Splenectomy protects against sepsis lethality and reduces serum HMGB1 levels.
High mobility group box 1 (HMGB1) is a critical mediator of lethal sepsis. Previously, we showed that apoptotic cells can activate macrophages to release HMGB1. During sepsis, apoptosis occurs primarily in lymphoid organs, including the spleen and thymus. Currently, it is unclear whether this accelerated lymphoid organ apoptosis contributes to systemic release of HMGB1 in sepsis. In this study, we report that splenectomy significantly reduces systemic HMGB1 release and improves survival in mice with polymicrobial sepsis. Treatment with a broad-spectrum caspase inhibitor reduces systemic lymphocyte apoptosis, suppresses circulating HMGB1 concentrations, and improves survival during polymicrobial sepsis, but fails to protect septic mice following splenectomy. These findings indicate that apoptosis in the spleen is essential to the pathogenesis of HMGB1-mediated sepsis lethality.
Huston
Jared M
JM
Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.
Wang
Haichao
H
Ochani
Mahendar
M
Ochani
Kanta
K
Rosas-Ballina
Mauricio
M
Gallowitsch-Puerta
Margot
M
Ashok
Mala
M
Yang
Lihong
L
Tracey
Kevin J
KJ
Yang
Huan
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D024243:HMGB1 Protein / Q000097:blood*; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D018805:Sepsis / Q000401:mortality / Q000628:therapy*; D013154:Spleen / Q000166:cytology; D013156:Splenectomy; D015996:Survival Rate
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D024243:HMGB1 Protein