Gao Yunhuan, Yue Jianmei, Ha Fushuang, Wang Ya, Wang Rong, Yang Xiaorong, Zhang Junqi, Liu Xinqi, Zhang Yuan, Han Tao, Yang Rongcun
Translational Medicine Institute, Affiliated Tianjin Union Medical Center of Nankai University, Tianjin 300071, China.
State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China.
Int J Biol Sci. 2024 Oct 28;20(15):5831-5849. doi: 10.7150/ijbs.97059. eCollection 2024.
Lipopolysaccharide (LPS) mediated caspases-4 (humans) and caspase-11 (rodent) (caspase-4/11) signaling can cause maturation of inflammatory cytokine IL-1β and cellular pyroptosis in the macrophages through guanylate-binding proteins (GBPs). However, how caspase-4/11s bind with GBPs together to activate caspase-4/11 by LPS remains elusive. We here found that BA derivatives from gut microbiota can regulate sensitivity of macrophages to LPS and Gram-negative bacteria through . BA derivatives such as deoxycholic acid (DCA) could induce expression through sphingosine-1-phosphate receptor 2 (S1PR2) in the macrophages of mice and humans. Both murine and human knockout (KO) macrophages did not produce immune response(s) to LPS or gram negative bacteria. KO mice had also reduced inflammatory responses to LPS or typhimurium ( T) infection. Mechanistically, could bind intracellular proteases caspase-4/11 with GBP1 together in the macrophages of human and mice to cause LPS-mediated activation of caspase-4/11. Thus, BA derivatives from gut microbiota promote GBPs-mediated activation of caspase-4/11 by LPS through .
脂多糖（LPS）介导的胱天蛋白酶-4（人类）和胱天蛋白酶-11（啮齿动物）（胱天蛋白酶-4/11）信号传导可通过鸟苷酸结合蛋白（GBPs）导致巨噬细胞中炎性细胞因子白细胞介素-1β成熟和细胞焦亡。然而，胱天蛋白酶-4/11如何与GBPs结合在一起以被LPS激活仍不清楚。我们在此发现，来自肠道微生物群的胆汁酸（BA）衍生物可通过……调节巨噬细胞对LPS和革兰氏阴性菌的敏感性。脱氧胆酸（DCA）等BA衍生物可通过鞘氨醇-1-磷酸受体2（S1PR2）在小鼠和人类巨噬细胞中诱导……表达。小鼠和人类……基因敲除（KO）巨噬细胞对LPS或革兰氏阴性菌均不产生免疫反应。KO小鼠对LPS或鼠伤寒沙门氏菌（T）感染的炎症反应也有所降低。从机制上讲，……可在人类和小鼠巨噬细胞中将细胞内蛋白酶胱天蛋白酶-4/11与GBP1结合在一起，从而导致LPS介导的胱天蛋白酶-4/11激活。因此，来自肠道微生物群的BA衍生物通过……促进GBPs介导的LPS对胱天蛋白酶-4/11的激活。
