Paneth cells as a site of origin for intestinal inflammation

Abstract

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.

A20 controls intestinal homeostasis through cell-specific activities

“…In addition, mice defective in ER stress signalling or autophagy, such as XBP1 IEC-KO mice 36 and hypomorphic ATG16L1 mice 37 , respectively, display Paneth cell abnormalities. Moreover, intestinal inflammation may even emerge from malfunctioning Paneth cells 38 . A20 deficiency in IECs does not cause spontaneous Paneth cell defects, but sensitizes their apoptotic loss in inflammatory conditions, either by direct low-dose TNF exposure or by exposure to cytokines produced by hyperactive A20-deficient myeloid cells, including TNF and IFNg.…”

ATG16L1: A multifunctional susceptibility factor in Crohn disease

“…Accordingly, failure to remove ER stress-induced responses in mice with genetic deficiencies in either Atg16l1 or Atg7 causes a severe spontaneous Crohn disease-like transmural ileitis through NFKB (nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) activation and TNF signaling. 108 It should be noted, however, that pharmacological autophagy inhibition (e.g., by 3-methyladenine) could not always confirm the above-described autophagy-mediated effects, with 3-methyladenine being reported to both induce and decrease toll-like receptor-mediated TNF secretion. 83,109 These conflicting data should encourage more careful investigations using both genetic and pharmacological inhibition, as discrepancies may result from off-target or at least autophagyindependent inhibitory effects linked to the chosen inhibition strategy.…”

“…107 Moreover, a recent study reported a crucial interaction between ER stress and autophagy among the inflamed Paneth cells of the intestinal epithelium. 108 Impairment of the unfolded protein response by deleting its key transcription factor, Xbp1, or secondary to deficiency in the autophagic functions due to the genetic removal of Atg16l1 or Atg7 in intestinal epithelial cells, results in antagonistic compensatory engagement; 108 the induction of ER stress in Xbp1 knockout mice triggers the activation of a compensatory autophagic response and the formation of autophagosomes in Paneth cells. Accordingly, failure to remove ER stress-induced responses in mice with genetic deficiencies in either Atg16l1 or Atg7 causes a severe spontaneous Crohn disease-like transmural ileitis through NFKB (nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) activation and TNF signaling.…”

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

“…Also, Blumberg et al has shown that XBP1, a transcription factor that is induced upon ER stress, is another susceptibility gene that leads to Paneth cell dysfunction [60]. By combining functional deletion of both ATG16L1 and XBP1 in mice models, they identified that ileal CD may arise solely from Paneth cell dysfunction [61]. Another study has shown that in Crohn's disease, a Paneth cell-specific cell death is promoted by a mechanism called ''Necroptosis'' [62].…”