Zhao Shengnan, Gong Zizhen, Zhou Jiefei, Tian Chunyan, Gao Yanhong, Xu Congfeng, Chen Yingwei, Cai Wei, Wu Jin
Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
State Key Laboratory of Proteomics, National Center for Proteomics Science, Beijing Institute of Radiation Medicine, Beijing, China; National Engineering Research Center for Protein Drugs, Beijing, China.
Front Immunol. 2016 Nov 28;7:536. doi: 10.3389/fimmu.2016.00536. eCollection 2016.
A westernized high-fat diet (HFD) is associated with the development of inflammatory bowel disease (IBD). High-level fecal deoxycholic acid (DCA) caused by HFD contributes to the colonic inflammatory injury of IBD; however, the mechanism concerning the initiation of inflammatory response by DCA remains unclear. In this study, we sought to investigate the role and mechanism of DCA in the induction of inflammation promoting NLRP3 inflammasome activation. Here, we, for the first time, showed that DCA dose-dependently induced NLRP3 inflammasome activation and highly pro-inflammatory cytokine-IL-1β production in macrophages. Mechanistically, DCA-triggered NLRP3 inflammasome activation by promoting cathepsin B release at least partially through sphingosine-1-phosphate receptor 2. Colorectal instillation of DCA significantly increased mature IL-1β level in colonic tissue and exacerbated DSS-induced colitis, while blockage of NLRP3 inflammasome or macrophage depletion dramatically reduced the mature IL-1β production and ameliorated the aggravated inflammatory injury imposed by DCA. Thus, our findings show that high-level fecal DCA may serve as an endogenous danger signal to activate NLRP3 inflammasome and contribute to HFD-related colonic inflammation. NLRP3 inflammasome may represent a new potential therapeutical target for treatment of IBD.
西式高脂肪饮食（HFD）与炎症性肠病（IBD）的发生有关。HFD导致的高水平粪便脱氧胆酸（DCA）会造成IBD的结肠炎症损伤；然而，DCA引发炎症反应的起始机制仍不清楚。在本研究中，我们试图探究DCA在诱导炎症促进NLRP3炎性小体激活中的作用和机制。在此，我们首次表明，DCA在巨噬细胞中剂量依赖性地诱导NLRP3炎性小体激活和高促炎细胞因子白细胞介素-1β（IL-1β）的产生。机制上，DCA至少部分通过鞘氨醇-1-磷酸受体2促进组织蛋白酶B释放，从而触发NLRP3炎性小体激活。结肠内滴注DCA显著增加结肠组织中成熟IL-1β水平，并加重葡聚糖硫酸钠（DSS）诱导的结肠炎，而阻断NLRP3炎性小体或清除巨噬细胞可显著降低成熟IL-1β的产生，并改善DCA所致的加重的炎症损伤。因此，我们的研究结果表明，高水平的粪便DCA可能作为一种内源性危险信号激活NLRP3炎性小体，并导致与HFD相关的结肠炎症。NLRP3炎性小体可能是治疗IBD的一个新的潜在治疗靶点。
