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
• Journal: JCI insight (JCI Insight) Vol. 6 Issue 14 (07 22 2021) ISSN: 2379-3708 [Electronic] United States
• PMID: 34291735 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cirbp protein, mouse
• Membrane Proteins
• RNA-Binding Proteins
• Sting1 protein, mouse

Topics

• Acute Lung Injury (immunology, pathology)
• Animals
• Disease Models, Animal
• Disease Progression
• Humans
• Macrophages (immunology, metabolism)
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Knockout
• RNA-Binding Proteins (metabolism)
• Severity of Illness Index
• Shock, Hemorrhagic (complications, diagnosis, immunology, pathology)
• Signal Transduction (genetics, immunology)