HMGB1 mediates cognitive impairment in sepsis survivors.
Severe sepsis, a syndrome that complicates infection and injury, affects 750,000 annually in the United States. The acute mortality rate is approximately 30%, but, strikingly, sepsis survivors have a significant disability burden: up to 25% of survivors are cognitively and physically impaired. To investigate the mechanisms underlying persistent cognitive impairment in sepsis survivors, here we developed a murine model of severe sepsis survivors following cecal ligation and puncture (CLP) to study cognitive impairments. We observed that serum levels of high mobility group box 1 (HMGB1), a critical mediator of acute sepsis pathophysiology, are increased in sepsis survivors. Significantly, these levels remain elevated for at least 4 wks after CLP. Sepsis survivors develop significant, persistent impairments in learning and memory, and anatomic changes in the hippocampus associated with a loss of synaptic plasticity. Administration of neutralizing anti-HMGB1 antibody to survivors, beginning 1 wk after onset of peritonitis, significantly improved memory impairments and brain pathology. Administration of recombinant HMGB1 to naïve mice recapitulated the memory impairments. Together, these findings indicate that elevated HMGB1 levels mediate cognitive decline in sepsis survivors, and suggest that it may be possible to prevent or reverse cognitive impairments in sepsis survivors by administration of anti-HMGB1 antibodies.
Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York 11030, United States of America.
Sangeeta S
SS
Chavan
Patricio T
PT
Huerta
Sergio
S
Robbiati
S I
SI
Valdes-Ferrer
Mahendar
M
Ochani
Meghan
M
Dancho
Maya
M
Frankfurt
Bruce T
BT
Volpe
Kevin J
KJ
Tracey
Betty
B
Diamond
D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D003072:Cognition Disorders / Q000097:blood* / Q000150:complications* / Q000503:physiopathology; D004195:Disease Models, Animal; D024243:HMGB1 Protein / Q000097:blood* / Q000276:immunology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018805:Sepsis / Q000097:blood* / Q000150:complications* / Q000503:physiopathology; D016019:Survival Analysis
D057134:Antibodies, Neutralizing; D024243:HMGB1 Protein