and leads to neutrophilic accumulation in the skin, which in turn leads to an exacerbated phenotype in a model of psoriasis-like local inflammation as well as improved clearance and immunity against cutaneous Staphylococcus aureus infection. Overall, our findings explain how impaired neutrophil migration and clearance in the dLNs could regulate cutaneous autoimmunity and infection.
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Diener, A. M., P. G. Beatty, H. D. Ochs, and J. M. Harlan. "The role of neutrophil membrane glycoprotein 150 (Gp-150) in neutrophil-mediated endothelial cell injury in vitro." Journal of Immunology 135, no. 1 (July 1, 1985): 537–43. http://dx.doi.org/10.4049/jimmunol.135.1.537.
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Abstract In this study we examined the importance of neutrophil adherence in neutrophil-mediated endothelial cell injury. Phorbol myristate acetate (PMA)-activated neutrophils from a patient with a congenital defect in neutrophil adherence (Gp-150 deficiency) and PMA-activated normal neutrophils pretreated with monoclonal antibody (MoAb) 60.3 were used. Both Gp-150-deficient and MoAb 60.3-treated normal neutrophils failed to adhere to cultured human umbilical vein endothelial cell (HEC) monolayers when activated by PMA (adherence less than 10% with patient and MoAb 60.3-treated cells compared with 53 +/- 3% with normal cells). The addition of PMA-activated normal neutrophils to 51Cr-labeled HEC monolayers failed to induce significant 51Cr release but did produce marked HEC detachment (percentage of detachment 50 +/- 3 at 6 hr). In marked contrast, PMA-activated Gp-150-deficient neutrophils failed to induce significant HEC detachment (percentage of detachment zero (0) at 6 hr). Moreover, the addition of MoAb 60.3 to normal neutrophils inhibited neutrophil-mediated HEC detachment in a time- and dose-dependent fashion. Non-lytic HEC detachment was determined to be largely oxygen radical independent, because PMA-activated chronic granulomatous disease neutrophils and PMA-activated normal neutrophils produced similar disruption of HEC monolayers. Soybean trypsin inhibitor, a chloromethylketone elastase inhibitor, and autologous serum all failed to inhibit neutrophil-mediated HEC detachment. From these studies there is no evidence that nonlytic HEC detachment by PMA-activated neutrophils is mediated by the neutrophil-derived proteases, elastase and cathepsin G. Neutrophil-mediated HEC detachment also required intact neutrophils, because postsecretory medium from PMA-activated normal neutrophils and a suspension of frozen-thawed PMA-activated normal neutrophils were without effect. These in vitro studies indicate that the neutrophil cell surface glycoprotein Gp-150 is required for nonlytic HEC detachment by intact PMA-activated neutrophils.
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Bargatze, R. F., S. Kurk, E. C. Butcher, and M. A. Jutila. "Neutrophils roll on adherent neutrophils bound to cytokine-induced endothelial cells via L-selectin on the rolling cells." Journal of Experimental Medicine 180, no. 5 (November 1, 1994): 1785–92. http://dx.doi.org/10.1084/jem.180.5.1785.
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Specific arrest of neutrophils in venules is central to their rapid accumulation during local inflammatory responses. Initial neutrophil rolling on endothelium is mediated by leukocyte L-selectin and the inducible vascular adhesion proteins P- and E-selectin. This rolling is a prerequisite for endothelial-dependent neutrophil arrest. Here we describe rolling of neutrophils on the surface of previously arrested neutrophils and demonstrate that this interaction involves L-selectin exclusively on rolling cells. The adherent neutrophil support of L-selectin-dependent neutrophil rolling in vivo can promote continuous and augmented leukocyte recruitment at sites of previous neutrophil accumulation.
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Nourshargh, S., and T. J. Williams. "Evidence that a receptor-operated event on the neutrophil mediates neutrophil accumulation in vivo. Pretreatment of 111In-neutrophils with pertussis toxin in vitro inhibits their accumulation in vivo." Journal of Immunology 145, no. 8 (October 15, 1990): 2633–38. http://dx.doi.org/10.4049/jimmunol.145.8.2633.
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Abstract The role of neutrophil chemoattractant receptors in neutrophil stimulation in vitro is well established, however, the precise mechanisms underlying local neutrophil accumulation at inflammatory sites in vivo have not been defined. A fundamental question that remains open is whether chemoattractants act on the endothelial cell or the neutrophil to initiate the process of neutrophil migration in vivo. To address this question we have investigated whether neutrophil accumulation in vivo can occur if chemoattractant receptor occupancy is uncoupled from neutrophil stimulation. For this purpose we have used pertussis toxin (PT) as the pharmacologic tool. We have investigated the effect of in vitro pretreatment of rabbit neutrophils with PT on their responses in vitro and on their accumulation in vivo. Pretreatment of rabbit neutrophils with PT inhibited FMLP- and C5a-, but not PMA- induced increases in CD18 expression, neutrophil adherence, and degranulation in vitro. This pretreatment procedure with PT inhibited the accumulation of radiolabeled neutrophils in vivo in response to intradermally injected FMLP, C5a, C5a des Arg, leukotriene B4, IL-8, and zymosan in rabbit skin. Further, in contrast to the in vitro results, PT inhibited the PMA-induced 111In-neutrophil accumulation in vivo. Interestingly, pretreatment of neutrophils with PT also inhibited accumulation in response to intradermally injected IL-1, despite the reports that IL-1 lacks neutrophil chemoattractant activity in vitro. Although the experimental techniques used cannot distinguish the different stages of neutrophil migration involved, these results suggest that the accumulation of neutrophils induced by local extravascular chemoattractants in vivo depends on a pertussis toxin-sensitive receptor operated event on the neutrophil itself. Further, PMA and IL-1 may release secondary chemoattractants in vivo.
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Hornick, Emma, Balaji Banoth, Ann Miller, Zeb Ralph Zacharias, Nidhi Jain, Mary E. Wilson, Katherine Gibson-Corley, et al. "Nlrp12 mediates adverse neutrophil recruitment during influenza virus infection." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 60.3. http://dx.doi.org/10.4049/jimmunol.200.supp.60.3.
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Abstract Exaggerated inflammatory responses during influenza A virus (IAV) infection are typically associated with severe disease. Neutrophils are among the immune cells that can drive this excessive and detrimental inflammation. In moderation, however, neutrophils are necessary for optimal viral control. In this study, we explore the role of the nucleotide-binding domain leucinerich repeat containing receptor (NLR) family member Nlrp12 in modulating neutrophilic responses during lethal IAV infection. Nlrp12−/− mice are protected from lethality during IAV infection and show decreased vascular permeability, fewer pulmonary neutrophils, and a reduction in levels of neutrophil chemoattractant CXCL1 in their lungs compared to wild-type (WT) mice. Nlrp12−/− neutrophils and dendritic cells (DCs) within the IAV-infected lungs produce less CXCL1 than their WT counterparts. Decreased CXCL1 production by Nlrp12−/− cells was not due to a difference in CXCL1 protein stability, but instead to a decrease in Cxcl1 mRNA stability. Together, these data demonstrate a previously unappreciated role for Nlrp12 in exacerbating the pathogenesis of IAV infection through the regulation of CXCL1 mediated neutrophilic responses.
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Mattila, Joshua, and JoAnne Flynn. "Neutrophils in granulomas from Mycobacterium tuberculosis-infected macaques express granzyme B in response to mycobacterial products and pro-inflammatory signals (INC7P.406)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 186.7. http://dx.doi.org/10.4049/jimmunol.192.supp.186.7.
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Abstract Inflammation is a critical component of tuberculosis (TB), and may contribute to a poor prognosis. The factors responsible for this inflammation are poorly studied. In addition, the role of neutrophils in TB, and whether neutrophils express granzyme B (grzB), a cytotoxic pro-apoptosis enzyme, is controversial. We examined neutrophils in peripheral blood (PB) and granulomas to determine if mycobacterial products or pro-inflammatory factors induce neutrophil grzB expression. PB neutrophils did not express grzB. In contrast, granuloma neutrophils expressed grzB and these cells contained more grzB than T cells. Elevated neutrophil, but not T cell, grzB expression correlated with higher tissue bacterial load. Perforin is required for T cell-mediated cytotoxicity but was not expressed by neutrophils. PB neutrophils upregulated grzB expression when infected with M. tuberculosis or stimulated with M. tuberculosis culture filtrate protein or LPS from E. coli, but not peptide antigens associated with T cell stimulation. Moreover, stimulated PB neutrophils secreted grzB in a perforin-independent process. GrzB was not bactericidal or bacteriostatic, suggesting secreted neutrophil grzB acts on extracellular targets, potentially enhancing neutrophil migration or regulating activation in other cell types. These data indicate M. tuberculosis-specific factors in granulomas upregulate neutrophil grzB expression and suggest a previously unappreciated aspect of neutrophil biology in TB.
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von Asmuth, E. J., C. J. van der Linden, J. F. Leeuwenberg, and W. A. Buurman. "Involvement of the CD11b/CD18 integrin, but not of the endothelial cell adhesion molecules ELAM-1 and ICAM-1 in tumor necrosis factor-alpha-induced neutrophil toxicity." Journal of Immunology 147, no. 11 (December 1, 1991): 3869–75. http://dx.doi.org/10.4049/jimmunol.147.11.3869.
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Abstract TNF-alpha can incite neutrophil-mediated endothelial cell damage and neutrophil H2O2 release. Both effects require adherent neutrophils. Using specific mAb, we showed in this in vitro study that the CD18 beta 2-chain and the CD11b alpha M-chain of the CD11/CD18 integrin heterodimer have a major role in both TNF-alpha-induced neutrophil-mediated detachment of human umbilical vein endothelial cells and H2O2 release by TNF-alpha-activated human neutrophils. In contrast to anti-CD18 mAb, which consistently prevented neutrophil activation, anti-CD11a mAb and two of three anti-CD11b mAb did not reduce endothelial cell detachment and neutrophil H2O2 release, although they decreased neutrophil adhesion to human umbilical vein endothelial cells. mAb 904, directed against the bacterial LPS binding region of CD11b, reduced endothelial cell detachment for about 40% and neutrophil H2O2 release for more than 50%, demonstrating that CD11b/CD18 is engaged in TNF-induced neutrophil activation. Dependence on CD11b/CD18 could not be overcome by CD18-independent anchoring of neutrophils via PHA. Additionally, neither induction of increased expression of the endothelial cell adhesion molecules ICAM-1 and ELAM-1, nor subsequent addition of specific mAb, influenced endothelial cell injury or H2O2 release by TNF-activated neutrophils. Interaction with ICAM-1 and ELAM-1 therefore appears not to induce additional activation of TNF-stimulated neutrophils. These studies suggest that a specific, CD11b/CD18-mediated signal, instead of adherence only, triggers toxicity of TNF-activated neutrophils.
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Nandi, Bisweswar, and Samuel M. Behar. "Regulation of neutrophils by interferon-γ limits lung inflammation during tuberculosis infection." Journal of Experimental Medicine 208, no. 11 (October 3, 2011): 2251–62. http://dx.doi.org/10.1084/jem.20110919.
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Resistance to Mycobacterium tuberculosis requires the host to restrict bacterial replication while preventing an over-exuberant inflammatory response. Interferon (IFN) γ is crucial for activating macrophages and also regulates tissue inflammation. We dissociate these two functions and show that IFN-γ−/− memory CD4+ T cells retain their antimicrobial activity but are unable to suppress inflammation. IFN-γ inhibits CD4+ T cell production of IL-17, which regulates neutrophil recruitment. In addition, IFN-γ directly inhibits pathogenic neutrophil accumulation in the infected lung and impairs neutrophil survival. Regulation of neutrophils is important because their accumulation is detrimental to the host. We suggest that neutrophilia during tuberculosis indicates failed Th1 immunity or loss of IFN-γ responsiveness. These results establish an important antiinflammatory role for IFN-γ in host protection against tuberculosis.
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Silva, Carla Lima, Janaina Cardoso dos Santos, Lidiane Zito Grund, Carla Simone Seibert, Elineide Eugenio Marques, Anderson Brito Soares, Valerie F. Quesniaux, Bernhard Ryffel, and Monica Lopes-Ferreira. "Stingray venom activates IL-33 producing cardiomyocytes, but not mast cell, to promote acute neutrophil-mediated injury." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 170.1. http://dx.doi.org/10.4049/jimmunol.200.supp.170.1.
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Abstract One of the hallmarks of acute inflammation is neutrophil infiltration of tissues. We investigated molecular mechanisms implicated in acute neutrophilic inflammation induced by the venom of a freshwater stingray (Potamotrygon cf. henlei) in mice. Ray venom induced early mobilization of neutrophil in the microvasculature of cremaster mice and infiltration of the peritoneal cavity 2 hours after injury, in a dose-response manner. IL-1b, IL-6, TNF-a, and KC were produced. The neutrophilic infiltration did not occur in mice with ST2 receptor and MyD88 adapters neutralized, or in those with PI3K and p38 MAPK signaling blocked. Drastic reduction of neutrophil infiltration to peritoneal cavities was observed in ST2−/−, TLR2/TLR4−/−, MyD88−/−, TRIF−/− and IL-17A−/− mice, and a partial reduction was observed in IL-18R−/− mice. Mast cell Kit W(sh)/W(sh)-, AHR-, NLRP3-, ICE-, IL-1b-, P2RX7-, CD39-, IL-17RA-, and TBX21 KO mice retain the ability to induce neutrophilia in peritoneal cavity after ray venom injection. IL-6 and TNF-a alone were insufficient for promote neutrophilia in the absence of ST2 signaling. Finally, abundant production of IL-33 by cardiomyocytes was observed. These results refine our understanding of the importance of the IL-33/ST2 axis and IL-33-producing cardiomyocytes in the early acute neutrophilia induced by freshwater stingray venoms.
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Jagels, M. A., and T. E. Hugli. "Neutrophil chemotactic factors promote leukocytosis. A common mechanism for cellular recruitment from bone marrow." Journal of Immunology 148, no. 4 (February 15, 1992): 1119–28. http://dx.doi.org/10.4049/jimmunol.148.4.1119.
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Abstract We investigated cellular responses in a rabbit to i.v. administration of five established chemotactic factors (leukotriene B4 (LTB4), platelet-activating factor (PAF), C5a, N-Formyl-Met-Leu-Phe (F-MLF), and IL-8), and each exerted a characteristic effect on circulating white blood cell levels. All five factors induced a rapid and transient leukopenia. The blood was nearly devoid of circulating neutrophils 5 min after administration of each chemotactic factor. Other leukocytes were also variably depleted during the leukopenic phase, including eosinophils, basophils, monocytes, and lymphocytes. The lymphocyte numbers remained significantly depressed (approximately 30%) for as long as 3 h after administration of PAF or f-MLF. Each chemotactic factor produced a marked neutrophilia (i.e., 250-400% of baseline levels) after the initial leukopenia. Eosinophil numbers were elevated along with the neutrophil response in the C5a- and LTB4-treated animals. Basophil levels were significantly elevated only in LTB4-treated animals. The cellular response to PAF, f-MLF, and IL-8 appeared to be specific for the neutrophils. The kinetic profiles of the neutrophilia induced by PAF (10 micrograms/kg) or f-MLF (2.5 micrograms/kg) were similar, with maximal responses occurring 3 to 4 h after administration. In contrast, LTB4 (10 micrograms/kg), IL-8 (2.5 micrograms/kg), and C5a (5 micrograms/kg) induced a more rapid neutrophilia, with peak responses occurring 1 to 1.5 h after injection, and remaining elevated for 3 to 4 h. In all animals the neutrophilia was accompanied by a relative increase in the number of nonsegmented neutrophils (bands), suggesting that a major component of leukocytosis is caused by the release of bone marrow reserves. Phenidone (10 mg/kg), a dual cyclooxygenase/5-lipoxygenase inhibitor, affected neither the neutropenia nor the neutrophilia induced by C5a, f-MLF, or PAF. The protein synthesis inhibitor actinomycin D also failed to suppress neutrophil responses induced by either C5a or PAF. These results suggest that leukocytosis is a common response induced by all neutrophil chemotactic factors. Leukocytosis appears to be a direct result of the dynamic adaptive response of neutrophils to chemotactic factor stimulation without involvement of a secondary mediator system.
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Gordy, Claire, Heather Pua, Gregory D. Sempowski, and You-Wen He. "Regulation of steady-state neutrophil homeostasis by macrophages." Blood 117, no. 2 (January 13, 2011): 618–29. http://dx.doi.org/10.1182/blood-2010-01-265959.
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Abstract The timely clearance of apoptotic neutrophils from inflammation sites is an important function of macrophages; however, the role of macrophages in maintaining neutrophil homeostasis under steady-state conditions is less well understood. By conditionally deleting the antiapoptotic gene cellular FLICE-like inhibitory protein (C-FLIP) in myeloid cells, we have generated a novel mouse model deficient in marginal zone and bone marrow stromal macrophages. These mice develop severe neutrophilia, splenomegaly, extramedullary hematopoiesis, decreased body weight, and increased production of granulocyte colony-stimulating factor (G-CSF) and IL-1β, but not IL-17. c-FLIPf/f LysM-Cre mice exhibit delayed clearance of circulating neutrophils, suggesting that failure of macrophages to efficiently clear apoptotic neutrophils causes production of cytokines that drive excess granulopoiesis. Further, blocking G-CSF but not IL-1R signaling in vivo rescues this neutrophilia, suggesting that a G-CSF–dependent, IL-1β–independent pathway plays a role in promoting neutrophil production in mice with defective clearance of apoptotic cells.
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Weisbart, R. H. "An antibody that binds a neutrophil membrane protein, ERp72, primes human neutrophils for enhanced oxidative metabolism in response to formyl-methionyl-leucyl-phenylalanine. Implications for ERp72 in the signal transduction pathway for neutrophil priming." Journal of Immunology 148, no. 12 (June 15, 1992): 3958–63. http://dx.doi.org/10.4049/jimmunol.148.12.3958.
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Abstract Human neutrophils are primed by cytokines for enhanced oxidative metabolism in response to chemotactic factors, but the signal transduction pathways for cytokine activation and priming are unknown. Neutrophil priming may play an important role in mechanisms of host defense and inflammatory responses associated with autoimmune diseases. A rabbit antibody was produced that reacted with human neutrophils and induced priming in response to the chemoattractant, FMLP. The protein responsible for neutrophil priming in response to binding antibody was identified in a neutrophil cDNA library by expression cloning. The cloned protein absorbed the neutrophil-priming activity from rabbit serum. Furthermore, antibody priming activity was recovered by elution from the cloned protein. The gene for the protein associated with neutrophil priming was sequenced and identified as the endoplasmic reticulum protein, ERp72, which contains three copies of the active site sequences of protein disulfide isomerase. The antibody that primed neutrophils was shown to bind ERp72 in neutrophil membranes by immunoprecipitation of the same 72-kDa protein from neutrophils as a known antibody to ERp72. These studies implicate ERp72 in the signal transduction pathway for priming human neutrophils.
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Cowan, Catharine, Rujuan Dai, Bettina Heid, and S. Ahmed. "Phenotypic and functional characterization of neutrophils from lupus-prone mice (BA4P.223)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 46.14. http://dx.doi.org/10.4049/jimmunol.192.supp.46.14.
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Abstract Neutrophils constitute a critical component of cellular immunity that eliminate infectious organisms through oxidative burst, phagocytosis and the formation of neutrophil extracellular traps (NETs). Recently it has been reported that neutrophils contribute to autoimmunity through NET formation and interactions with auto-reactive immune cells. Our goal is to characterize phenotypic and functional properties of neutrophils in mouse models of systemic lupus (SLE) to determine if and how neutrophil dysregulation occurs. Using flow cytometry we have measured neutrophil populations in healthy control and diseased SLE mouse models. We found neutrophils are consistently increased in the spleen of MRL-Faslpr, C57BL/6-Faslpr and NZBWF1 lupus mice compared to controls. Further characterization of neutrophil functions including phagocytosis, reactive oxygen production, NET formation, protease activity and histone citrullination indicate increased DNA release, increased citrullination and alterations in serine protease activity in lupus neutrophils. Differences in the results between the NZBWF1 and MRL-Faslpr models suggest the background genetics play a role in neutrophil dysregulation in these two models. Ultimately we hope to understand the cause of altered neutrophil function in mouse models of SLE, whether they contribute to lupus disease progression, and hopefully develop newer targeted therapies for lupus.
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Kim, Nancy D., Richard C. Chou, Edward Seung, Andrew M. Tager, and Andrew D. Luster. "A unique requirement for the leukotriene B4 receptor BLT1 for neutrophil recruitment in inflammatory arthritis." Journal of Experimental Medicine 203, no. 4 (March 27, 2006): 829–35. http://dx.doi.org/10.1084/jem.20052349.
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Neutrophil recruitment into tissue plays an important role in host defense and disease pathogenesis, including the inflammatory arthritides. A multitude of diverse chemoattractants have been implicated in neutrophil recruitment, suggesting that they have overlapping functions in mediating this critical biological response. However, here we demonstrate a unique, non-redundant role for the leukotriene B4 receptor BLT1 in mediating neutrophil recruitment into the joint in the K/BxN mouse model of inflammatory arthritis. We demonstrate that neutrophil expression of BLT1 was absolutely required for arthritis generation and chemokine production in this model, and that specific BLT1 inhibition reversed established disease. Adoptive transfer of wild-type (WT) neutrophils restored arthritis and chemokine production in BLT1−/− mice. Surprisingly, the primary effect of the transferred WT neutrophils into BLT1−/− mice was to promote the entry of endogenous BLT1−/− neutrophils into the joints of these mice. However, continued joint inflammation was dependent on the presence of WT neutrophils, indicating an ongoing specific requirement for BLT1-activated neutrophils in mediating BLT1−/− neutrophil recruitment by other chemoattractants. These experiments demonstrate that neutrophil BLT1 functions in a novel and essential non–cell-autonomous manner to enable the recruitment of additional neutrophils not expressing this receptor, thereby amplifying the inflammatory response in autoantibody-induced arthritis.
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SAHA, PIU, Beng San Yeoh, Rodrigo A. Olvera, Xia Xiao, Deepika Awasthi, Vishal Singh, Madhu Dikshit, Yanming Wang, and MATAM VIJAY-KUMAR. "Bacterial Siderophores Hijack Neutrophil Functions." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 151.13. http://dx.doi.org/10.4049/jimmunol.198.supp.151.13.
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Abstract Neutrophils are primary immune cells that respond to inflammation and eliminate microbial transgression. Yet, E. coli have been reported to bloom during gut inflammation despite the heightened neutrophil activity. The survivability of E. coli in inflamed gut are not completely understood, although their production of enterobactin (Ent; a siderophore) to circumvent inflammation-induced iron scarcity may be one of the potential mechanisms. Herein, we report that Ent is not only an iron chelator, but is an immune-regulator that counter an array of neutrophil functions. We showed that Ent inhibited PMA and LPS induced generation of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) in both mouse and human neutrophils. Ent also impaired the degranulation of primary granules, inhibited phagocytosis and bactericidal activity of neutrophils, but without affecting their migration and chemotaxis. Molecular analysis revealed that Ent can chelate intracellular labile iron that are required for neutrophil oxidative responses. Other siderophores (pyoverdine, ferrichrome, deferoxamine) likewise inhibited ROS and NETs in neutrophils, thus indicating that the chelation of iron may, in part, explain their inhibitory effects. To counter iron theft by Ent, neutrophils rely on the siderophore-binding protein lipocalin 2 (Lcn2) in a ‘tug-of-war’ for iron. The inhibition of neutrophil ROS and NETs by Ent was augmented in Lcn2-deficient than WT neutrophils, but rescued by the exogenous addition of recombinant Lcn2. Taken together, our findings illustrate the novel concept that microbial siderophore’s iron scavenging property may serve as an antiradical defense system, that neutralize immune functions of neutrophils.
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von Asmuth, E. J., and W. A. Buurman. "Endothelial cell associated platelet-activating factor (PAF), a costimulatory intermediate in TNF-alpha-induced H2O2 release by adherent neutrophil leukocytes." Journal of Immunology 154, no. 3 (February 1, 1995): 1383–90. http://dx.doi.org/10.4049/jimmunol.154.3.1383.
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Abstract TNF is a strong secretagogue for surface-contacting neutrophils. During inflammation, endothelium offers the first substrate for neutrophil adherence and for modulation of the toxic response of neutrophils to soluble agonists such as TNF. In this in vitro study, evidence is presented that endothelium participates actively in TNF-induced neutrophil respiratory burst activity by expressing platelet-activating factor (PAF) in response to initial neutrophil H2O2 release. Three findings are shown that favor such a mechanism. First, PAF receptor antagonists reduced H2O2 release by TNF-activated neutrophils placed on endothelium approximately by 50%, whereas H2O2 responses by neutrophils placed on serum-coated polystyrene remained intact. Second, preincubation of HUVEC with known PAF-inducing agents PMA, H2O2, and thrombin, followed by fixation, enhanced neutrophil H2O2 release in response to TNF. H2O2 release by these neutrophils was sensitive to the presence of PAF receptor antagonists, whereas H2O2-release from neutrophils placed on fixed nonactivated endothelial cells was not. Finally, replacing endothelium by monolayers of human renal cortical epithelial cells and human fibroblasts, cells that are known to produce less PAF than endothelial cells, reduced the effect of PAF receptor antagonists. P-selectin expression and IL-8 release, two other ways by which endothelial cells might influence H2O2-release by TNF preincubated neutrophils, were examined in parallel, and were found not to influence TNF-induced neutrophil H2O2-release. We conclude that during neutrophil-endothelial interaction in inflammation, endothelium modulates the toxic response of neutrophils to TNF. Endothelial cell-associated PAF, but not endothelial cell IL-8 release and P-selectin expression, is likely to participate in TNF-induced neutrophil respiratory burst activity.
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Abdelrahman, Zakia, Lobna Abou-Shamaa, Nadia Sadek, Abeer El hadidy, and Bassam Kabary. "Immunomodulatory effect of pentoxifylline and stored blood on neutrophil functions (TRAN3P.862)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 202.1. http://dx.doi.org/10.4049/jimmunol.192.supp.202.1.
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Abstract Background: Allogeneic blood transfusions expose a patient to many soluble and cell-bound antigens, expressed on viable and decaying cells. Blood transfusion is a risk factor for many inflammatory processes. Its supernatant fraction has been proven to activate neutrophils Objective: To evaluate the immunomodulatory effects of stored blood supernatant and pentoxifylline on neutrophil functions Methods: Neutrophils(N) of recipient blood samples were incubated with supernatant stored blood (35 days blood bags) (N+S)or fMLP(N+F) or(N+S+F).Neutrophils incubated with PTX (N+P),(N+S+P), (N+F+P) and (N+S+F+P) .Also neutrophil functions studied by CD11b expression, phagocytosis, respiratory burst and apoptosis Results: Neutrophil expression of CD11b ,phagocytic activity, neutrophil intracellular superoxide anion production and neutrophil apoptosis in presence of (N+F), (N+S) and (N+F+S) were significantly increased in comparing to baseline. Combined incubation with (N+ F + S) induced significant increase in neutrophil functions than (N+F) or (N+S). PTX significantly attenuated neutrophil functions induced by (N+F), (N+S), ( N+S+F) Conclusion: Stored blood supernatant has an immunomodulatory effects on neutrophil function(priming them) through CD11b expression, phagocytosis, respiratory burst and apoptosis. PTX downregulates these neutrophil functions. PTX may have therapeutic potential in inflammatory injury due to blood transfusion.
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Issekutz, T. B., M. Miyasaka, and A. C. Issekutz. "Rat blood neutrophils express very late antigen 4 and it mediates migration to arthritic joint and dermal inflammation." Journal of Experimental Medicine 183, no. 5 (May 1, 1996): 2175–84. http://dx.doi.org/10.1084/jem.183.5.2175.
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Blood neutrophils contribute to joint injury in human and experimental models of arthritis. Neutrophil migration out of the blood in joint inflammation involves both the CD18 (beta2) integrins and a CD18 integrin-independent pathway. To investigate this migration, radiolabeled rat blood neutrophils were used to measure neutrophil accumulation in the inflamed joints of rats with adjuvant arthritis and the role of leukocyte integrins in migration to these joints and to dermal inflammation was determined. Neutrophils migrated rapidly (<2 h) to the inflamed joints 14-18 d after immunization with adjuvant. Blocking monoclonal antibodies (mAbs) to both LFA-1 and Mac-1 together, as well as a mAb to CD18, inhibited neutrophil accumulation in the inflamed joints by 50-75%. However, migration to dermal inflammation induced by C5a(des Arg)' tumor necrosis factor alpha, lipopolysaccharide, and poly-inosine:cytosine was inhibited by approximately 90%. Flow cytometry revealed the expression of low levels of very late antigen 4 (VLA-4) on nearly all rat blood neutrophils. Treatment with anti-VLA-4 plus anti-LFA-1 but neither mAb alone, strongly (60-75%) inhibited neutrophil accumulation in arthritic joints. This mAb combination also inhibited neutrophil migration to dermal inflammatory reactions by 30-70%. Blocking VLA-4 together with the CD18 integrins inhibited neutrophil accumulation by 95-99%, virtually abolishing neutrophil accumulation in cutaneous inflammation. A similar blockade of VLA-4 and CD18 decreased neutrophil accumulation in the inflamed joints by 70-83%, but a significant portion of the neutrophil accumulation to these joints still remained. In conclusion, rat blood neutrophils express functional VLA-4 that can mediate neutrophil migration to both inflamed joints and dermal inflammatory sites. VLA-4 appears to be able to substitute for LFA-1 in this migration and is particularly important for accumulation in inflamed joints. However, there exists an additional CD18- and VLA-4-independent pathway of neutrophil migration to arthritic joints that is not involved in acute dermal inflammation.
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Barnard, J. W., M. G. Biro, S. K. Lo, S. Ohno, M. A. Carozza, M. Moyle, H. R. Soule, and A. B. Malik. "Neutrophil inhibitory factor prevents neutrophil-dependent lung injury." Journal of Immunology 155, no. 10 (November 15, 1995): 4876–81. http://dx.doi.org/10.4049/jimmunol.155.10.4876.
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Abstract Neutrophil inhibitory factor (NIF) is a recently cloned 41-kDa protein from the canine hookworm that binds CD11b/CD18 and inhibits CD11b/CD18-dependent neutrophil adhesion. We evaluated NIF's effects on neutrophil-dependent lung injury in guinea pigs. Pulmonary vascular endothelial CD54 (ICAM-1) was induced in buffer-perfused lungs by 90-min exposure to 1000 U/ml TNF-alpha. Human neutrophils (2 x 10(7)) were added to the perfusate and activated by 5 x 10(-9) PMA; in some lungs, the neutrophils were pretreated with NIF (100 nM) before their addition to the perfusate. Lung injury was assessed by wet:dry weight ratio, and neutrophil uptake by lung myeloperoxidase (MPO) activity. HUVEC exposed to TNF-alpha for 90 min were assayed for neutrophil adhesion, and we compared PMA-stimulated neutrophil adhesion to endothelial cells and fibrinogen-coated plates. PMA-induced pulmonary edema (lung wet:dry ratio increased from 8.8 +/- 0.7 to 18.8 +/- 4.4) was inhibited by NIF (10.0 +/- 1.0). Lung MPO activity concomitantly decreased from 17.1 +/- 6.1 to 8.7 +/- 1.8 U/mg dry lung tissue in the NIF-treated group, similar to controls (6.9 +/- 2.0). Endothelial monolayer experiments confirmed that NIF reduced neutrophil adherence (basal adhesion of 11 +/- 3% increased to 30 +/- 5% with TNF-alpha pretreatment of endothelial cells, an increase that was reduced to 10 +/- 4% with NIF). Moreover, NIF prevented PMA-induced neutrophil adhesion to fibrinogen, a CD11b/CD18-dependent event, but produced a smaller decrease in adherence to endothelial cells, which also involves CD11a/CD18 integrins. These studies indicate that NIF prevents neutrophil-dependent lung vascular injury by inhibiting neutrophil adhesion to the TNF-alpha-activated endothelium.
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O'Flaherty, J. T., D. Jacobson, and J. Redman. "Mechanism involved in the mobilization of neutrophil calcium by 5-hydroxyeicosatetraenoate." Journal of Immunology 140, no. 12 (June 15, 1988): 4323–28. http://dx.doi.org/10.4049/jimmunol.140.12.4323.
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Abstract 5-Hydroxyeicosatetraenoate (5-HETE), like leukotriene B4 and platelet-activating factor, stimulated human polymorphonuclear neutrophils to mobilize intracellular calcium. The three compounds acted through mechanisms that were inhibited by pertussis toxin, cholera toxin, and PMA. Each agonist, furthermore, desensitized (or down-regulated) the neutrophil's calcium mobilization response to a second challenge with the same agonist. However, 5-HETE and leukotriene B4 had little or no activity in cross-desensitizing neutrophil responses to each other or to platelet-activating factor. Furthermore, 5-HETE interfered minimally or not at all with the binding of radiolabeled leukotriene B4 and platelet-activating factor to their respective receptors on neutrophils. Thus, 5-HETE mobilizes neutrophil calcium by a mechanism different from those used by leukotriene B4 and platelet-activating factor. This mechanism appears to involve specific 5-HETE receptors that couple to pertussis toxin-inhibitable, GTP-binding proteins.
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Mattila, Joshua, Tao Sun, and JoAnne Flynn. "Neutrophils in pulmonary granulomas from Mycobacterium tuberculosis-infected cynomolgus macaques upregulate granzyme B expression in response to mycobacterial products and pro-inflammatory signals (P3058)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 125.7. http://dx.doi.org/10.4049/jimmunol.190.supp.125.7.
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Abstract The role of neutrophils in tuberculosis (TB) and whether neutrophils can express granzyme B (grzB), a pro-apoptotic enzyme associated with cytotoxic T cells, are controversial. We compared neutrophil and T cell grzB expression in peripheral blood and pulmonary granulomas from cynomolgus macaques to better understand the biology of neutrophils in TB. Flow cytometric analysis indicated that T cells were the dominant grzB-producing cell in unstimulated peripheral blood whereas very few neutrophils expressed grzB. Similarly, neutrophil-depleted PBMCs had significantly more grzB activity than neutrophils. Stimulation with M. tuberculosis culture filtrate, but not peptide antigens, caused neutrophil upregulation of grzB to levels equivalent to stimulation with LPS from E. coli. In contrast to peripheral blood, we found that more neutrophils than T cells expressed grzB in granulomas. Granuloma neutrophils contained significantly more grzB than T cells with respect to the cross-sectional area of the cell occupied by grzB and number of granules per cell. Perforin, a protein required for target cell pore formation and grzB-mediated cytotoxicity, was found on T cells but not neutrophils, suggesting that neutrophils in granulomas may not use grzB as a cytotoxic effector. These data indicate mycobacterial products in the pro-inflammatory environment of granulomas upregulate neutrophil grzB expression and suggest a previously unappreciated aspect of neutrophil biology in TB.
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SenGupta, Shuvasree, Silvia M. Uriarte, Robert K. Ernst, and Thomas C. Mitchell. "Possible link between cystic fibrosis specific lipid A adaptations by Pseudomonas aeruginosa and disease associated hyperinflammation." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 65.23. http://dx.doi.org/10.4049/jimmunol.196.supp.65.23.
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Abstract Pseudomonas aeruginosa infection in cystic fibrosis (CF) lung disease causes airway neutrophilia and hyperinflammation without being cleared effectively. We evaluated the immunostimulatory activities of lipid A variants synthesized by P. aeruginosa (PA) exclusively in CF patients to determine if they correlate with CF disease severity and progression. One third of the PA isolates from CF patients with late severe stage express a unique hepta–acylated lipid A; hepta-1855 (m/z=1855) isoform. In primary cell cultures, we found that hepta-1855 functioned as a potent TLR4 agonist by priming neutrophil respiratory burst and stimulating strong chemokine response (interleukin-8 or IL-8) from monocytes and neutrophils. Hepta-1855 also had a potent survival effect on neutrophils. However, it was less efficient in inducing neutrophil granule exocytosis and was also less potent in triggering pro-inflammatory TNF-α response from monocytes. A precursor hexa-1616, found in hepta-1855 containing LPS mixtures, did not have direct inflammatory activity on neutrophils but induced moderate IL-8 response. Together, our data suggest a potential contribution of hepta-1855 to late CF stage associated excessive inflammatory burden by recruiting neutrophils via IL-8 and promoting their maintenance through its survival effect. Being a chemoattractant stimulus, hexa-1616, may serve as an accomplice to hepta-1855. Moreover, the relative inefficiency of hepta-1855 in triggering degranulation may partly explain the persistence of PA in CF disease in spite of neutrophil dominated inflammation.
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Zeng, Jiajia, Yueyue Xu, Lu Tan, Xiaoyu Zha, Shuaini Yang, Hong Zhang, Yuqing Tuo, et al. "IL-21/IL-21R Regulates the Neutrophil-Mediated Pathologic Immune Response during Chlamydial Respiratory Infection." Mediators of Inflammation 2022 (June 1, 2022): 1–14. http://dx.doi.org/10.1155/2022/4322092.
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IL-21/IL-21R was documented to participate in the regulation of multiple infection and inflammation. During Chlamydia muridarum (C. muridarum) respiratory infection, our previous study had revealed that the absence of this signal induced enhanced resistance to infection with higher protective Th1/Th17 immune responses. Here, we use the murine model of C. muridarum respiratory infection and IL-21R deficient mice to further identify a novel role of IL-21/IL-21R in neutrophilic inflammation. Resistant IL-21R-/- mice showed impaired neutrophil recruitment to the site of infection. In the absence of IL-21/IL-21R, pulmonary neutrophils also exhibited reduced activation status, including lower CD64 expression, MPO activity, and neutrophil-produced protein production. These results correlated well with the decrease of neutrophil-related chemokines (KC and MIP-2), inflammatory cytokines (IL-6, IL-1β, and TNF-α), and TLR/MyD88 pathway mediators (TLR2, TLR4, and MyD88) in infected lungs of IL-21R-/- mice than normal mice. Complementarily, decreased pulmonary neutrophil infiltration, activity, and levels of neutrophilic chemotactic factors and TLR/MyD88 signal in infected lungs can be corrected by rIL-21 administration. These results revealed that IL-21/IL-21R may aggravate the neutrophil inflammation through regulating TLR/MyD88 signal pathway during chlamydial respiratory infection.
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Ogilvie, A. C., C. E. Hack, J. Wagstaff, G. J. van Mierlo, A. J. Erenberg, L. L. Thomsen, K. Hoekman, and E. M. Rankin. "IL-1 beta does not cause neutrophil degranulation but does lead to IL-6, IL-8, and nitrite/nitrate release when used in patients with cancer." Journal of Immunology 156, no. 1 (January 1, 1996): 389–94. http://dx.doi.org/10.4049/jimmunol.156.1.389.
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Abstract The use of IL-1 in humans is associated with dose-limiting toxicity which resembles that of TNF-alpha or IL-2. Activation of neutrophils is thought to contribute to the toxicity caused by these two cytokines. We studied the effect of IL-1 in vivo on changes in neutrophil numbers and neutrophil degranulation as well as on the formation of neutrophil agonists, such as complement activation products, and on levels of TNF, IL-6, IL-8, and nitrite/nitrate (as a measure of nitric oxide production). Six patients with metastatic melanoma were treated with 3 ng/kg recombinant human IL-1 beta daily. One hour after the start of the 30-min IL-1 infusion, which caused mild cardiovascular toxicity, plasma levels of IL-6 reached a peak of 25 +/- 9 ng/L (mean +/- SEM), IL-8 reached a peak of 311 +/- 100 ng/L at 2 h, and nitrite/nitrate peaked after 10 h to 89 +/- 27 mumol/L. IL-1 did not induce significant changes in plasma levels of TNF or of the complement activation products C3a and C4b/c. Although IL-1 induced neutrophilia, levels of elastase and lactoferrin did not change. The failure of IL-1 to degranulate neutrophils was confirmed in an ex vivo model with whole blood culture in which doses of up to 100 microgram/L IL-1 beta or IL-1 alpha failed to induce significant elastase or lactoferrin release, whereas TNF, tested as a positive control, was able to do so. These results demonstrate that, unlike TNF, IL-1 does not cause neutrophil degranulation in man, despite its ability to cause neutrophilia and the rapid release of IL-6, IL-8, and nitrite/nitrate.
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Christofidou-Solomidou, M., M. T. Nakada, J. Williams, W. A. Muller, and H. M. DeLisser. "Neutrophil platelet endothelial cell adhesion molecule-1 participates in neutrophil recruitment at inflammatory sites and is down-regulated after leukocyte extravasation." Journal of Immunology 158, no. 10 (May 15, 1997): 4872–78. http://dx.doi.org/10.4049/jimmunol.158.10.4872.
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Abstract Platelet endothelial cell adhesion molecule-1 (PECAM-1), a member of the Ig superfamily, is found on endothelial cells and neutrophils, and has been shown to be involved in the migration of leukocytes across the endothelium. Although studies have supported a role for endothelial PECAM-1 in this process, the participation of neutrophil PECAM-1 in vivo has not been unambiguously demonstrated. Therefore, to examine the involvement of neutrophil PECAM-1 in leukocyte recruitment, we studied the effect of a blocking Ab against murine PECAM-1 on neutrophil recruitment in an established model of murine peritonitis and in a murine model for studying leukocyte-endothelial interactions involving the human vasculature. These studies not only confirmed that neutrophil PECAM-1 is important in the accumulation of neutrophils at inflammatory sites, but that extravasated neutrophils displayed decreased surface expression of PECAM-1. In vitro, the surface expression of murine neutrophil PECAM-1 was not decreased significantly by inflammatory mediators, but was reduced after transendothelial migration. These studies, consistent with previous in vitro observations, confirm that neutrophil PECAM-1, as well as endothelial PECAM-1, is involved in the recruitment of neutrophils into inflammatory sites in vivo, and suggest that the expression of neutrophil PECAM-1 is down-regulated after extravasation into inflamed tissues possibly as a result of engagement of its ligand.
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Warheit-Niemi, Helen I., Gabrielle P. Huizinga, Summer J. Edwards, Yizhou Wang, Susan K. Murray, David N. O’Dwyer, and Bethany B. Moore. "Fibrotic Lung Disease Alters Neutrophil Trafficking and Promotes Neutrophil Elastase and Extracellular Trap Release." ImmunoHorizons 6, no. 12 (December 1, 2022): 817–34. http://dx.doi.org/10.4049/immunohorizons.2200083.
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Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible disease characterized by collagen deposition within the interstitium of the lung. This impairs gas exchange and results in eventual respiratory failure. Clinical studies show a correlation between elevated neutrophil numbers and IPF disease progression; however, the mechanistic roles neutrophils play in this disease are not well described. In the present study, we describe alterations to the trafficking and function of neutrophils after the development of fibrosis. We observed increased numbers of total and aged neutrophils in peripheral tissues of fibrotic mice. This appeared to be driven by an upregulation of neutrophil chemokine Cxcl2 by lung cells. In addition, neutrophil recruitment back to the bone marrow for clearance appeared to be impaired, because we saw decreased aged neutrophils in the bone marrow of fibrotic mice. Neutrophils in fibrosis were activated, because ex vivo assays showed increased elastase and extracellular trap release by neutrophils from fibrotic mice. This likely mediated disease exacerbation, because mice exhibiting a progressive disease phenotype with greater weight loss and mortality had more activated neutrophils and increased levels of extracellular DNA present in their lungs than did mice with a nonprogressive disease phenotype. These findings further our understanding of the dynamics of neutrophil populations and their trafficking in progressive fibrotic lung disease and may help inform treatments targeting neutrophil function for patients with IPF experiencing disease exacerbation in the future.
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Jun, Hyun Sik, Goo-Young Kim, Joon Hyun Kwon, and Janice Chou. "Aberrant expression of CD11b and CD11a underlies impaired neutrophil adhesion in glucose-6-phosphate transporter-deficient mice." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 50.1. http://dx.doi.org/10.4049/jimmunol.196.supp.50.1.
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Abstract Neutrophils play an essential role in defense against intruding microorganisms. They are produced in great number in the bone marrow and circulate in blood where they are found in a quiescent state. In response to inflammatory stimuli, neutrophils take different steps-rolling, adhesion, and transmigration-to migrate towards inflammation sites. In this study, we investigated the underlying mechanisms of impaired neutrophil adhesion in glycogen storage disease type Ib (GSD-Ib) which is caused by a deficiency of the glucose-6-phosphate transporter (G6PT). GSD-Ib is characterized not only by disrupted glucose homeostasis but also by neutropenia and neutrophil dysfunction. GSD-Ib mice were infused with a recombinant adeno-associated virus (rAAV) vector expressing human G6PT only in liver to increase their survival. Unlike control mice, GSD-Ib-rAAV mice manifested severe neutropenia in both blood and bone marrow and neutrophils of GSD-Ib-rAAV mice were defective in adhesion to tumor necrosis factor-a-treated epithelial cells and intercellular adhesion molecule 1 and fibrinogen. The β2-integrins including CD11a/CD18 and CD11b/CD18 are recognized as vital players in neutrophil recruitment. Consistent with impaired neutrophil adhesion, the expression of CD11a and CD11b were found to be decreased in neutrophils of GSD-Ib-rAAV mice, compared with that of control mice. Particularly neutrophils of GSD-Ib-rAAV mice showed increased proteolytic degradation of CD11b. Given the central role of β2-integrins in neutrophil adhesion, this alternation of CD11a and CD11b molecules and their effect on neutrophil adhesion probably define a molecular mechanism to neutrophil dysfunction manifested in GSD-Ib.
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Dean, Kristin T., Bockgie Jung, and Buka Samten. "Identification of N-formylated peptides as the neutrophilic chemotactic factors of Mycobacterium tuberculosis." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 148.19. http://dx.doi.org/10.4049/jimmunol.204.supp.148.19.
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Abstract Since tuberculosis (TB) remains a major cause of human death, it is urgent to understand the pathology of TB. Lung neutrophil infiltration initiates granuloma formation and is associated with disease severity. Though several cytokines and chemokines are associated with neutrophil infiltration in chronic inflammation, neutrophil chemotactic factors of Mycobacterium tuberculosis (Mtb) remain unexplored. Thus, we performed neutrophil chemotactic assays by culturing neutrophils of healthy human blood samples and mouse bone marrow in the upper chamber of a transwell plate with 5–8 μm pores with the culture filtrates of Mtb H37Rv (CF) in the lower chamber using N-formyl-met-leu-phe (fMLF), a bacterial neutrophil chemotactic tripeptide, as a positive control. The cell numbers in the lower chamber were determined by flow cytometry as a chemotactic indicator. Our results show that CF induced chemotaxis of both human and mouse neutrophils in an Mtb culture period dependent manner. Testing CF of 11 clinical isolates of Mtb also showed neutrophil chemotactic activity. Sulfasalazine, a formylated peptide receptor inhibitor, blocked chemotaxis of neutrophils, indicating the involvement of fPRs in CF induces chemotaxis of neutrophils. Mass spectrometry analysis of CF identified three candidate N-formylated heptapeptides. Authentication of the chemotactic activities of the identified peptides with synthetic mimetics confirmed their neutrophil chemotactic activities and indicated the requirement of N-formylation for their chemotactic activities. Thus, we have identified novel formylated peptides of Mtb with neutrophil chemotactic activities, and further studies are in progress to determine their significance in TB infection.
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Mårdh, Carina Kärrman, James Root, Mohib Uddin, Kristina Stenvall, Anna Malmgren, Kostas Karabelas, and Matthew Thomas. "Targets of Neutrophil Influx and Weaponry: Therapeutic Opportunities for Chronic Obstructive Airway Disease." Journal of Immunology Research 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/5273201.
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Neutrophils are important effector cells of antimicrobial immunity in an acute inflammatory response, with a primary role in the clearance of extracellular pathogens. However, in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), there is excessive infiltration and activation of neutrophils, subsequent production of reactive oxygen species, and release of serine proteases, matrix metalloproteinases, and myeloperoxidase—resulting in collateral damage as the cells infiltrate into the tissue. Increased neutrophil survival through dysregulated apoptosis facilitates continued release of neutrophil-derived mediators to perpetuate airway inflammation and tissue injury. Several target mechanisms have been investigated to address pathologic neutrophil biology and thereby provide a novel therapy for respiratory disease. These include neutrophil influx through inhibition of chemokine receptors CXCR2, CXCR1, and PI3Kγsignaling and neutrophil weaponry by protease inhibitors, targeting matrix metalloproteinases and neutrophil serine proteases. In addition, neutrophil function can be modulated using selective PI3Kδinhibitors. This review highlights the latest advances in targeting neutrophils and their function, discusses the opportunities and risks of neutrophil inhibition, and explores how we might better develop future strategies to regulate neutrophil influx and function for respiratory diseases in dire need of novel effective therapies.
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Powell, David W., Kenneth R. McLeish, Min Tan, Ryan M. Sheehan, Shirong Zheng, Dawn J. Caster, and Erik A. Korte. "A novel mechanism for enhanced neutrophil recruitment, retention, and podocyte damage in immune complex-mediated glomerular disease." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 124.29. http://dx.doi.org/10.4049/jimmunol.196.supp.124.29.
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Abstract Glomerulonephritis (GN) is characterized by immune complex deposition and ensuing inflammation within the glomerulus of the kidney. Frank J. Dixon, a pioneer in immunologic kidney disease research, reported in 1965 that injection of nephrotoxic antibodies in rats and rabbits resulted in proteinuria and glomerular accumulation of neutrophils, and that depletion of circulating neutrophils reduced this immune-mediated glomerular damage and proteinuria. In the decades since, studies have confirmed a role for glomerular neutrophil accumulation in human GN, but the mechanisms for neutrophil recruitment and neutrophil-directed injury have not been resolved. We previously reported genetic variants for a NF-κB inhibitor ABIN1 as risks for GN. Others also report that glomerular ABIN1 gene expression is altered in GN in mice and humans. Here we present that transgenic disruption of ABIN1 function results in exacerbated podocyte injury, glomerular expression of inflammatory mediators, and glomerular recruitment and retention of neutrophils in a mouse model of acute antibody-mediated GN. Moreover, a novel inhibitor of neutrophil granule release (SNAP23 peptide) also attenuates podocyte injury in this model. These in vivo findings are supported by in vitro experiments showing that secretome from homologous ABIN1 mutant podocytes activates neutrophil chemotaxis and granule release and neutrophil granule contents specifically disrupts cytoskeletal organization of ABIN1 mutant podocytes. These studies unfold a role for ABIN1 dysfunction in a novel neutrophil-mediated mechanism of podocyte injury in GN and presents inhibition of neutrophil granule release as a promising novel therapeutic direction for kidney inflammation.
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Erzurum, S. C., G. P. Downey, D. E. Doherty, B. Schwab, E. L. Elson, and G. S. Worthen. "Mechanisms of lipopolysaccharide-induced neutrophil retention. Relative contributions of adhesive and cellular mechanical properties." Journal of Immunology 149, no. 1 (July 1, 1992): 154–62. http://dx.doi.org/10.4049/jimmunol.149.1.154.
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Abstract Intravascular LPS rapidly induces neutrophil sequestration in pulmonary capillaries by mechanisms that, although currently unknown, must take into account the size difference between the neutrophil and capillary diameter. To determine whether LPS alters neutrophil stiffness, and hence the ability of neutrophils to traverse capillaries, neutrophil passage through pulmonary capillaries was modeled by passage through filters with 6.5-microns pores. LPS increased retention in the pores in a concentration-dependent fashion that required the presence of heat-inactivated platelet-poor plasma, and was evident as early as 10 min after stimulation. The effect of LPS on the structural properties of the neutrophil was then studied. LPS induced f-actin reorganization in neutrophils in the presence of plasma. Disruption of actin organization and assembly with cytochalasin D completely inhibited early LPS-induced retention and attenuated retention at later timepoints, indicating that LPS-stimulated retention depends on filament organization. LPS-induced actin assembly and retention were abrogated by an antibody directed against CD14, a putative LPS receptor. CD18-dependent adherence of neutrophils contributed significantly to retention only at later timepoints with no significant contribution to retention at 20 min as determined by inhibition of adherence with the mAb 60.3. Morphometric assessment of neutrophil accumulation in the lungs of rabbits given 1 microgram LPS showed a marked increase in apparent neutrophil number, which was unaltered by antibodies to CD18, suggesting that mechanisms other than adhesion may account for accumulation in vivo. Direct measurements showed that neutrophil stiffness increased with exposure to LPS in a fashion similar to LPS-induced retention and actin organization. Pretreatment of neutrophils with cytochalasin D attenuated the increased stiffness. These data suggest that reorganization of filamentous-actin induced by LPS leads to cell stiffening and retention in capillary-sized pores. Although the organization of f-actin continues to be important in retention at later time points, adherence of cells also contributes significantly to cell retention. The changes in mechanical properties of the neutrophil may be important in the sequestration of neutrophils in pulmonary capillaries noted in endotoxemia.
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Ibrahim, Safaa A., Arpita Kulshrestha, Gajendra K. Katara, and Kenneth D. Beaman. "Delayed neutrophil apoptosis is regulated by cancer associated a2 isoform vacuolar ATPase." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 76.15. http://dx.doi.org/10.4049/jimmunol.198.supp.76.15.
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Abstract Neutrophils are short life span cells but they can live for weeks in cancer tissues and promote tumor progression. Identifying cancer derived factors that enhance neutrophil survival will provide new targets for cancer therapy. A peptide from the N-terminal domain of a2- isoform vacuolar ATPase (a2NTD) is specifically secreted from cancer cells and promotes the neutrophil protumorigenic properties which in turn, enhance tumor progression. This gives a2NTD the propensity to regulate neutrophil survival. In fact the treatment of human neutrophils with recombinant a2NTD led to 2.1 fold increase in the percentage survival of neutrophils (P < 0.001). a2NTD treatment modulates different apoptosis pathways. Executive pathway; a2NTD treated neutrophils (a2Neuφ) showed a significantly decreased gene expression of caspase-3, -6, -7, that corresponded with decreased activity of these caspases. Intrinsic pathway; a2NTD treatment upregulates the gene expression of anti-apoptotic factors; Bcl2-A1, Bcl-xL and downregulates the pro-apoptotic factors; BAX and Apaf-1. Extrinsic pathway; a2NTD treatment dowenregulats the gene expression and the activity of caspase-8 and upregulates the gene expression of c-Flip. a2NTD treatment also stimulates reactive oxygen species generation that activate NF-kB p65 in neutrophils. Moreover, NF-kB inhibition negated that promoted neutrophil survival that was associated with downregulation of the gene expression of Bcl2-A1, Bcl-xL, G-CSF and upregulation of BAX. Thus, a2NTD enhances neutrophil survival by activating the NF-kB pathway in neutrophils. Together, these data demonstrate a novel role of the cancer associated a2-vacuolar ATPase on regulating neutrophil survival by the action of a2NTD.
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Kuckleburg, Christopher, Sarah Tilkens, Sentot Santoso, and Peter J. Newman. "Neutrophil Proteinase (PR3) Regulates Neutrophil Transendothelial Cell Migration." Blood 116, no. 21 (November 19, 2010): 1492. http://dx.doi.org/10.1182/blood.v116.21.1492.1492.
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Abstract Abstract 1492 Neutrophil transmigration requires the localization of neutrophils to endothelial cell junctions where receptor-ligand interactions between these cells promotes leukocyte diapedesis. Neutrophils contain several different proteases which are thought to play a role in aiding in transendothelial cell migration, either by degrading extracellular matrix components or junctional proteins, or by inducing endothelial cell activation. Proteinase 3 (PR3) is a serine protease stored in azurophil granules that is released by activated neutrophils and can rebind to the neutrophil expressed cell surface protein NB1 (CD177). The neutrophil marker NB1 is expressed on a subset of neutrophils (∼50%) and has recently been demonstrated to be a heterophilic binding partner for PECAM-1, a protein highly expressed at endothelial cell junctions. Disrupting NB1-PECAM interactions has been reported to significantly inhibit neutrophil transmigration. Because of the critical role of NB1 in neutrophil transmigration we believe that the interactions between NB1 and PECAM-1 have the potential to localize PR3 to endothelial cell junctions where it may aid in leukocyte transmigration. For this study we sought to test the hypothesis that NB1-PR3 interactions contribute to neutrophil transmigration. Human umbilical vein endothelial cells (HUVEC) were cultured on transwell membranes, treated with IL-1β, TNFα or fMLP and then incubated with NB1+ or NB1- PMN. Using flow cytometry we observed that transmigration alone resulted in a significant increase in PR3 expression on NB1+ but not NB1- neutrophils. Using a pan-serine protease inhibitor (AEBSF) total neutrophil transmigration was significantly inhibited. However, using a highly specific PR3 inhibitor (Elafin) we observed a selective inhibition in NB1+ but not NB1- neutrophil transmigration on IL-1β stimulated HUVEC. Similarly, antibodies against the NB1 recognition site on PECAM (Ig domain 6) inhibited neutrophil transmigration of NB1+ but not NB1- cells. Interestingly, in the presence of different stimuli (TNFα, fMLP), neutrophil transmigration was significantly less dependent on NB1-PECAM interactions and inhibition of PR3 activity did not inhibit transmigration. This is despite the fact that PR3 expression was highly up-regulated on NB1+ neutrophils incubated with either of these stimuli or following neutrophil transmigration. In conclusion, the serine protease PR3 appears to play a significant role in the transmigration of NB1+ but not NB1- neutrophils. Likewise, the contribution of NB1 and PR3 in neutrophil transmigration is regulated in a stimulus-dependent mechanism which involves NB1 interactions with PECAM. These data therefore suggest that NB1 and PR3 may regulate recruitment of a neutrophil subset in response to specific inflammatory signals and this regulation may play a role in modulating the immune response. Disclosures: No relevant conflicts of interest to declare.