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Monocyte/Macrophage-Derived CCL11 Inflammatory + CCR2 High Colonic Eosinophilic Inflammation in Experimental Colitis Is Mediated by Ly6C high CCR2+ Inflammatory Monocyte/Macrophage-Derived CCL11 This information is current as of October 1, 2021. Amanda Waddell, Richard Ahrens, Kris Steinbrecher, Burke Donovan, Marc E. Rothenberg, Ariel Munitz and Simon P. Hogan J Immunol 2011; 186:5993-6003; Prepublished online 15 April 2011; Downloaded from doi: 10.4049/jimmunol.1003844 http://www.jimmunol.org/content/186/10/5993 Supplementary http://www.jimmunol.org/content/suppl/2011/04/15/jimmunol.100384 http://www.jimmunol.org/ Material 4.DC1 References This article cites 67 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/186/10/5993.full#ref-list-1 Why The JI? Submit online. by guest on October 1, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Colonic Eosinophilic Inflammation in Experimental Colitis Is Mediated by Ly6Chigh CCR2+ Inflammatory Monocyte/Macrophage-Derived CCL11 Amanda Waddell,* Richard Ahrens,* Kris Steinbrecher,† Burke Donovan,* Marc E. Rothenberg,* Ariel Munitz,*,‡ and Simon P. Hogan* Recent genome-wide association studies of pediatric inflammatory bowel disease have implicated the 17q12 loci, which contains the eosinophil-specific chemokine gene CCL11, with early-onset inflammatory bowel disease susceptibility. In the current study, we employed a murine model of experimental colitis to define the molecular pathways that regulate CCL11 expression in the chronic intestinal inflammation and pathophysiology of experimental colitis. Bone marrow chimera experiments showed that hematopoi- etic cell-derived CCL11 is sufficient for CCL11-mediated colonic eosinophilic inflammation. We show that dextran sodium sulfate (DSS) treatment promotes the recruitment of F4/80+CD11b+CCR2+Ly6Chigh inflammatory monocytes into the colon. F4/80+ Downloaded from CD11b+CCR2+Ly6Chigh monocytes express CCL11, and their recruitment positively correlated with colonic eosinophilic inflam- mation. Phenotypic analysis of purified Ly6Chigh intestinal inflammatory macrophages revealed that these cells express both M1- and M2-associated genes, including Il6, Ccl4, Cxcl2, Arg1, Chi3l3, Ccl11, and Il10, respectively. Attenuation of DSS-induced F4/80+ CD11b+CCR2+Ly6Chigh monocyte recruitment to the colon in CCR22/2 mice was associated with decreased colonic CCL11 expression, eosinophilic inflammation, and DSS-induced histopathology. These studies identify a mechanism for DSS-induced colonic eosinophilia mediated by Ly6ChighCCR2+ inflammatory monocyte/macrophage-derived CCL11. The Journal of Immu- http://www.jimmunol.org/ nology, 2011, 186: 5993–6003. he inflammatory bowel diseases (IBD) Crohn’s disease prognostic indicator (3, 4). Notably, elevated fecal concentrations (CD) and ulcerative colitis (UC) are chronic relapsing of the eosinophil-derived granule proteins ECP and EPO were T gastrointestinal (GI) inflammatory diseases that cause associated with clinical relapse within 3 mo in CD (5). Since these substantial morbidity and decreased quality of life. Over 30 years initial studies, there have been a number of studies suggesting ago, Rutgeerts and colleagues (1) observed that apthous ulcers eosinophil involvement in IBD. Elevated levels of eosinophils containing an eosinophilc infiltrate and blunted villi were the ear- have been observed in colonic biopsy samples from UC patients, by guest on October 1, 2021 liest endoscopic signs of recurrence in the neoterminal ileum and increased numbers of this cell and eosinophil-derived granule and anastomosis following surgical resection for CD. Eosinophils proteins MBP, ECP, EPO, and EDN have been shown to correlate usually represent only a small percentage of the infiltrating leu- with morphological changes to the GI tract, disease severity, and kocytes (2, 3), but their level has been proposed to be a negative GI dysfunction (5–10). Increased numbers of tissue eosinophils with ultrastructural evidence of activation has also been observed *Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Cen- in patients with CD (11–13). Consistent with this clinical obser- ter, Cincinnati, OH 45229; †Division of Gastroenterology, Hepatology and Nutri- vation, dextran sodium sulfate (DSS)-induced histopathology is tion, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229; and attenuated in mice deficient in eosinophils (14–16). ‡Department of Microbiology and Clinical Immunology, Sackler Faculty of Medi- cine, Tel Aviv University, Ramat Aviv 69978, Israel Genome-wide association studies of pediatric and adult IBD Received for publication November 23, 2010. Accepted for publication March 12, have revealed a number of IBD susceptibility genes associated with 2011. innate (CARD15, ATG16L1, and IRGM) and adaptive (IL23R, This work was supported by a Crohn’s and Colitis Foundation of America Career IL10, IL12B, and STAT3) immunity. Furthermore, a recent in- Development Award (to S.P.H.), National Institutes of Health Grant R01 AI073553 vestigation identified a significant association between the C-C (to S.P.H.), National Institutes of Health Grant R01 AI45898 (to M.E.R.), and an American Gastroenterological Association Foundation Graduate Student Research motif chemokine cluster on 17q12 loci, which contains the Fellowship Award (to A.W.). eosinophil-specific chemokine gene CCL11, and early-onset CD A.W. and S.P.H. designed and performed experiments, analyzed and interpreted data, (17). CCL11 is a member of the CC chemokine family (18) and is and wrote the manuscript. B.D. performed experiments and analyzed and interpreted data. M.E.R. provided mice. K.S., R.A., and A.M. discussed experimental design and a relatively potent and specific eosinophil chemoattractant (19– data analysis. 21). CCL11 is constitutively expressed in a variety of tissues that Address correspondence and reprint requests to Dr. Simon P. Hogan, Division of contain eosinophils such as the GI tract and thymus (22–25). Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Bur- Genetic deletion of CCL11 abrogates eosinophil recruitment dur- net Avenue, Cincinnati, OH 45229. E-mail address: [email protected] ing eosinophil-associated pulmonary and GI disease, suggesting The online version of this article contains supplemental material. an important role for CCL11 in eosinophil trafficking during Abbreviations used in this article: BM, bone marrow; CD, Crohn’s disease; DAI, disease activity index; DSS, dextran sodium sulfate; eGFP, enhanced GFP; GI, gas- disease (26–29). Consistent with this, clinical investigations by us trointestinal; hpf, high-power field; IBD, inflammatory bowel diseases; MF, macro- and others demonstrate increased CCL11 mRNA levels in sputum phages; PDL1, programmed death ligand 1; PHIL, mice deficient in eosinophils; SC, and intestinal biopsy samples from asthmatic and eosinophilic GI stromal compartment; UC, ulcerative colitis; WT, wild-type. disorder patients. Importantly, the levels of CCL11 positively Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 correlated with tissue eosinophilia (14, 25, 26). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1003844 5994 LY6Chigh MONOCYTE/MACROPHAGES REGULATE COLONIC INFLAMMATION Although a link between CCL11 and eosinophils in IBD has been Real-time PCR analysis established, the cellular source of CCL11 and molecular regulation Mouse Hprt, Ccl11, Retnla, Chi3l3, Arg1, Trem1, Ccl22, Ccl17, Cxcl2, of CCL11 expression in experimental colitis is not yet delineated. Ccl4, Cxcl10, Pdgfb, Il1b, Tnf, Il6, Ccl3, and Il10 mRNA were quantified In the current study, we employed a model of DSS-induced coli- by real-time PCR as previously described (34). In brief, the RNA samples tis, which features a pronounced CCL11-dependent eosinophilic (1 mg) were subjected to reverse transcription analysis using SuperScript II inflammation, to decipher the molecular regulation of CCL11 in reverse transcriptase (Invitrogen) according to the manufacturer’s instructions and quantified using the iQ5 multicolor real-time PCR de- experimental colitis. Performing bone marrow (BM) chimera ex- tection system (Bio-Rad, Hercules, CA) with iQ5 software V2.0 and periments, we show that hematopoietic cell-derived CCL11 is LightCycler FastStart DNA Master SYBR Green I (Bio-Rad). Primer sets required for DSS-induced colonic eosinophilic inflammation. We are listed in Supplemental Table I. Gene expression was determined as show that DSS exposure promotes the recruitment of F4/80+ relative expression on a linear curve based on a gel-extracted standard and + + high was normalized to Hprt amplified from the same cDNA mix. Results were CD11b CCR2 Ly6C inflammatory monocytes to the colon and expressed
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