Reduction of circulating histone toxicity is a major function of C-reactive protein after extensive tissue damage

Abstract

C-reactive protein (CRP) is a major acute phase protein. Although known to interact with chromatin, nucleosomes and histones, its functional roles are not clearly understood. Using both in vitro and in vivo models and samples from patients, this study demonstrates for the first time that CRP plays important roles in reducing the toxic effects of histones released into the circulation after extensive cell death. CRP protects endothelial cells by preventing histone integration into the cell membrane and thus reducing Ca2+ influx. In vivo, circulating histones cause endothelial damage, increased microvascular permeability, coagulation activation and IL-6 secretion. The latter induces CRP production in hepatocytes to form a negative feedback loop, a possible evolutionally conserved mechanism to limit secondary damage after extensive tissue injury. However, CRP responses lagged behind the histone surge following severe trauma. This indicates a time window for histone toxicity and also for potential clinical interventions using anti-histone therapy.

Molecular circuits in thrombosis and inflammation

“…In addition, histones are degraded slowly by an unknown protease, the regulation of which is also uncharacterised. Finally, C-reactive protein is reported to effectively decrease histone toxicity (42).…”