Pivotal role of the CC chemokine, macrophage-derived chemokine, in the innate immune response

Macrophage-derived chemokine (MDC), a recently identified CC chemokine, has been regarded to be involved in chronic inflammation and dendritic cell an d lymphocyte homing, In this study, we demonstrate a pivotal role for MDC d uring experimental sepsis induced by cecal ligation and puncture (CLP), Int raperitoneal administration of MDC (1 mu g/mouse) protected mice from CLP-i nduced lethality. The survival was accompanied by increased number of perit oneal macrophages and decreased recovery of viable bacteria from the perito neum and peripheral blood. In addition, mice treated with an i.p. injection of MDC cleared bacteria more effectively than those in the control when 3 x 10(8) CFU live Escherichia coli was i.p. inoculated. Endogenous MDC was d etected in the peritoneum after CLP, and neutralization of the MDC with ant i-MDC Abs decreased CLP-induced recruitment of peritoneal macrophages and i ncreased the recovery of viable bacteria from the peritoneum and peripheral blood. MDC blockade was deleterious in the survival of mice after CLP. In vitro, MDC enhanced the phagocytic and killing activities of peritoneal mac rophages to E, coli and induced both a respiratory burst and the release of lysozomal enzyme from macrophages, Furthermore, MDC dramatically ameliorat ed CLP-induced systemic tissue inflammation as well as tissue dysfunction, which were associated in part with decreased levels of TNF-alpha, macrophag e inflammatory proteins-1 alpha and -2, and KC in specific tissues. Collect ively, these results indicate novel regulatory activities of MDC in innate immunity during sepsis and suggest that MDC may aid in an adjunct therapy i n sepsis.