Abstract：
Ulcerative colitis is a complex inflammatory bowel disorder disease that can induce rectal and colonic dysfunction. Although the prevalence of IBD in Western countries is almost 0.5% of the general population, genetic causes are still not fully understood. In a recent discovery, itaconate was found to function as an immune-modulating metabolite in mammalian immune cells, wherein it is synthesized as an antimicrobial compound from the citric acid cycle intermediate cis-aconitic acid. However, the association between the Acod1 (Aconitate decarboxylase 1)-itaconate axis and ulcerative colitis has rarely been studied. To elucidate this, we established a DSS-induced colitis model with Acod1-deficient mice and then measured the mouse body weights, colon lengths, histological changes, and cytokines/chemokines in the colon. We first confirmed the upregulation of Acod1 RNA and protein expression levels in DSS-induced colitis. Then, we found that colitis symptoms, including weight loss, the disease activity index, and colon shortening, were worsened by the depletion of Acod1. In addition, the extent of intestinal epithelial barrier breakdown, the extent of immune cell infiltration, and the expression of proinflammatory cytokines and chemokines in Acod1-deficient mice were higher than those in wild-type mice. Finally, we confirmed that 4-octyl itaconate (4-OI) alleviated DSS-induced colitis in Acod1-deficient mice and decreased the expression of inflammatory cytokines and chemokines. To our knowledge, this study is the first to elucidate the role of the Acod1-itaconate axis in colitis. Our data clearly showed that Acod1 deletion resulted in severe DSS-induced colitis and substantial increases in inflammatory cytokine and chemokine levels. Our results suggest that Acod1 may normally play an important regulatory role in the pathogenesis of colitis, demonstrating the potential for novel therapies using 4-OI.
摘要：
溃疡性结肠炎是一种复杂的炎症性肠病，可引起直肠和结肠功能障碍。尽管在西方国家IBD的患病率几乎是一般人群的0.5%,遗传原因仍未完全了解。在最近的一项发现中，发现衣康酸酯在哺乳动物免疫细胞中作为免疫调节代谢产物发挥作用，其中它作为抗微生物化合物从柠檬酸循环中间体顺式乌头酸合成。然而,Acod1(乌头脱羧酶1)-衣康酸轴与溃疡性结肠炎之间的关联研究很少。为了阐明这一点，用Acod1缺陷小鼠建立DSS诱导的结肠炎模型，然后测量小鼠体重，结肠长度,组织学变化,和结肠中的细胞因子/趋化因子。我们首先证实了DSS诱导的结肠炎中Acod1RNA和蛋白质表达水平的上调。然后，我们发现结肠炎的症状,包括减肥,疾病活动指数，结肠缩短，因Acod1的耗尽而恶化。此外,肠上皮屏障破坏的程度，免疫细胞浸润的程度，Acod1缺陷小鼠的促炎细胞因子和趋化因子的表达高于野生型小鼠。最后,我们证实,4-辛基衣康酸(4-OI)缓解了Acod1缺陷小鼠DSS诱导的结肠炎,并降低了炎性细胞因子和趋化因子的表达.据我们所知,本研究首次阐明Acod1-衣康酸轴在结肠炎中的作用.我们的数据清楚地表明，Acod1缺失导致严重的DSS诱导的结肠炎和炎性细胞因子和趋化因子水平的显著增加。我们的结果表明，Acod1可能在结肠炎的发病机制中发挥重要的调节作用。证明了使用4-OI的新疗法的潜力。
