Journal Article

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

Nicastro, Jeffrey, Wang, Haichao, Yang, Weng-Lang, Zhou, Mian, Dong, Weifeng, Ji, Youxin, Fujita, Jun, Wang, Ping, Qiang, Xiaoling, Kuncewitch, Michael, Coppa, Gene F, Tracey, Kevin J, Wu, Rongqian, Yang, Huan, Jacob, Asha

2013

Overview

Cellular stress results in the release of damage-associated molecular pattern (DAMP) molecules that promote inflammatory responses. Here Ping Wang and colleagues show that cold-inducible RNA-binding protein (CIRP) is a DAMP that is released into the circulation in response to hemorrhagic shock and sepsis. It promotes proinflammatory cytokine release by binding to the TLR4-MD2 complex. Blockade of CIRP reduces inflammation, organ injury and mortality in animal models of hemorrhage and sepsis, suggesting that CIRP may be targeted therapeutically in these conditions. A systemic inflammatory response is observed in patients undergoing hemorrhagic shock and sepsis. Here we report increased levels of cold-inducible RNA-binding protein (CIRP) in the blood of individuals admitted to the surgical intensive care unit with hemorrhagic shock. In animal models of hemorrhage and sepsis, CIRP is upregulated in the heart and liver and released into the circulation. In macrophages under hypoxic stress, CIRP translocates from the nucleus to the cytosol and is released. Recombinant CIRP stimulates the release of tumor necrosis factor-α (TNF-α) and HMGB1 from macrophages and induces inflammatory responses and causes tissue injury when injected in vivo . Hemorrhage-induced TNF-α and HMGB1 release and lethality were reduced in CIRP-deficient mice. Blockade of CIRP using antisera to CIRP attenuated inflammatory cytokine release and mortality after hemorrhage and sepsis. The activity of extracellular CIRP is mediated through the Toll-like receptor 4 (TLR4)–myeloid differentiation factor 2 (MD2) complex. Surface plasmon resonance analysis indicated that CIRP binds to the TLR4-MD2 complex, as well as to TLR4 and MD2 individually. In particular, human CIRP amino acid residues 106–125 bind to MD2 with high affinity. Thus, CIRP is a damage-associated molecular pattern molecule that promotes inflammatory responses in shock and sepsis.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13 / 631/250/256/1980 / Adult / Aged / Aged, 80 and over / Amino acids / Animal models / Animals / Antibodies, Neutralizing - administration & dosage / Binding proteins / Binding sites / Biomedicine / Blood / Cancer Research / Cell Hypoxia / Cell Line / Cell receptors / Cold Shock Proteins and Peptides - antagonists & inhibitors / Cold Shock Proteins and Peptides - blood / Cytokines / Cytokines - blood / Disease Models, Animal / Female / Hemorrhage / Hemorrhagic shock / Humans / Hypoxia / Infectious Diseases / Inflammation Mediators - blood / Macrophages / Macrophages - metabolism / Male / Metabolic Diseases / Mice / Mice, Inbred C57BL / Mice, Knockout / Middle Aged / Molecular Medicine / Mortality / Neurosciences / Pathogens / Physiological aspects / Properties / Proteins / Rats / Rats, Sprague-Dawley / Resonance / RNA-Binding Proteins - antagonists & inhibitors / RNA-Binding Proteins - blood / RNA-Binding Proteins - genetics / Sepsis / Sepsis - blood / Shock, Hemorrhagic - blood / Toll-Like Receptor 4 - metabolism / Up-Regulation