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

Abstract

Life-threatening polytrauma results in early activation of the complement and apoptotic system, as well as leukocytes, ultimately leading to the clearance of damaged cells. However, little is known about interactions between the complement and apoptotic systems in PMN (polymorphonuclear neutrophils) after multiple injuries. PMN from polytrauma patients and healthy volunteers were obtained and assessed for apoptotic events along the post-traumatic time course. In vitro studies simulated complement activation by the exposure of PMN to C3a or C5a and addressed both the intrinsic and extrinsic apoptotic pathway. Specific blockade of the C5a-receptor 1 (C5aR1) on PMN was evaluated for efficacy to reverse complement-driven alterations. PMN from polytrauma patients exhibited significantly reduced apoptotic rates up to 10 days post trauma compared to healthy controls. Polytrauma-induced resistance was associated with significantly reduced Fas-ligand (FasL) and Fas-receptor (FasR) on PMN and in contrast, significantly enhanced FasL and FasR in serum. Simulation of systemic complement activation revealed for C5a, but not for C3a, a dose-dependent abrogation of PMN apoptosis in both intrinsic and extrinsic pathways. Furthermore, specific blockade of the C5aR1 reversed C5a-induced PMN resistance to apoptosis. The data suggest an important regulatory and putative mechanistic and therapeutic role of the C5a/C5aR1 interaction on PMN apoptosis after polytrauma.

Complementing Testicular Immune Regulation: The Relationship between Sertoli Cells, Complement, and the Immune Response

“…Anaphylatoxin receptor interaction enhances phagocytosis and leads to the production and release of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β [ 171 ]. Regarding high-inflammatory cells such as neutrophils, the anaphylatoxin signaling pathway activates neutrophils to degranulate and undergo respiratory burst, and C5aR1 inhibits their apoptosis, thus increasing their capacity to destroy grafts [ 171 , 172 , 173 ].…”

From complement to complosome in non‐alcoholic fatty liver disease: When location matters

“…105 C3aR and C5aR signalling was also indicated to regulate other immune cells, such as T cells and neutrophils, which potentially may play an important role in NAFLD pathogenesis. [113][114][115][116][117] These lines of evidence imply that in the stage of NASH, the complement system drives this process by regulating the abundance and function of immune cells, such as macrophages, T cells and neutrophils. However, there remains a paucity of evidence in this area, and future studies are needed.…”

C5aR Expression in Kidney Tubules, Macrophages and Fibrosis

“…Upon recruitment to injured or diseased kidneys, immune cell activity may be restricted by their short life spans. For myeloid cells, complement may contribute to survival as well as recruitment (39), thus the effect of C5a on apoptosis was examined. Neutrophils were assessed rather than macrophages, since for the latter CSF-1 promotes survival and may complicate the interpretation of in vitro apoptosis.…”