Journal
JOURNAL OF IMMUNOLOGY
Volume 181, Issue 5, Pages 3535-3539Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.181.5.3535
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Funding
- Faculty Award program
- The Feinstein Institute for Medical Research [M01-RR018535]
- National Institute of General Medical Sciences (NIGMS)
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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.
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