The negative regulation of inflammation is very important for the resolution of inflammatory diseases. Although many components and mediators in inflammation have been identified, how inflammation is finely regulated remains lack of evidence. Here we show that Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) translocates to mitochondria in the early time of inflammatory stimulation. The RRWFH motif in SH2 domain is essential for the translocation of SHP2. This phosphatase finally localizes in the mitochondrial matrix with the help of Tom20/Tom40 in outer membrane and Tim23 in inner membrane. Then SHP2 interacts with ANT1, a central molecule controlling mitochondrial permeability transition. This mechanism prevents the collapse of mitochondrial membrane potential, mtDNA release and ROS production, and thus inhibits the hyperactivation of NLRP3 inflammasome. Ablation or inhibition of SHP2 in macrophage causes intensified NLRP3 inflammasome activation, production of IL-1β and IL-18, and increased sensitivity to peritonitis. Collectively, our data highlight that SHP2 orchestrates an intrinsic regulatory loop for the mitochondrial homeostasis to limit excessive NLRP3 inflammasome activation, suggesting a possibility to treat inflammatory diseases via maintaining mitochondrial homeostasis.
*This study is supported by National Natural Science Foundation of China (81330079 and 81730100).
Key words: SHP2, resolution of inflammation, mitochondrial homeostasis, NLRP3 inflammasome.

To: 要旨(抄録)