• Jean-François Augusto, Céline Beauvillain, Caroline Poli, Léa Paolini, Isabelle Tournier, Pascale Pignon, Simon Blanchard, Laurence Preisser, Raffaella Soleti, Chloé Delépine, 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, and Yves Delneste.
• Univ Angers, Nantes Université, INSERM, CNRS, CRCI2ICAT, Angers, France.
• Am. J. Respir. Crit. Care Med. 2023 Jul 15; 208 (2): 176187176-187.

AbstractRationale: 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.

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