HMGB1 mediates Splenomegaly, Anemia and Leukocytosis in Mice Surviving Sepsis (44.7)

Abstract Severe sepsis, a syndrome complicating infection or injury, is a leading cause of death. It also has long-term deleterious effects on survivors, including high mortality and diminished quality of life. High-mobility group box 1 (HMGB1) is a critical late mediator of acute sepsis that remains elevated after other inflammatory cytokines have normalized. Here we studied the kinetics of circulating HMGB1 in mice surviving severe abdominal sepsis, and the effects of administering neutralizing anti HMGB1 mAb. In a standardized model of murine sepsis, we observed that mice surviving sepsis developed splenomegaly for at least four weeks. Splenocytes from sepsis survivors produced significantly more cytokines following exposure to TLR ligands. Circulating HMGB1 levels are significantly increased for at least 4 weeks after sepsis. Treatment with anti-HMGB1 neutralizing monoclonal antibodies effectively prevented the development of splenomegaly, leukocytosis and anemia. Chronic administration of recombinant HMGB1 to healthy mice induced significant splenomegaly and leukocytosis. Recombinant HMGB1 also sensitized splenocytes and significantly increased the release of TNF and IL-6. In conclusion, serum HMGB1 levels are persistently elevated for at least 4 weeks in mice that survive lethal sepsis. Anti-HMGB1 mAb administration reverses the development of splenomegaly, leukocytosis and anemia, which may have implications for understanding the pathogenesis of post-sepsis complications.