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

Abstract

The Nod-like receptor protein 3 (NLRP3) 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 NLRP3 inflammasome activation by damping basal and lipopolysaccharide-induced nuclear factor-κB-mediated up-regulation of NLRP3 and interleukin-1β 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 NLRP3 inflammasome. In mice with alum-induced peritonitis, blockade of Tim-3 exacerbates peritonitis by overcoming the inhibitory effect of Tim-3 on NLRP3 inflammasome activation, while transgenic expression of Tim-3 attenuates inflammation by inhibiting NLRP3 inflammasome activation. Our results show that Tim-3 is a critical negative regulator of NLRP3 inflammasome and provides a potential target for intervention of diseases with uncontrolled inflammasome activation.

• Authors: Wei Wang, Qingzhu Shi, Shuaijie Dou, Ge Li, Xinhui Shi, Xingwei Jiang, Zhiding Wang, Dandan Yu, Guojiang Chen, Renxi Wang, He Xiao, Chunmei Hou, Jiannan Feng, Beifen Shen, Yuanfang Ma, Gencheng Han
• Journal: Immunology (Immunology) Vol. 153 Issue 1 Pg. 71-83 (01 2018) ISSN: 1365-2567 [Electronic] England
• PMID: 28799242 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 John Wiley & Sons Ltd.

Chemical References

• HAVCR2 protein, human
• Hepatitis A Virus Cellular Receptor 2
• Inflammasomes
• Interleukin-1beta
• NF-kappa B
• NLR Family, Pyrin Domain-Containing 3 Protein
• Reactive Oxygen Species
• Adenosine Triphosphate
• Caspase 1
• Potassium

Topics

• Adenosine Triphosphate (biosynthesis)
• Adult
• Animals
• Case-Control Studies
• Caspase 1
• Cell Line
• Disease Models, Animal
• Female
• Hepatitis A Virus Cellular Receptor 2 (chemistry, metabolism)
• Humans
• Inflammasomes (immunology, metabolism)
• Interleukin-1beta (genetics, metabolism)
• Macrophages (immunology, metabolism)
• Male
• Mice
• Middle Aged
• NF-kappa B (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (antagonists & inhibitors, metabolism)
• Peritonitis (immunology, metabolism, pathology)
• Potassium (metabolism)
• Protein Binding
• Protein Interaction Domains and Motifs
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• Young Adult