Extracellular CIRP activates STING to exacerbate hemorrhagic shock
Kehong Chen, Joaquin Cagliani, Monowar Aziz, Chuyi Tan, Max Brenner, Ping Wang
Kehong Chen, Joaquin Cagliani, Monowar Aziz, Chuyi Tan, Max Brenner, Ping Wang
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Research Article Inflammation

Extracellular CIRP activates STING to exacerbate hemorrhagic shock

Abstract

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.

Authors

Kehong Chen, Joaquin Cagliani, Monowar Aziz, Chuyi Tan, Max Brenner, Ping Wang

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Figure 1

STING–/– mice have less serum organ injury and inflammatory markers, and they exhibit survival benefit in HS.

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STING–/– mice have less serum organ injury and inflammatory markers, and...
(A) HS was induced in WT and STING–/– mice, and mean arterial pressure (MAP) was recorded at the induction phase (0–20 min), the hemorrhage phase (20–110 min), and the first 30 minutes of the resuscitation phase (110–140 min). Sham-operated mice with the same time frame were also recorded. Data are expressed as mean ± SEM (n = 6 mice/group). (B–F) Blood from WT and STING–/– mice at 4 hours after HS and sham mice were collected for the analysis of the serum levels of (B) ALT, (C) AST, (D) LDH, (E) IL-6, and (F) IFN-β. Data are expressed as mean ± SEM (n = 6 mice/group) and compared by ANOVA and SNK tests. The experiments were performed 3 times, and all data were used for analysis. *P < 0.05 versus WT-sham; #P < 0.05 versus WT-HS mice. (G) HS was induced in WT and STING–/– mice. Mice were monitored for survival for 10 days. Survival rates were analyzed by the Kaplan-Meier estimator using a log-rank test (n = 10 mice/group; *P < 0.05 versus WT-HS). HS, hemorrhagic shock; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDH, lactate dehydrogenase.