The mechanisms by which mucosal homeostasis is maintained are of central importance to inflammatory bowel disease. Critical to these processes is the intestinal epithelial cell (IEC), which regulates immune responses at the interface between the commensal microbiota and the host1,2. CD1d presents self and microbial lipid antigens to natural killer T (NKT) cells, which are involved in the pathogenesis of colitis in animal models and human inflammatory bowel disease3,4,5,6,7,8. As CD1d crosslinking on model IECs results in the production of the important regulatory cytokine interleukin (IL)-10 (ref. 9), decreased epithelial CD1d expression—as observed in inflammatory bowel disease10,11—may contribute substantially to intestinal inflammation. Here we show in mice that whereas bone-marrow-derived CD1d signals contribute to NKT-cell-mediated intestinal inflammation, engagement of epithelial CD1d elicits protective effects through the activation of STAT3 and STAT3-dependent transcription of IL-10, heat shock protein 110 (HSP110; also known as HSP105), and CD1d itself. All of these epithelial elements are critically involved in controlling CD1d-mediated intestinal inflammation. This is demonstrated by severe NKT-cell-mediated colitis upon IEC-specific deletion of IL-10, CD1d, and its critical regulator microsomal triglyceride transfer protein (MTP)12,13, as well as deletion of HSP110 in the radioresistant compartment. Our studies thus uncover a novel pathway of IEC-dependent regulation of mucosal homeostasis and highlight a critical role of IL-10 in the intestinal epithelium, with broad implications for diseases such as inflammatory bowel disease.
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The authors thank H.-C. Hung for technical assistance with microinjection, Y. Xie for performing osmium staining, A. Bedynek and M. Friedrich for performing immunohistochemistry of the human biopsies, F. A. Zhu for assistance with antigen presentation assays, D. Shouval, M. Sablon and D. Perez for animal care and husbandry, K. Tashiro for technical assistance with adenovirus preparation, V. M. Thiele for technical assistance, J. Cusick for help with manuscript preparation, and S. E. Plevy for discussions and reagents. This work was supported by: National Institutes of Health (NIH) (grants DK044319, DK051362, DK053056, DK088199) and the Harvard Digestive Diseases Center (DK0034854) (R.S.B.); the European Research Council (ERC Starting Grant agreement no. 336528), the Deutsche Forschungsgemeinschaft (DFG) (ZE 814/4-1, ZE 814/5-1, ZE 814/6-1), the Crohn’s and Colitis Foundation of America (Postdoctoral Fellowship Award), the European Commission (Marie Curie International Reintegration Grant no. 256363) and the DFG Excellence Cluster “Inflammation at Interfaces” (S.Z.); the DFG (OL 324/1-1) (T.O.); HL38180, DK56260, Washington University DDRCC P30DK52574 (morphology core) (N.O.D.); HDDC Pilot and Feasibility Grant (K.B.); NCI P30CA013696 (C.-S.L.), the DFG (BR 1912/6-1) and the Else Kroener-Fresenius-Stiftung (Else Kroener-Exzellenzstipendium 2010_EKES.32) (S.B.); Grant-in-Aid for Challenging Exploratory Research 24659823 from Japan Society for Promotion of Science (K.W.); the ERC under the European Community’s Seventh Framework Programme (FP7/2007-2013/ERC Grant agreement no. 260961), the National Institute for Health Research Cambridge Biomedical Research Centre, the Austrian Science Fund and Ministry of Science P21530-B18 and START Y446-B18, Innsbruck Medical University (MFI 2007-407) and the Addenbrooke’s Charitable Trust, CiCRA (A.K.); the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement SysmedIBD (no. 305564) (W.M., S.S.); the NIH (grants HL59561, DK034854, AI50950), the Helmsley Charitable Trust and the Wolpow Family Chair in IBD Treatment and Research (S.B.S.). PBS57-loaded and unloaded mouse CD1d tetramer was obtained through the NIH Tetramer Facility. The authors thank M. A. Exley and S. P. Colgan for discussions.
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This file contains a Supplementary Discussion of potential mechanisms responsible for divergent outcomes of CD1d engagement on intestinal epithelial cells and professional antigen presenting cells.
About this article
Mucosal Immunology (2018)