Bile acid derivatives from gut microbiota promote GBPs-mediated activation of caspase-4/11 by LPS through <i>lncRNA57RIK</i>

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 <i>lncRNA57RIK</i>. BA derivatives such as deoxycholic acid (DCA) could induce <i>lncRNA57RIK</i> expression through sphingosine-1-phosphate receptor 2 (S1PR2) in the macrophages of mice and humans. Both murine and human <i>lncRNA57RIK</i> knockout (KO) macrophages did not produce immune response(s) to LPS or gram negative bacteria. <i>LncRNA57RIK</i> KO mice had also reduced inflammatory responses to LPS or <i>Salmonella</i> typhimurium (<i>S.</i> T) infection. Mechanistically, <i>lncRNA57RIK</i> 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 <i>lncRNA57RIK</i>.