Autophagy related 16-like 1 (ATG16L1) as a genetic risk factor has exposed the critical role of autophagy in Crohn’s disease (CD)1. Homozygosity for the highly prevalent ATG16L1 risk allele, or murine hypomorphic (HM) activity causes Paneth cell dysfunction2,3. As Atg16l1HM mice do not develop spontaneous intestinal inflammation, the mechanism(s) by which ATG16L1 contributes to disease remains obscure. Deletion of the unfolded protein response (UPR) transcription factor X-box binding protein-1 (Xbp1) in intestinal epithelial cells (IECs), whose human orthologue harbors rare inflammatory bowel disease (IBD) risk variants, results in endoplasmic reticulum (ER) stress, Paneth cell impairment and spontaneous enteritis4. Unresolved ER stress is a common feature of IBD epithelium4,5, and several genetic risk factors of CD affect Paneth cells2,4,6-9. Here we show that impairment in either UPR (Xbp1ΔIEC) or autophagy function (Atg16l1ΔIEC or Atg7ΔIEC) in IECs results in each other’s compensatory engagement, and severe spontaneous CD-like transmural ileitis if both mechanisms are compromised. Xbp1ΔIEC mice exhibit autophagosome formation in hypomorphic Paneth cells, which is linked to ER stress via protein kinase RNA-like endoplasmic reticulum kinase (PERK), elongation initiation factor 2α (eIF2α) and activating transcription factor 4 (ATF4). Ileitis is dependent on commensal microbiota and derives from increased IEC death, inositol requiring enzyme 1α (IRE1α)-regulated NFκB activation and tumor necrosis factor signaling which are synergistically increased when autophagy is deficient. ATG16L1 restrains IRE1α activity and augmentation of autophagy in IECs ameliorates ER stress-induced intestinal inflammation and eases NFκB overactivation and IEC death. ER stress, autophagy induction and spontaneous ileitis emerge from Paneth cell-specific deletion of Xbp1. Genetically and environmentally controlled UPR function within Paneth cells may therefore set the threshold for the development of intestinal inflammation upon hypomorphic ATG16L1 function and implicate ileal CD as a specific disorder of Paneth cells.
T he huge intestinal surface area is physically protected by a layer of tightly joined epithelial cells, which prevent most enteric environmental antigens from penetrating the host (1). However, entry into the host is made possible by a special gateway, comprised of M cells, located over organized mucosal lymphoid follicles such as Peyer's patches (PP). The M cells, characterized by an irregular brush border and reduced glycocalyx, efficiently take up and transport a wide variety of macromolecules and microorganisms from the gut lumen to the inside of the PP (2-6), which contain all of the necessary lymphoid cells for the induction and regulation of antigen-specific IgA responses (7). However, the origin of M cells and the regulation of their development are not understood. A previous study (8) The common mucosal immune system (CMIS), which connects the inductive (e.g., PP) and effector (e.g., lamina propria; LP) sites, has been shown to be a central pathway for the induction of antigen-specific IgA immune responses in the gastrointestinal tract (7). For example, oral administration of Salmonella typhimurium leads to the transport of the bacterial antigen from the lumen of the intestinal tract into the PP by means of M cells for the initial priming of antigen-specific CD4 ϩ T cells and IgA-committed B cells (12). These antigen-sensitized cells leave the PP and contribute to the subsequent induction of Salmonella-specific IgA response in the distant intestinal LP by means of CMIS. In addition to the wellcharacterized CMIS-dependent IgA induction pathway, recent evidence suggests the presence of an additional IgA induction pathway that is independently operated from the PP-originated CMIS (13-15). Interestingly, it also has been reported that induction of intestinal mucosal IgA against the commensal bacteria was independent from T cell help and organized lymphoid tissue (16). Further, our recent study (17) has demonstrated that antigenspecific IgA antibody responses can be induced in the absence of PP. These studies imply the existence of a PP-independent mucosal immune pathway for dietary antigen and bacteria uptake.A recent study (18) has suggested that the invasion gene (SPI1)-deficient S. typhimurium can be disseminated from the intestinal epithelium to the systemic compartment in the absence of PPassociated M cells by means of the CD18-dependent pathway. Further, dendritic cells in the lamina propria of the small intestine expressing tight junction protein offer another possible antigen uptake site (19). Thus, intestinal DCs are capable of extending dendrites to the lumen side by opening the tight junction. However, the exact mechanism for inducing Ag-specific immune responses independently of PP requires further elucidation.In this study, we have discovered intestinal villous M cells, which serve as an antigen gateway for the sampling of gut bacteria and subsequent induction of Ag-specific immune responses in a PPindependent manner. These lines of study are crucial for understanding the mechanisms of antige...
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