During sepsis, excessive activation of the complement system with generation of the anaphylatoxin C5a results in profound disturbances in crucial neutrophil functions. Moreover, because neutrophil activity is highly dependent on intracellular pH (pH), we propose a direct mechanistic link between complement activation and neutrophil pH In this article, we demonstrate that in vitro exposure of human neutrophils to C5a significantly increased pH by selective activation of the sodium/hydrogen exchanger. Upstream signaling of C5a-mediated intracellular alkalinization was dependent on C5aR1, intracellular calcium, protein kinase C, and calmodulin, and downstream signaling regulated the release of antibacterial myeloperoxidase and lactoferrin. Notably, the pH shift caused by C5a increased the glucose uptake and activated glycolytic flux in neutrophils, resulting in a significant release of lactate. Furthermore, C5a induced acidification of the extracellular micromilieu. In experimental murine sepsis, pH of blood neutrophils was analogously alkalinized, which could be normalized by C5aR1 inhibition. In the clinical setting of sepsis, neutrophils from patients with septic shock likewise exhibited a significantly increased pH These data suggest a novel role for the anaphylatoxin C5a as a master switch of the delicate pH balance in neutrophils resulting in profound inflammatory and metabolic changes that contribute to hyperlactatemia during sepsis.

Trauma represents the leading cause of death among young people in industrialized countries. Recent clinical and experimental studies have brought increasing evidence for activation of the innate immune system in contributing to the pathogenesis of trauma-induced sequelae and adverse outcome. As the "first line of defense", the complement system represents a potent effector arm of innate immunity, and has been implicated in mediating the early posttraumatic inflammatory response. Despite its generic beneficial functions, including pathogen elimination and immediate response to danger signals, complement activation may exert detrimental effects after trauma, in terms of mounting an "innocent bystander" attack on host tissue. Posttraumatic ischemia/reperfusion injuries represent the classic entity of complement-mediated tissue damage, adding to the "antigenic load" by exacerbation of local and systemic inflammation and release of toxic mediators. These pathophysiological sequelae have been shown to sustain the systemic inflammatory response syndrome after major trauma, and can ultimately contribute to remote organ injury and death. Numerous experimental models have been designed in recent years with the aim of mimicking the inflammatory reaction after trauma and to allow the testing of new pharmacological approaches, including the emergent concept of site-targeted complement inhibition. The present review provides an overview on the current understanding of the cellular and molecular mechanisms of complement activation after major trauma, with an emphasis of emerging therapeutic concepts which may provide the rationale for a "bench-to-bedside" approach in the design of future pharmacological strategies.

The role of adaptive immunity in contributing to post-traumatic neuroinflammation and neuropathology after head injury remains largely unexplored. The present study was designed to investigate the pathophysiological sequelae of closed head injury in Rag1 -/ -mice devoid of mature B and T lymphocytes. C57BL/6 wild-type and Rag1 -/ -mice were subjected to experimental closed head injury, using a standardized weight-drop device. Outcome parameters consisted of neurological scoring, quantification of blood-brain barrier (BBB) function, measurement of inflammatory markers and mediators of apoptosis in serum and brain tissue, and assessment of neuronal cell death, astrogliosis, and tissue destruction. There was no difference between wild-type and Rag1-/ -mice with regard to injury severity and neurological impairment for up to 7 days after head injury. The extent of BBB dysfunction was in a similar range for both groups. Quantification of complement activation fragments in serum revealed significantly attenuated C3a levels in Rag1 -/ -mice compared to wild-type animals. In contrast, the levels of pro-and anti-inflammatory cytokines and pro-apoptotic and anti-apoptotic mediators remained in a similar range for both groups, and the histological analysis of brain sections did not reveal a difference in reactive astrogliosis, tissue destruction, and neuronal cell death in Rag1 -/ -compared to wild-type mice. These findings suggest that adaptive immunity is not of crucial importance for initiating and sustaining the inflammatory neuropathology after closed head injury. The attenuated extent of post-traumatic complement activation seen in Rag1 -/ -mice implies a cross-talk between innate and adaptive immune responses, which requires further investigation in future studies.

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