Self-control mechanism in mucosal immunity closely related to development of inflammatory bowel disease

Self-control mechanism in mucosal immunity closely related to development of inflammatory bowel disease

Intestinal epithelial cells play crucial role

Apr 7, 2014

A group of researchers from Osaka University, Harvard University, Yokohama City University, University of Cambridge, University of Washington, Columbia University, and Kyoto University have discovered a self-control mechanism in mucosal immunity that is closely related to the development of inflammatory bowel disease.

Osaka University -- WADA Koichiro , Associate Professor, Graduate School of Dentistry; MIZUGUCHI Hiroyuki , Professor, Graduate School of Pharmaceutical Sciences

Cluster of Differentiation 1d (CD1d)-mediated activation of natural killer T (NKT) cells by antigen-possessing cells is an important innate immune reaction to virus and bacteria; however, excessive immune activation may cause serious inflammation. This joint group has discovered that CD1d in intestinal epithelium cells (IEC), together with Heat-Shock Protein (HSP 110) and Interleukin-10 (IL-10), exhibit a self-control mechanism for suppressing excessive activation of immune reaction. Inflammatory bowel disease such as Crohn disease and colitis are designated as intractable diseases; however, the mechanism behind the development of the disease is unclear.

CD1d activates CD1d-restricted NKT cells by presenting glycolipid antigen to NKT cells and reinforces the production of interferon γ and Interleukin-4. Excessive activation of NKT cells by CD1d may be one cause of inflammatory bowel diseases; however, previous research has demonstrated that when CD1d expression is blocked, inflammatory bowel disease worsened. Therefore, this group assumed that there was a self-control mechanism in the expression of CD1d that mediated excessive inflammation, or CD1d in the intestinal epithelium might regulate mucosal immune response by playing a suppressive role.

This group clarified a self-control mechanism: CD1d expressed in antigen-possessing cells promoted inflammatory reaction by activating NKT cells; however, CD1d in the intestinal epithelium suppressed NKT cell activation, preventing excessive inflammatory reaction. This group also clarified that three molecules: Heat-Shock Protein (HSP 110) in the intestinal epithelium, Interleukin-10 (IL-10), and microsomal triglyceride transfer protein (MTP) played an important role in this self-control mechanism. Mice lacking one of these molecules were not able to control the inflammatory reaction and bowel inflammation worsened. These molecules work together in the intestinal epithelium to control CD1d-mediated inflammatory reaction. In some patients with inflammatory bowel disease, the possibility of poor control of CD1d-mediated inflammation has been suggested and epitherial HSP110 expression in the bowel decreased in bowel inflammation patients. Further examination of this control mechanism will elucidate the cause of this disease and further promote the development of more effective drugs.

Abstract

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, 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.

To learn more about this research, please read the full research report entitled " TProtective mucosal immunity mediated by epithelial CD1d and IL-10 " at this page of the Nature website.

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