Cutting Edge: Critical Role for C5aRs in the Development of Septic Lymphopenia in Mice

In the early stages of sepsis, lymphocytes undergo apoptosis, resulting in lymphopenia and immunosuppression. The trigger for septic lymphopenia is unknown. Using the polymicrobial model of murine sepsis, we investigated the role of C5a receptors in septic lymphopenia. In wild-type mice, cecal ligation and puncture resulted in splenocyte apoptosis and significant lymphopenia after 3 d, which was not observed in C5aR1(-)/(-) or C5aR2(-)/(-) mice. Our data show that mouse neutrophils exposed to recombinant mouse C5a cause release of histones in a dose-dependent and time-dependent manner. Histone levels in spleen were significantly elevated following cecal ligation and puncture but were reduced by the absence of C5aR1. Histones induced significant lymphocyte apoptosis in vitro. Ab-mediated neutralization of histones prevented the development of lymphopenia in sepsis. Together, these results describe a new pathway of septic lymphopenia involving complement and extracellular histones. Targeting of this pathway may have therapeutic benefit for patients with sepsis or other serious illness.