Frontline Science: HMGB1 induces neutrophil dysfunction in experimental sepsis and in patients who survive septic shock

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

, Jean-Marc²  Gacouin, Arnaud³  Tarte, Karin⁵  Piau, Caroline⁶  Bone, Nathaniel⁷  Uhel, Fabrice⁹  Zmijewski, Jaroslaw W.^1,11  Tadié^1,16  Le Tulzo, Yves^1,17  Abraham, Edward^1,18 

[1] Mixte de Recherche (UMR) U917, INSERM, Rennes, France;Rennes 1, Rennes, France;and;..Centre dˈ..Etablissement Francais du sang, UMR U917, Rennes, France;..Maladies Infectieuses et Ré..Suivi Immunologique des Thé..UMR U917, UniversitéDepartment of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA;Investigation Clinique (CIC) 1414, INSERM, Rennes, France;Maladies Infectieuses et RéOffice of the Dean, Wake Forest University School of Medicine, Winston‐Salem, North Carolina, USA;Service de BactéUnitéanimation Médicale, CHU Rennes, Rennes, France;rapeutiques Innovantes, Pole de Biologie, Centre Hospitalier Universitaire (CHU) Rennes, Rennes, France;riologie, CHU Rennes, Rennes, France

关键词: NADPH oxidase;    sepsis;    HMGB1;    neutrophils;    immunosuppression;   

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Sepsis is accompanied by the initial activation of proinflammatory pathways and long-lasting immunosuppression that appears to contribute to late-occurring mortality. Although high-mobility group box 1 (HMGB1) is involved in many aspects of inflammation, its role in sepsis-induced immune suppression remains unclear. In this study, we examined HMGB1's contribution to neutrophil NADPH oxidase activity dysfunction and associated neutrophil-dependent bacterial clearance in mice subjected to sepsis and in patients who survive septic shock. Using a murine model of polymicrobial septic peritonitis, we demonstrated that treatment with anti-HMGB1 Ab significantly diminished sepsis-induced dysfunction of neutrophil NADPH oxidase activity. In a subsequent set of experiments, we found that blocking HMGB1 preserved the ability of neutrophils from patients recovering from septic shock to activate NADPH oxidase. Taken together, our data suggest that HMGB1 accumulation in the late phase of sepsis plays a specific role in the development of postsepsis immunosuppression and specifically affects neutrophil-dependent antibacterial defense mechanisms. Thus, blocking HMGB1 may be a promising therapeutic intervention to diminish the adverse effects of sepsis-induced immunosuppression.

【 授权许可】

CC BY