Paneth cells as a site of origin for intestinal inflammation.
Paneth cells as a site of origin for intestinal inflammation.
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自噬相关16-样蛋白1（ATG 16 L1）作为一种遗传危险因子，揭示了自噬在克罗恩病（CD）中的重要作用。高度流行的ATG 16 L1风险等位基因的纯合性，或小鼠亚型（HM）活动导致潘氏细胞功能障碍。由于Atg 16 l1 HM小鼠不发生自发性肠道炎症，因此ATG 16 L1导致疾病的机制仍然不清楚。肠上皮细胞（IEC）中未折叠蛋白反应（UPR）转录因子X盒结合蛋白-1（Xbp 1）的缺失导致内质网（ER）应激、潘氏细胞损伤和自发性肠炎，所述IEC的人类直系同源物具有罕见的炎性肠病（IBD）风险变体。未解决的ER应激是IBD上皮的共同特征，CD的几个遗传风险因素影响潘氏细胞。在这里，我们发现IEC中UPR（Xbp 1 ΔIEC）或自噬功能（Atg 16 l1 ΔIEC或Atg 7 ΔIEC）的损伤导致彼此的代偿性接合，如果两种机制都受到损害，则会导致严重的自发性CD样透壁性回肠炎。Xbp 1 ΔIEC小鼠在低形态潘氏细胞中表现出自噬体形成，其通过蛋白激酶RNA样内质网激酶（PERK）、延伸起始因子2α（eIF 2 α）和转录激活因子4（ATF 4）与ER应激相关。回肠炎依赖于肠道微生物群，并源于IEC死亡增加、肌醇需要酶1α（IRE 1 α）调节的NFκB激活和肿瘤坏死因子信号传导，当自噬缺乏时，这些信号传导协同增加。ATG 16 L1抑制IRE 1 α活性和增强IEC中的自噬，减轻ER应激诱导的肠道炎症，减轻NFκB过度活化和IEC死亡。ER应激、自噬诱导和自发性回肠炎源于Paneth细胞特异性Xbp 1缺失。因此，潘氏细胞内遗传和环境控制的UPR功能可能为亚型ATG 16 L1功能后肠道炎症的发展设定阈值，并暗示回肠CD是潘氏细胞的一种特异性疾病。
Autophagy related 16-like 1 (ATG16L1) as a genetic risk factor has exposed the critical role of autophagy in Crohn’s disease (CD). Homozygosity for the highly prevalent ATG16L1 risk allele, or murine hypomorphic (HM) activity causes Paneth cell dysfunction. 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 enteritis. Unresolved ER stress is a common feature of IBD epithelium, and several genetic risk factors of CD affect Paneth cells. 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.
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