Tyrosine phosphatase SHP2 negatively regulates NLRP3 inflammasome activation via ANT1-dependent mitochondrial homeostasis

Yan Shen,Wen Liu,Gen-Sheng Feng,Zhen Chen,Wenjie Guo,Yanhong Gu,Qiang Xu,Lihong Shen,Yang Sun,Xingqi Wang,Shuang Peng

doi:10.1038/s41467-017-02351-0

Abstract

Aberrant activation of NLRP3 inflammasome has an important function in the pathogenesis of various inflammatory diseases. Although many components and mediators of inflammasome activation have been identified, how NLRP3 inflammasome is regulated to prevent excessive inflammation is unclear. Here we show NLRP3 inflammasome stimulators trigger Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) translocation to the mitochondria, to interact with and dephosphorylate adenine nucleotide translocase 1 (ANT1), a central molecule controlling mitochondrial permeability transition. This mechanism prevents collapse of mitochondrial membrane potential and the subsequent release of mitochondrial DNA and reactive oxygen species, thus preventing hyperactivation of NLRP3 inflammasome. Ablation or inhibition of SHP2 in macrophages causes intensified NLRP3 activation, overproduction of proinflammatory cytokines IL-1β and IL-18, and increased sensitivity to peritonitis. Collectively, our data highlight that, by inhibiting ANT1 and mitochondrial dysfunction, SHP2 orchestrates an intrinsic regulatory loop to limit excessive NLRP3 inflammasome activation.

Highlights

Inflammasomes are multi-molecular signaling complexes that have a crucial function in host defense against infection, as well as various autoimmune and inflammatory disorders[1]
In primary peritoneal macrophages isolated from cSHP2-KO mice, NLRP3 inflammasome activation by adenosine triphosphate (ATP), monosodium urate (MSU), or Nigericin was remarkably intensified, evidenced by increased caspase-1 cleavage, as well as over-production of IL-1β and IL-18 (Fig. 1a–c)
ATPstimulated ASC oligomerization was higher in cells with Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) knockdown, when compared with that in cells transfected with control short hairpin RNA (Fig. 1i)

Summary

Introduction

Inflammasomes are multi-molecular signaling complexes that have a crucial function in host defense against infection, as well as various autoimmune and inflammatory disorders[1]. Given the importance of NLRP3 inflammasome in the pathogenesis of many inflammatory diseases such as peritonitis, multiple sclerosis and obesity[7,8,9], understanding the positive and negative regulation of NLRP3 inflammasome may provide insight into pathology and identify new therapeutic strategies. Protein complex comprised ANT1, voltage-dependent anion channel, and cyclophilin D has a crucial function in the maintenance of mitochondrial membrane potential and permeability[16,17]. We identify ANT1 as phosphatase substrate of SHP2 upon its translocation to mitochondria, which mediates the negative regulation of NLRP3 inflammasome by SHP2. Our findings provide new insights into the dynamic regulation of NLRP3 inflammasome activation through a SHP2-ANT1-mediated negative regulatory loop

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Conclusion