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

肠上皮细胞死亡作为肠道生态失调、全身自身免疫和关节炎发作的调节剂

• 批准号: 418295699
• 负责人: Professorin Dr. Aline Bozec, Ph.D.
• 金额: --
• 依托单位: Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/418295699?language=en
• 关键词: Intestinal; epithelial; cell; death; modulator

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

肠道炎症和生态失调与自身免疫性疾病如类风湿性关节炎（RA）有关，然而，其潜在机制仍不完全清楚。在第一个资助期内，我们已经证明，由CASP 8或HIF 2 α蛋白功能改变引起的肠上皮细胞死亡失调会影响肠道微生物群，随后影响肠道和外周局部的免疫细胞功能。在功能水平上，我们可以进一步发现HIF蛋白影响紧密连接生物学和caspase-8上游的上皮细胞死亡，在实验性关节炎中具有相反的功能。有趣的是，我们进一步确定了上皮坏死性凋亡影响色氨酸代谢，补充SCFA可改善CASP 8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前途的治疗选择，特别是在关节炎的早期阶段。因此，在第二个资助期内，我们建议更好地描述上皮缺氧诱导的坏死性凋亡、SCFAs和关节炎之间的联系