Extracellular CIRP activates STING to exacerbate hemorrhagic shock

• Published in: JCI insight Vol. 6; no. 14
• Main Authors: Chen, Kehong, Cagliani, Joaquin, Aziz, Monowar, Tan, Chuyi, Brenner, Max, Wang, Ping
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 22.07.2021; American Society for Clinical investigation
• Subjects: Acute Lung Injury - immunology; Acute Lung Injury - pathology; Animals; Disease Models, Animal; Disease Progression; Humans; Inflammation; Macrophages - immunology; Macrophages - metabolism; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; RNA-Binding Proteins - metabolism; Severity of Illness Index; Shock, Hemorrhagic - complications; Shock, Hemorrhagic - diagnosis; Shock, Hemorrhagic - immunology; Shock, Hemorrhagic - pathology; Signal Transduction - genetics; Signal Transduction - immunology; Inflammation; Bacterial infections
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.143715

Stimulator of IFN genes (STING) activates TANK-binding kinase 1 (TBK1) and IFN regulatory factor 3 (IRF3) to produce type I IFNs. 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-β 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-α, IL-6, and IL-1β 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-α and IFN-β 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-α and IFN-β mRNAs and proteins compared with WT macrophages. HS increases eCIRP levels, which activate STING through TLR4/MyD88/TRIF pathways to exacerbate inflammation.