Regulatory Role of HMGB1 on complement activation via the classical pathway (169.3)

Abstract Serum complement proteins play an important role in resistance to infection. The complement system is strongly activated in sepsis and the complement-activated products of anaphylatoxins have biological activities leading to inflammation. The nuclear protein, high mobility group box 1 protein (HMGB1) is released by inflammatory stimuli and plays a key role as a pro-inflammatory cytokine-like molecule. To investigate whether HMGB1 can induce complement activation, we have looked at the relationship between HMGB1 and complement system in this study. We first demonstrated the involvement of HMGB1 in binding to C1q for classical pathway activation. We observed the activation of complement cascade components such as C4b, C3b, C3c, and the membrane attack complex after C1q activation by HMGB1 in a dose-dependent manner. Moreover, complement activation could be observed in serum from mice after the intravenous injection of HMGB1. We then investigated the involvement of the A and B domain of HMGB1 during complement activation. HMGB1 B box, a well-known pro-inflammatory domain, was able to activate the complement system like wild type HMGB1, while HMGB1 A box showed no activation. The possible role of HMGB1 A box as an inhibitory domain in complement activation is now under investigation. In conclusion, the classical pathway of complement activation could be activated by the interaction of HMGB1 and C1q, showing the novel role of HMGB1 in the pathogenesis of HMGB1-induced shock.