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

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.

CIRP increases ICAM-1+ phenotype of neutrophils exhibiting elevated iNOS and NETs in sepsis

“…CIRP also causes EC dysfunction by increasing inflammasome-mediated pyroptosis in sepsis [8, 9, 11]. It has recently been shown that CIRP induces lung endoplasmic reticulum (ER) stress and its associated downstream responses to promote sepsis-associated ALI [10]. …”

“…The protective and harmful effects of neutrophils depend on the stages of sepsis, as at the onset of sepsis neutrophils are important in attenuating bacteremia, whereas at the late onset of sepsis prolonged and excessive infiltration of neutrophils often cause organ dysfunction [36]. An indirect role of CIRP on neutrophils to cause ARDS was shown during sepsis, in which the CIRP knock-out mice had reduced levels of neutrophil chemoattractants, MPO, and nitric oxide [10]. Thus, the role of CIRP on neutrophils in sepsis has been implicated but still remains to be fully explored.…”

“…Here, we established an association between increased CIRP expression and ICAM-1 + neutrophils in lungs. Since CIRP was previously shown to cause ARDS during sepsis [10, 11], it is therefore exciting to know if ICAM-1 + neutrophils play pro-inflammatory role. We found that CIRP-treated neutrophils upregulated ICAM-1 expression which produced increased levels of iNOS.…”

“…pro-inflammatory cytokines and causes EC dysfunction. 8 The role of CIRP in macrophages, lymphocytes, and ECs has been demonstrated, [8][9][10][11] whereas the direct role of CIRP on neutrophils during sepsis is unknown.…”

Oxidative and endoplasmic reticulum stress in respiratory disease

“…In septic shock and lung stress induced in animal models by exposure to LPS and other TLR ligands, both oxidative stress and ER stress occur in the damaged lung and appear to be a feature of the pathological process 104, 105, 106. In sepsis/LPS‐induced lung injury, both ER stress and autophagy (which may be a response to ER stress) occur and the systemic factor cold‐induced RNA‐binding protein (CIRP), local inflammatory cytokines such as IL‐17 and neutrophil activation have been linked with the development of ER stress and activation of the UPR 104, 105, 106. Pulmonary arterial hypertension results in chronic hypoxia, inflammation, and consequently oxidative and ER stress, and induction of autophagy, in the respiratory mucosa 107.…”