Clusterin Neutralizes the Inflammatory and Cytotoxic Properties of Extracellular Histones in Sepsis

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 t...

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Published in:American journal of respiratory and critical care medicine 2023-07, Vol.208 (2), p.176-187
Main Authors: Augusto, Jean-François, Beauvillain, Céline, Poli, Caroline, Paolini, Léa, Tournier, Isabelle, Pignon, Pascale, Blanchard, Simon, Preisser, Laurence, Soleti, Raffaella, Delépine, Chloé, Monnier, Marine, Douchet, Isabelle, Asfar, Pierre, Beloncle, François, Guisset, Olivier, Prével, Renaud, Mercat, Alain, Vinatier, Emeline, Goret, Julien, Subra, Jean-François, Couez, Dominique, Wilson, Mark R, Blanco, Patrick, Jeannin, Pascale, Delneste, Yves
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents
Autophagy
Cell Death
Clusterin - metabolism
Cytokines
Cytotoxicity
Histones - metabolism
Inflammation
Mice
Pathogenesis
Sepsis
Sepsis - drug therapy
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Summary: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. We investigated whether CLU could protect against the deleterious properties of histones. We assessed CLU and histone expression in patients with sepsis and evaluated the protective role of CLU against histones in assays and models of experimental sepsis. 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. 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.
ISSN:1073-449X
1535-4970
DOI:10.1164/rccm.202207-1253OC