Extracellular CIRP activates STING to exacerbate hemorrhagic shock
Kehong Chen, … , Max Brenner, Ping Wang
Kehong Chen, … , Max Brenner, Ping Wang
Published July 22, 2021
Citation Information: JCI Insight. 2021;6(14):e143715. https://doi.org/10.1172/jci.insight.143715.
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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.