Intestinal epithelial cell death as modulator of intestinal dysbiosis, systemic autoimmunity and the onset of Arthritis

肠道炎症和生态失调与自身免疫性疾病如类风湿关节炎（RA）有关，然而，其潜在机制仍不完全清楚。在第一个资助期，我们已经证明，通过改变CASP8或HIF2α蛋白功能而失调的肠上皮细胞死亡会影响肠道微生物群，随后影响肠道和周围的局部免疫细胞功能。在功能水平上，我们可以进一步发现HIF蛋白影响caspase-8上游的紧密连接生物学和上皮细胞死亡，在实验性关节炎中具有相反的功能。有趣的是，我们进一步发现上皮坏死会影响色氨酸代谢，补充SCFAs可以改善CASP8缺陷小鼠的肠道炎症。这些数据表明，靶向肠上皮细胞死亡可能是一种新的有希望的治疗选择，特别是在关节炎的早期阶段。因此，在第二个资助期，我们建议更好地描述上皮缺氧诱导的坏死性上睑下垂、scfa和关节炎之间的联系

Intestinal inflammation and dysbiosis have been linked to autoimmune diseases such as rheumatoid arthritis (RA), however, the underlying mechanisms remain incompletely understood. During the first funding period, we have shown that dysregulated intestinal epithelial cell death by altered CASP8 or HIF2α protein function affects the gut microbiota and subsequently immune cell functions locally in the gut and in the periphery. On a functional level, we could further uncover that HIF proteins influence tight junction biology and epithelial cell death upstream of caspase-8 with opposing functions in experimental arthritis. Interestingly, we further identified that epithelial necroptosis influences tryptophan metabolism and that supplementation of SCFAs ameliorates intestinal inflammation in CASP8 deficient mice. These data indicate that targeting intestinal epithelial cell death might represent a novel promising therapeutic option particularly during the early phase of arthritis. During the second funding period, we therefore propose to better delineate the link between epithelial hypoxia induced necroptosis, SCFAs and arthritis