Negative regulation of Nod‐like receptor protein 3 inflammasome activation by T cell Ig mucin‐3 protects against peritonitis

摘要

Summary The Nod‐like receptor protein 3 ( NLRP 3) inflammasome plays roles in host defence against invading pathogens and in the development of autoimmune damage. Strict regulation of these responses is important to avoid detrimental effects. Here, we demonstrate that T cell Ig mucin‐3 (Tim‐3), an immune checkpoint inhibitor, inhibits NLRP 3 inflammasome activation by damping basal and lipopolysaccharide‐induced nuclear factor‐ κ B‐mediated up‐regulation of NLRP 3 and interleukin‐1 β during the priming step and basal and ATP /lipopolysaccharide‐induced ATP production, K + efflux, and reactive oxygen species production during the activation step. Residues Y256/Y263 in the C‐terminal region of Tim‐3 are required for these inhibitory effects on the NLRP 3 inflammasome. In mice with alum‐induced peritonitis, blockade of Tim‐3 exacerbates peritonitis by overcoming the inhibitory effect of Tim‐3 on NLRP 3 inflammasome activation, while transgenic expression of Tim‐3 attenuates inflammation by inhibiting NLRP 3 inflammasome activation. Our results show that Tim‐3 is a critical negative regulator of NLRP 3 inflammasome and provides a potential target for intervention of diseases with uncontrolled inflammasome activation.