Bride and groom in systemic inflammation - The bells ring for complement and Toll in cooperation

Attenuating the sepsis-induced systemic inflammatory response, with subsequent homeostatic imbalance, has for years been one of the main tasks in sepsis related research. Complement and the TLR family constitute two important upstream sensor and effector-systems of innate immunity. Although they act as partly independent branches of pattern recognition, recent evidence indicate a considerable crosstalk implying that they can either compensate, synergize or antagonize each other. Combined inhibition of these pathways is therefore a particularly interesting approach with a profound anti-inflammatory potential. In previous preclinical studies, we demonstrated that targeting the key molecules C3 or C5 of complement and CD14 of the TLR family had a vast anti-inflammatory effect on Gram-negative bacteria-induced inflammation and sepsis. In this review, we elucidate the significance of these key molecules as important targets for intervention in sepsis and systemic inflammatory response syndrome. Finally, we argue that a combined inhibition of complement and CD14 represent a potential general treatment regimen, beyond the limit of sepsis, including non-infectious systemic inflammation and ischemia reperfusion injury. (C) 2012 Elsevier GmbH. All rights reserved.