Complement in trauma—Traumatised complement?

Abstract

Physical trauma represents a major global burden. The trauma‐induced response, including activation of the innate immune system, strives for regeneration but can also lead to post‐traumatic complications. The complement cascade is rapidly activated by damaged tissue, hypoxia, exogenous proteases and others. Activated complement can sense, mark and clear both damaged tissue and pathogens. However, excessive and insufficient activation of complement can result in a dysfunctional immune and organ response. Similar to acute coagulopathy, complementopathy can develop with enhanced anaphylatoxin generation and an impairment of complement effector functions. Various remote organ effects are induced or modulated by complement activation. Frequently, established trauma treatments are double‐edged. On one hand, they help stabilising haemodynamics and oxygen supply as well as injured organs and on the other hand, they also drive complement activation. Immunomodulatory approaches aim to reset trauma‐induced disbalance of complement activation and thus may change surgical trauma management procedures to improve outcome. Linked Articles This article is part of a themed issue on Canonical and non‐canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc

Complement Factor C5a Inhibits Apoptosis of Neutrophils—A Mechanism in Polytrauma?

“…In the present study, already early inhibitory effects of PMN apoptosis (within 2 h) upon stimulation of the C5a–C5aR1 axis (in more physiological concentrations: 10–100 ng/mL) could be detected. In the context of polytrauma, an early generation of C5a has been reported by several groups [ 29 ] and could easily provide the anaphylatoxic microenvironment and C5a concentrations in a 10–100 ng/mL range for the PMN to become more resistant against apoptotic processes. Moreover, our group previously showed first evidence of cross-talking complement-apoptosis systems after trauma: the pro-apoptotic granzyme B within the leukocytes was enhanced after polytrauma and capable of cleaving C5 to C5a, which then can obviously exhibit anti-apoptotic features [ 17 ].…”

Canonical and non‐canonical functions of the complement system in health and disease

“…The contribution of complement to the development of arterial hypertension is a relatively new area of complement research and is discussed by Wenzel et al (2021). Huber‐Lang et al (2021), Portilla and Xavier (2021) and Rawish et al (2021) will summarize and discuss progress on our understanding of the emerging new roles of complement in thrombosis, kidney disease and trauma.…”

“…In the second part of this themed issue, Jodele and Köhl (2021) highlight the contribution of complement activation in infection with highly pathogenic coronaviruses with a particular focus on activation pathways, complement genetics and the potential of complement as a target in SARS-CoV-2 infection. The contribution of complement to the development of arterial hypertension is a relatively new area of complement research and is discussed by Wenzel et al (2021). Huber-Lang et al (2021, Portilla and Xavier (2021) and Rawish et al (2021) will summarize and discuss progress on our understanding of the emerging new roles of complement in thrombosis, kidney disease and trauma.…”

Neglected No More: Emerging Cellular Therapies in Traumatic Injury

“…Severe trauma is associated with elevated levels of complement factors C3a, C4a, and C5a. The root cause of the complement factor elevation is unknown [24], whether by interaction with PAMPS or by consequence of activated thrombin in the coagulation cascade [17,25,26], however, histones released by C5a's action on neutrophils were linked to induction of T cell apoptosis, suggesting that histone levels increased after trauma may contribute to T cell death through the indirect effect of C5a. In addition, C5aR activation was shown to enhance proinflammatory Th1 responses and to reduce anti-inflammatory Th2 responses, hereby shifting the balance toward a systemic inflammatory condition [24].…”

“…Excessive thrombin generation from the coagulation cascade leads to further hypocoagulation, characterized by fibrinolysis and platelet dysfunction [28][29][30][31]. This excessive thrombin generation can also further exacerbate activation of complement factors in the innate immune response [17,24,25].…”