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Chronic Colitis by Neutrophils Isolated from Mice with Acquisition of Antigen-Presenting Functions

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Chronic Colitis by Neutrophils Isolated from Mice with Acquisition of Antigen-Presenting Functions Published January 4, 2012, doi:10.4049/jimmunol.1102296 The Journal of Immunology Acquisition of Antigen-Presenting Functions by Neutrophils Isolated from Mice with Chronic Colitis Dmitry V. Ostanin,*,† Elvira Kurmaeva,† Katie Furr,* Richard Bao,‡ Jason Hoffman,* Seth Berney,† and Matthew B. Grisham* Active episodes of the inflammatory bowel diseases are associated with the infiltration of large numbers of myeloid cells including neutrophils, monocytes, and macrophages. The objective of this study was to systematically characterize and define the different populations of myeloid cells generated in a mouse model of chronic gut inflammation. Using the T cell transfer model of chronic colitis, we found that induction of disease was associated with enhanced production of myelopoietic cytokines (IL-17 and G-CSF), increased production of neutrophils and monocytes, and infiltration of large numbers of myeloid cells into the mesenteric lymph nodes (MLNs) and colon. Detailed characterization of these myeloid cells revealed three major populations including Mac-1+ Ly6ChighGr-1low/neg cells (monocytes), Mac-1+Ly6CintGr-1+ cells (neutrophils), and Mac-1+Ly6Clow/negGr-1low/neg leukocytes (mac- rophages, dendritic cells, and eosinophils). In addition, we observed enhanced surface expression of MHC class II and CD86 on neutrophils isolated from the inflamed colon when compared with neutrophils obtained from the blood, the MLNs, and the spleen of colitic mice. Furthermore, we found that colonic neutrophils had acquired APC function that enabled these granulocytes to induce proliferation of OVA-specific CD4+ T cells in an Ag- and MHC class II-dependent manner. Finally, we observed a syner- gistic increase in proinflammatory cytokine and chemokine production following coculture of T cells with neutrophils in vitro. Taken together, our data suggest that extravasated neutrophils acquire APC function within the inflamed bowel where they may perpetuate chronic gut inflammation by inducing T cell activation and proliferation as well as by enhancing production of proinflammatory mediators. The Journal of Immunology, 2012, 188: 000–000. nflammatory bowel diseases (IBD; Crohn’s disease [CD] and Gr-1 in the bone marrow (BM), circulation, mesenteric lymph ulcerative colitis) are multifactorial inflammatory disorders nodes (MLNs), the spleen, and colonic lamina propria (cLP). I of the gastrointestinal tract that result from a complex in- Although T cells undoubtedly play an important role in the in- teraction among genetic, environmental, and immune factors. duction and perpetuation of disease, the role of myeloid cells in Active episodes of the disease are associated with the infiltration disease pathogenesis has not been defined clearly. of large numbers of leukocytes including lymphocytes, gran- The accumulation of myeloid cells such as neutrophils, mono- ulocytes, monocytes, and macrophages (1–3). This enhanced in- cytes, and macrophages and others in the inflamed gut and their flammatory infiltrate is thought to contribute to the intestinal release of a variety of proinflammatory reactive oxygen and injury and dysfunction resulting in abdominal pain, rectal bleed- nitrogen species, cytokines, chemokines, and proteases are thought ing, and diarrhea. Using mouse models of IBD, we and others to contribute to tissue injury and disruption of the epithelial barrier. (D.V. Ostanin, E. Kurmaeva, S.M. Berney, and M.B. Grisham, Indeed, neutrophil-associatedmarkers are highlyexpressedin chronic unpublished observations; 4–7) have demonstrated that in addition active IBD (8), and the transepithelial migration of neutrophils to expansion of colitogenic T cells, induction of chronic intestinal into the bowel lumen to form crypt abscesses is a characteristic fea- inflammation is associated with a large and significant increase in ture of active disease (9, 10). Despite these observations, no clear the numbers of myeloid cells bearing markers CD11b (Mac-1) and consensus has been reached from several different studies that have attempted to define the role of myeloid cells in the pathogen- *Department of Molecular and Cellular Physiology, Louisiana State University esis of intestinal inflammation. Although some studies have sug- Health Sciences Center, Shreveport, LA 71130; †Department of Medicine, Louisiana ‡ gested that neutrophils or other myeloid cells promote inflammatory State University Health Sciences Center, Shreveport, LA 71130; and Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA 71130 tissue injury (11, 12), other investigations were unable to confirm Received for publication August 8, 2011. Accepted for publication November 27, these findings (13, 14). Contributing even further to the confusion 2011. has been the observation that depletion of intestinal mononuclear This work was supported by a grant from the National Institutes of Health (PO1-DK phagocytes using clodronate–encapsulate liposomes worsened the 43785, Project 1, and Cores B and C) (to M.B.G.). D.V.O. is supported by funding from the Center of Excellence for Arthritis and Rheumatology (Louisiana State colonic inflammation induced by dextran sulfate sodium. The en- University Health Sciences Center, Shreveport, LA). hanced inflammation and injury observed in this study was found to Address correspondence and reprint requests to Dr. Matthew B. Grisham, Department be associated with an increased neutrophil infiltration into the co- of Molecular and Cellular Physiology, Louisiana State University Health Sciences lon, suggesting a pathogenic role for these cells (12). In contrast Center, 1501 Kings Highway, P.O. Box 33932, Shreveport, LA 71130-3932. E-mail address: [email protected] to these studies, recent reports have demonstrated that depletion The online version of this article contains supplemental material. of neutrophils actually exacerbates colonic inflammation and the systemic wasting syndrome in chronic (5, 6) and acute colitis Abbreviations used in this article: BM, bone marrow; cLP, colonic lamina propria; DC, dendritic cell; DN, double-negative; IBD, inflammatory bowel diseases; LP, models (7), suggesting that neutrophils may function to suppress 2 2 lamina propria; MLN, mesenteric lymph node; MPO, myeloperoxidase; RAG / , intestinal inflammation. The depletion of neutrophils in these recombination activating gene-1–deficient; WT, wild-type. studies used the in vivo administration of the anti–Gr-1 Ab (clone Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 RB6-8C5) prior to or following induction of disease. Although this www.jimmunol.org/cgi/doi/10.4049/jimmunol.1102296 2 NEUTROPHILS AS APCs IN CHRONIC COLITIS strategy has previously proven effective in depleting neutrophils in Quantification of circulating leukocytes, and serum cytokines healthy mice (15), administration of this Ab to mice with inflam- Blood was withdrawn from anesthetized mice at the time of sacrifice via the mation is known to induce profound and lethal respiratory and inferior vena cava using a 25 g needle attached to a 1-ml heparinized syringe. cardiovascular complications that may have devastating systemic After 500 ml heparinized blood was mixed with an equal volume of 3% effects including death of the animal (16, 17). Another confounding dextran (.400,000 m.w.) in PBS, the erythrocytes were allowed to settle variable that makes interpretation difficult is the fact that anti–Gr-1 for 30 min at room temperature, and leukocyte-rich supernatant was re- moved and stored on ice. Remaining erythrocytes in the supernatant were Ab recognizes both Ly6G and Ly6C; thus, its administration would lysed, and leukocytes were pelleted by centrifugation, resuspended in PBS, deplete not only neutrophils (bearing Ly6G on their surface) but and mixed with crystal violet dissolved in 3% acetic acid for counting also Ly6C+ myeloid cells with potent immunosuppressive proper- using a hemocytometer. Total blood leukocytes were expressed as cells per ties (18, 19). A recent study that analyzed the effects of in vivo anti- milliliter of blood. For differential cell counts, 50,000–100,000 circulating or tissue-derived/flow-purified leukocytes were resuspended in 100 ml13 Ly6G (clone 1A8) and anti–Gr-1 (RB6-8C5) Ab administration on PBS and dispensed into the cytospin chamber loaded with Colorfrost Plus blood neutrophils and monocytes confirmed that the latter signifi- Microscope Slides (Fisher Scientific) and cardboard filter (Thermo Elec- cantly depleted Gr-1intF4/80+ monocytes (20). tron) and centrifuged (600 rpm, 2 min) using Shandon Cytospin3 centri- Because of these experimental limitations and lack of a clear fuge. Following this, samples were air-dried for 1–2 min and stained using consensus as to the role of neutrophils and other myeloid cells in the a Diff-Quick kit (Siemens Healthcare Diagnostics), according to the manufacturer’s instructions. The slides were mounted under coverslip pathogenesis of chronic gut inflammation, we undertook a sys- using Permount mounting agent (Fisher Scientific). At least 200 total cells tematic analysis and characterization of myeloid cell generation, were counted from at least four to five different fields, and those with phenotype, and function in a mouse model of chronic gut in- mononuclear or polymorphonuclear morphology were quantified and ex- flammation. pressed as a percentage of the total cells counted. For serum cytokine determinations, blood was withdrawn from anes- thetized mice and allowed to clot for 30–60 min at room temperature. The Materials
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