C5a

C5a is a potent inflammatory peptide and one of the anaphylatoxins of the complement system. It is generated by proteolytic cleavage of complement component C5 by C5 convertases during activation of the classical, lectin, or alternative pathways. C5a acts as a strong chemoattractant for neutrophils and other immune cells and promotes inflammatory mediator release, including histamine from mast cells, and increased vascular permeability.

Biology and receptors: The major biological effects of C5a are mediated primarily through the G protein–coupled receptor C5aR (CD88) expressed on neutrophils, monocytes, eosinophils, basophils, mast cells, and endothelial cells. A second receptor, C5L2 (also called C5aR2), is thought to modulate C5a signaling, with roles that are still being clarified. C5a is rapidly inactivated by carboxypeptidases to C5a des-Arg, which has markedly reduced activity at C5aR and contributes less to inflammation.

Physiological and pathological roles: C5a enhances leukocyte recruitment to sites of infection or tissue injury and amplifies inflammatory responses. While important for host defense, excessive C5a generation can contribute to inflammatory damage seen in sepsis, acute lung injury and ARDS, ischemia–reperfusion injury, and various autoimmune or allergic conditions.

Therapeutic considerations: Pharmacological strategies aim to reduce C5a activity either by preventing C5 cleavage (for example, anti-C5 antibodies such as eculizumab) or by blocking C5a signaling with receptor antagonists (such as C5aR antagonists). Research and clinical development continue for agents that modulate C5a–C5aR interactions to treat inflammatory diseases.

Measurement and regulation: C5a levels can be measured in plasma and tissues, and its activity is regulated in part by rapid inactivation to C5a des-Arg and by local receptor expression.