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Glucocorticoids Inhibit Group 3 Innate Lymphocyte IL-22 Production Sudarshan Seshadri, Rosemary L

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Glucocorticoids Inhibit Group 3 Innate Lymphocyte IL-22 Production Sudarshan Seshadri, Rosemary L Glucocorticoids Inhibit Group 3 Innate Lymphocyte IL-22 Production Sudarshan Seshadri, Rosemary L. Pope and Lauren A. Zenewicz This information is current as of September 28, 2021. J Immunol published online 6 July 2018 http://www.jimmunol.org/content/early/2018/07/06/jimmun ol.1800484 Downloaded from Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision http://www.jimmunol.org/ • 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 by guest on September 28, 2021 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 © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published July 6, 2018, doi:10.4049/jimmunol.1800484 The Journal of Immunology Glucocorticoids Inhibit Group 3 Innate Lymphocyte IL-22 Production Sudarshan Seshadri, Rosemary L. Pope, and Lauren A. Zenewicz Glucocorticoids (GCs) are commonly prescribed to patients with a variety of inflammatory disorders, including inflammatory bowel disease (IBD). GCs mediate their immunomodulatory effects through many different mechanisms and target multiple signaling pathways. The GC dexamethasone downmodulates innate and adaptive immune cell activation. IBD is the manifestation of a dys- regulated immune response involving many different immune cells. Group 3 innate lymphocytes (ILC3s) have critical roles in mu- cosal inflammation. ILC3s secrete high levels of the cytokine IL-22, promoting epithelial proliferation, antimicrobial peptides, and mucins. In this study, we examined the effects of dexamethasone on IL-22 production by ILC3s. We found that dexamethasone suppressed IL-23–mediated IL-22 production in human and mouse ILC3s. This was mediated in part through dexamethasone k k modulation of the NF- B pathway. Inhibition of NF- B signaling with a small molecule inhibitor also downmodulated IL-23– and Downloaded from IL-1b–mediated IL-22 production in ILC3s. These findings implicate NF-kB as a regulator of IL-22 in ILC3s and likely have repercussions on GC treatment of IBD patients. The Journal of Immunology, 2018, 201: 000–000. nflammatory bowel disease (IBD) is a grouping of chronic compose a mucosal barrier that shields the epithelium (5). Through diseases caused by dysregulated immune responses within the effects on the epithelium, IL-22 also modulates the composition of I gastrointestinal tract (1). Lifelong treatment is required to minimize the microbiome, which can have an impact on the severity of IBD http://www.jimmunol.org/ inflammation and, hopefully, improve quality of life. Although many (6). In contrast, IL-22 has also been shown to be immunopathogenic new biologics have been developed that target specific aspects of mu- in other IBD models by causing hyperplasia and colonic thickening cosal biology, such as cytokines and immune cell trafficking (2), general or increased inflammation (7, 8). IL-22 is a potential target for drug immunosuppression via steroids is still often the first line of treatment for therapy, either directly or indirectly, by targeting the cytokine itself patients. Glucocorticoids (GCs) are oneclassofsteroidusedtosuppress or upstream factors that regulate its production (9). inflammatory cytokine production. IL-22 is predominantly produced by CD4 T cells and group 3 Numerous cytokines are upregulated in IBD patients, and these innate lymphocytes (ILC3s) (10). ILC3s are rare immune cells immune mediators are at least partially responsible for the inflam- that, upon stimulation with IL-23 or IL-1b, become activated and matory milieu, leading to ulceration and/or granulomas (3). The produce IL-22 as well as other factors occasionally, such as IL-17 by guest on September 28, 2021 cytokine IL-22 is upregulated in both the sera and inflamed tissue of and GM-CSF (11). These cells can be found in mucosal tissues Crohn’s disease and ulcerative colitis patients (4). Using experi- and have important roles in homeostatic barrier maintenance, in- mental animal models of IBD, studies have shown that IL-22 is fectious disease, and IBD (12–16). IL-22 expression in ILC3s is protective of tissues during IBD through induction of epithelial and primarily regulated by the STAT3 and aryl hydrocarbon signaling stem cell proliferation, antimicrobial peptides, and mucins, which pathways (17, 18), but other signaling pathways, such as Notch and MAPK, also contribute (19, 20). Understanding the pathways Department of Microbiology and Immunology, University of Oklahoma Health that regulate IL-22 biology is, therefore, important for developing Sciences Center, Oklahoma City, OK 73104 therapies for many chronic inflammatory diseases. ORCIDs: 0000-0003-4910-8664 (S.S.); 0000-0002-8787-5955 (L.A.Z.). GCs are a commonly used therapy for many chronic inflammatory Received for publication March 29, 2018. Accepted for publication June 15, 2018. diseases. GCs diffuse through the cell membrane to bind to GC re- This work was supported by an American Heart Association Scientist Development ceptors (GR), activating or repressing gene transcription through Grant (14SDG18700043), the National Institute of General Medical Sciences of the several different mechanisms (21, 22). GRs can directly bind to GC National Institutes of Health under Award P20GM103447 (principal investigator: response elements encoded in the DNA, can bind to and modulate D. Akins, University of Oklahoma Health Sciences Center), the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under other transcription factors, and can perform composite binding to Subaward A199F from 5 U19 AI062629 (principal investigator: K.M. Coggeshall, both DNA and other transcription factors. All nucleated cells express Oklahoma Medical Research Foundation), an Oklahoma Center for the Advance- ment for Science and Technology Health Research Grant (HR 13-003), and the GRs, and the effects of GCs on many cell types have been well Oklahoma Center for Adult Stem Cell Research grant, a program of the Oklahoma described (21). GCs can modulate cells of the gastrointestinal epi- Tobacco Settlement Endowment Trust (to L.A.Z.). S.S. was supported in part by thelium (23) and have pleiotropic effects on the immune system, the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Subaward A179F from 5 U19 AI062629. including both immunosuppressive and inflammatory activities (21). Address correspondence and reprint requests to Dr. Lauren A. Zenewicz, Department Dexamethasone is a prototypical synthetic GC and modulates the of Microbiology and Immunology, College of Medicine, University of Oklahoma function of many types of immune cells. The effects of dexa- Health Sciences Center, 940 Stanton L. Young Boulevard, BMSB 1053, Oklahoma methasone on T lymphocyte function are well described (21); City, OK 73104. E-mail address: [email protected] however, it is not known if dexamethasone modulates the critical Abbreviations used in this article: BFA, brefeldin A; CST, Cell Signaling Technol- ogy; DSS, dextran sodium sulfate; FP, fluticasone propionate; GC, glucocorticoid; function of ILC3s or if dexamethasone regulates the cytokine IL-22. GR, GC receptor; IBD, inflammatory bowel disease; ILC, innate lymphocyte; In this study, we show that the GC dexamethasone negatively reg- ILC3, group 3 innate lymphocyte; OUHSC, University of Oklahoma Health ulates IL-22 production in homeostatic and activated mouse and Sciences Center. human ILC3s. Dexamethasone did not modulate the IL-23 canonical Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 signaling pathway of JAK2/STAT3 but did suppress phosphorylation www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800484 2 GLUCOCORTICOIDS INHIBIT ILC3s Downloaded from FIGURE 1. Dexamethasone negatively modulates IL-22 production by human ILC3s. (A and B) Human tonsillar lymphocytes were treated with DMSO or dexamethasone (100 nM or indicated dose) for 2 h, followed by recombinant human IL-23 (50 ng/ml) stimulation for 18 h. Cell supernatants were analyzed for IL-22 secretion by ELISA. Shown are replicates from one experiment expressed as mean 6 SD performed at least three times with similar results. (C and D) Human tonsillar lymphocytes were treated as in (A) in the presence of BFA for 5 h, and IL-22 was analyzed in ILCs (CD32 CD142 CD192 CD127+ CD161+) by intracellular cytokine staining and flow cytometry for IL-22. (C) Gating strategy for identification of ILC3s. (D) Summary of 6 # , data from multiple donors. Data represent mean SD of four independent experiments. *p 0.05, **p 0.01. http://www.jimmunol.org/ of IkBa, an important regulator in NF-kB activation. Inhibition of Splenocyte preparation k NF- B signaling with a small molecule inhibitor also down- Spleens were excised, and single-cell suspensions were made by disruption modulated IL-23– and IL-1b–mediated IL-22 production in ILC3s. of the spleen on wire mesh using the plunger of a 3-ml syringe. Cells were GCsuppressionofILC3smaybeanimportantcomponentoftheir
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