Cold-inducible RNA-binding protein (CIRP) causes sepsis-associated acute lung injury via induction of endoplasmic reticulum stress

Mohammad Moshahid Khan,Ping Wang,Weng-Lang Yang,Max Brenner,Alexandra Cerutti Bolognese

doi:10.1038/srep41363

Abstract

Cold-inducible RNA-binding protein (CIRP), released into the circulation during sepsis, causes lung injury via an as yet unknown mechanism. Since endoplasmic reticulum (ER) stress is associated with acute lung injury (ALI), we hypothesized that CIRP causes ALI via induction of ER stress. To test this hypothesis, we studied the lungs of wild-type (WT) and CIRP knockout (KO) mice at 20 h after induction of sepsis by cecal ligation and puncture (CLP). WT mice had significantly more severe ALI than CIRP KO mice. Lung ER stress markers (BiP, pIRE1α, sXBP1, CHOP, cleaved caspase-12) were increased in septic WT mice, but not in septic CIRP KO mice. Effector pathways downstream from ER stress – apoptosis, NF-κB (p65), proinflammatory cytokines (IL-6, IL-1β), neutrophil chemoattractants (MIP-2, KC), neutrophil infiltration (MPO activity), lipid peroxidation (4-HNE), and nitric oxide (iNOS) – were significantly increased in WT mice, but only mildly elevated in CIRP KO mice. ER stress markers were increased in the lungs of healthy WT mice treated with recombinant murine CIRP, but not in the lungs of TLR4 KO mice. This suggests CIRP directly induces ER stress via TLR4 activation. In summary, CIRP induces lung ER stress and downstream responses to cause sepsis-associated ALI.

Highlights

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection and results in an estimated 5.3 million deaths worldwide every year[1,2]
We have previously shown that in sepsis and septic shock, Cold-inducible RNA-binding protein (CIRP) translocates from the nucleus to the cytosol and is subsequently released into the circulation, where it acts as a damage-associated molecular pattern molecule (DAMP) to increase disease severity and mortality[7]
CIRP was required for the induction of five key endoplasmic reticulum (ER) stress proteins: the chaperone protein BiP, the phosphorylated form of the ER stress sensor IRE1α, the spliced form of transcription factor XBP1, and the pro-apoptotic components CHOP and cleaved Casp-12

Summary

Introduction

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection and results in an estimated 5.3 million deaths worldwide every year[1,2]. We have recently shown that exogenous CIRP administered to healthy mice causes lung injury, as evidenced by vascular leakage, neutrophil infiltration, local production of TNF-αand IL-1β,and activation of the NRLP3 inflammasome in lung vascular endothelial cells[9]. These observations suggest that CIRP plays a critical role in the development of sepsis-associated ALI. We hypothesized that CIRP released during sepsis leads to sepsis-associated ALI through the induction of ER stress and its downstream events in the lungs

Methods

Results

Conclusion