Clusterin Neutralizes the Inflammatory and Cytotoxic Properties of Extracellular Histones in Sepsis
Jean‐François Augusto, Céline Beauvillain, Caroline Poli, Léa Paolini, Isabelle Tournier, Pascale Pignon, Simon Blanchard, Laurence Preisser, Raffaella Soleti, C. Prum Delepine, Marine Monnier, Isabelle Douchet, Pierre Asfar, François Beloncle, Olivier Guisset, Renaud Prével, Alain Mercat, Emeline Vinatier, Julien Goret, Jean‐François Subra, Dominique Couez, Mark R. Wilson, Patrick Blanco, Pascale Jeannin, Yves Delneste
Abstract
Abstract Rationale Extracellular histones, released into the surrounding environment during extensive cell death, promote inflammation and cell death, and these deleterious roles have been well documented in sepsis. Clusterin (CLU) is a ubiquitous extracellular protein that chaperones misfolded proteins and promotes their removal. Objectives We investigated whether CLU could protect against the deleterious properties of histones. Methods We assessed CLU and histone expression in patients with sepsis and evaluated the protective role of CLU against histones in in vitro assays and in vivo models of experimental sepsis. Measurements and Main Results We show that CLU binds to circulating histones and reduces their inflammatory, thrombotic, and cytotoxic properties. We observed that plasma CLU levels decreased in patients with sepsis and that the decrease was greater and more durable in nonsurvivors than in survivors. Accordingly, CLU deficiency was associated with increased mortality in mouse models of sepsis and endotoxemia. Finally, CLU supplementation improved mouse survival in a sepsis model. Conclusions This study identifies CLU as a central endogenous histone–neutralizing molecule and suggests that, in pathologies with extensive cell death, CLU supplementation may improve disease tolerance and host survival.