Bile Acids Activate NLRP3 Inflammasome, Promoting Murine Liver Inflammation or Fibrosis in a Cell Type-Specific Manner.
Bile Acids Activate NLRP3 Inflammasome, Promoting Murine Liver Inflammation or Fibrosis in a Cell Type-Specific Manner.
复制标题
作者：
Holtmann TM;Inzaugarat ME;Knorr J;Geisler L;Schulz M;Bieghs V;Frissen M;Feldstein AE;Tacke F;Trautwein C;Wree A
胆汁酸作为一种重要的信号分子，在胆汁淤积性肝损伤的发生发展中起着至关重要的作用，但对其涉及的细胞类型和信号通路的了解有限。本研究的目的是评估关键BA的炎症和纤维化潜能，以及专注于NLRP3炎症小体的不同肝细胞亚群的作用。C57BL/6野生型（WT）和Nlrp3−/−小鼠分别饲喂添加胆酸（CA）、脱氧胆酸（DCA）或石胆酸（LCA）的日粮7 d。此外，在体外用上述BA刺激WT和Nlrp3 - / -小鼠的原代肝细胞、库普弗细胞（KC）和肝星状细胞（HSC）。LCA喂养导致肝损伤和NLRP3炎性体的激活。离体KC细胞受LCA影响最大，导致促炎表型。nlrp3缺陷小鼠或细胞的肝损伤和原发性KC激活均得到改善。DCA喂养诱导纤维化改变。在DCA刺激下，原代HSC上调NLRP3炎性体和早期纤维化标志物，但LCA不上调。在Nlrp3−/−小鼠或细胞中，肝脏和原代HSC中的促纤维化信号减弱。数据显示，不同的BA诱导HSC或KC的NLRP3炎性体活化，促进纤维化或炎症。
Bile acids (BA) as important signaling molecules are considered crucial in development of cholestatic liver injury, but there is limited understanding on the involved cell types and signaling pathways. The aim of this study was to evaluate the inflammatory and fibrotic potential of key BA and the role of distinct liver cell subsets focusing on the NLRP3 inflammasome. C57BL/6 wild-type (WT) and Nlrp3−/− mice were fed with a diet supplemented with cholic (CA), deoxycholic (DCA) or lithocholic acid (LCA) for 7 days. Additionally, primary hepatocytes, Kupffer cells (KC) and hepatic stellate cells (HSC) from WT and Nlrp3−/− mice were stimulated with aforementioned BA ex vivo. LCA feeding led to strong liver damage and activation of NLRP3 inflammasome. Ex vivo KC were the most affected cells by LCA, resulting in a pro-inflammatory phenotype. Liver damage and primary KC activation was both ameliorated in Nlrp3-deficient mice or cells. DCA feeding induced fibrotic alterations. Primary HSC upregulated the NLRP3 inflammasome and early fibrotic markers when stimulated with DCA, but not LCA. Pro-fibrogenic signals in liver and primary HSC were attenuated in Nlrp3−/− mice or cells. The data shows that distinct BA induce NLRP3 inflammasome activation in HSC or KC, promoting fibrosis or inflammation.
登录
查看更多内容
Farnesoid X 受体对 NLRP3 炎性体的调节是胆汁淤积相关脓毒症的基础
影响因子：
29
作者：
Hao H;Cao L;Jiang C;Che Y;Zhang S;Takahashi S;Wang G;Gonzalez FJ
通讯作者：
Gonzalez FJ
影响因子：
8.7
作者：
Elliott EI;Sutterwala FS
通讯作者：
Sutterwala FS
DOI：
10.1016/j.jcmgh.2019.12.008
发表时间：
2020-01-01
影响因子：
7.2
作者：
Cai, Shi-Ying;Ge, Maoxu;Boyer, James L.
通讯作者：
Boyer, James L.
影响因子：
6
作者：
Allen, Katryn;Jaeschke, Hartmut;Copple, Bryan L.
通讯作者：
Copple, Bryan L.
影响因子：
6
作者：
O'Brien, Kate M.;Allen, Katryn M.;Copple, Bryan L.
通讯作者：
Copple, Bryan L.