Editors' ChoiceInflammation

Shocking Response

Sci. Signal.  26 Nov 2013:
Vol. 6, Issue 303, pp. ec286
DOI: 10.1126/scisignal.2004940

Pattern-recognition receptors, including Toll-like receptors (TLRs), are activated by pathogen-associated molecular patterns (PAMPs), which are released by certain infectious organisms, and damage-associated molecular patterns (DAMPs), which are released by damaged or apoptotic cells (see commentary by Ward). These molecules stimulate multiple signaling pathways that lead to systemic inflammation in patients with sepsis or hemorrhagic shock (loss of blood volume). Qiang et al. found that compared with healthy volunteers, patients with hemorrhagic shock had increased serum concentrations of cold-induced RNA-binding protein (CIRP), an RNA chaperone. When subjected to hemorrhagic shock and then reconstituted with fluids or when subjected to cecal ligation and puncture (to induce sepsis), rats exhibited increased amounts of serum CIRP compared with control animals. CIRP stimulated the release of the proinflammatory cytokine tumor necrosis factor–α (TNF-α) and the DAMP high-mobility group protein B1 (HMGB1) by macrophages in vitro. When administered to rats, recombinant CIRP increased the serum concentrations of TNF-α and HMGB1 compared with those in control rats and caused liver damage. Rats treated with CIRP-specific neutralizing antisera and then subjected to hemorrhagic shock and fluid resuscitation or cecal ligation and puncture exhibited decreased systemic inflammation and increased survival compared to animals treated with a control antibody. Surface plasmon resonance studies indicated that CIRP bound to TLR4 and its co-receptor MD2. Macrophages from mice deficient in TLR4 had reduced inflammatory responses to CIRP in vitro, and TLR4-deficient mice treated with CIRP had decreased serum concentrations of inflammatory cytokines compared with those of treated wild-type mice. Together, these data suggest that CIRP is an endogenous DAMP released in response to hemorrhagic and septic shock and that it stimulates systemic inflammation through its interaction with TLR4 in macrophages.

X. Qiang, W.-L. Yang, R. Wu, M. Zhou, A. Jacob, W. Dong, M. Kuncewitch, Y. Ji, H. Yang, H. Wang, J. Fujita, J. Nicastro, G. F. Coppa, K. J. Tracey, P. Wang, Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nat. Med. 19, 1489–1495 (2013). [PubMed]

P. A. Ward, An endogenous factor mediates shock-induced injury. Nat. Med. 19, 1368–1369 (2013). [PubMed]