Protective mucosal immunity mediated by epithelial CD1d and IL-10.
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 host. 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 disease. 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 disease--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), 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.
1] Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [2].
Torsten
T
Olszak
1] Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [2].
Joana F
JF
Neves
1] Department of Internal Medicine I, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany [2].
C Marie
CM
Dowds
Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kristi
K
Baker
GI Pathology, Miraca Life Sciences, Newton, Massachusetts 02464, USA.
Jonathan
J
Glickman
Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Nicholas O
NO
Davidson
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
Chyuan-Sheng
CS
Lin
Department of Medicine, Department of Infectious Diseases & Pathology, University of Florida, Gainesville, Florida 32611, USA.
Christian
C
Jobin
Department of Medicine II-Grosshadern, Ludwig Maximilians University, Munich 81377, Germany.
Stephan
S
Brand
Institute of Pathology, Ludwig Maximilians University, Munich 80337, Germany.
Karl
K
Sotlar
Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan.
Koichiro
K
Wada
Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan.
Kazufumi
K
Katayama
Gastroenterology Division, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0027, Japan.
Atsushi
A
Nakajima
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
Hiroyuki
H
Mizuguchi
Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-ku, Kyoto 603-8555, Japan.
Kunito
K
Kawasaki
Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-ku, Kyoto 603-8555, Japan.
Kazuhiro
K
Nagata
Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK.
Werner
W
Müller
1] Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, USA.
Scott B
SB
Snapper
Department of Internal Medicine I, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany.
Stefan
S
Schreiber
Division of Gastroenterology, Addenbrooke Hospital, University of Cambridge, Cambridge CB2 0QQ, UK.
Arthur
A
Kaser
1] Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Department of Internal Medicine I, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany [3].
Sebastian
S
Zeissig
1] Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [2].
Richard S
RS
Blumberg
D000818:Animals; D055610:Antigens, CD1d / Q000276:immunology*; D002352:Carrier Proteins / Q000378:metabolism; D003092:Colitis / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D050957:HSP110 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D007413:Intestinal Mucosa / Q000166:cytology* / Q000276:immunology*; D008297:Male; D051379:Mice; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism; D010081:Oxazolone; D050796:STAT3 Transcription Factor / Q000378:metabolism
D055610:Antigens, CD1d; C584692:CD1d antigen, mouse; D002352:Carrier Proteins; D050957:HSP110 Heat-Shock Proteins; D050796:STAT3 Transcription Factor; C106092:microsomal triglyceride transfer protein; D016753:Interleukin-10; D010081:Oxazolone