Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis

Excessive production of proinflammatory mediators is observed in patients undergoing hemorrhagic and septic shock. Here, we report the detection of cold-inducible RNA-binding protein (CIRP) in the blood of surgical ICU individuals. In animal models of hemorrhage and sepsis, CIRP is up-regulated in several organs and released into the circulation. Under hypoxic stresses, CIRP in macrophages is translocated from the nucleus to the cytosol and actively released. Recombinant CIRP stimulates TNF-α and HMGB1 release in macrophages as well as induces inflammatory responses and causes tissue injury in animals. Antisera to CIRP attenuate shock-induced inflammation, tissue injury, and lethality. Extracellular CIRP's activity is mediated through the TLR4/MD2 complex. Surface plasmon resonance analysis indicates that CIRP binds to the TLR4/MD2 complex as well as to individual TLR4 and MD2. The human CIRP amino-acid segment 106-125 binds to MD2 with high affinity. Collectively, CIRP is a new proinflammatory mediator of shock.