Extracellular CIRP activates STING to exacerbate hemorrhagic shock

Stimulator of IFN genes (STING) activates TANK-binding kinase 1 (TBK1) and IFN regulatory factor 3 (IRF3) to produce type HFNs. Extracellular cold-inducible RNA-binding protein (eCIRP) is released from cells during hemorrhagic shock (HS). We hypothesized that eCIRP activates STING to induce inflammation and acute lung injury (ALI) after HS. WT and STING(-/-) mice underwent controlled hemorrhage by bleeding, followed by fluid resuscitation. Blood and lungs were collected at 4 hours after resuscitation. Serum ALT, AST, LDH, IL-6, and IFN-beta were significantly decreased in STING(-/-) mice compared with WT mice after HS. In STING(-/-) mice, the levels of pTBK1 and pIRF3, and expression of TNF-alpha, IL-6, and IL-1 beta mRNAs and proteins in the lungs, were significantly decreased compared with WT HS mice. The 10-day mortality rate in STING(-/- )mice was significantly reduced. I.v. injection of recombinant mouse CIRP (rmCIRP) in STING(-/-) mice showed a significant decrease in pTBK1 and pIRF3 and in IFN-alpha and IFN-beta mRNAs and proteins in the lungs compared with rmCIRP-treated WT mice. Treatment of TLR4(-/-), MyD88(-/-), and TRIF-/- macrophages with rmCIRP significantly decreased pTBK1 and pIRF3 levels and IFN-alpha and IFN-beta mRNAs and proteins compared with WT macrophages. HS increases eCIRP levels, which activate STING through TLR4/MyD88/TRIF pathways to exacerbate inflammation.