Complement C3a and C5a Receptors Are Presented in Mouse Sciatic and Human Sural Nerves and Selectively Modulate the Neuronal Function of Large-Caliber Fibers in Mice.

Dysregulated complement activation drives peripheral inflammatory neuropathies by promoting immune attacks that exacerbate inflammation and tissue damage. Beyond immune functions, complement signaling may influence neuronal activity. To explore the role of C3a receptor (C3aR) and C5a receptor 1 (C5aR1) in peripheral nerve pathology, we examined their localization in mouse sciatic and human sural nerves and assessed their impact on nerve conduction. Immunofluorescence identified C3aR and C5aR1 in mice and human nerves. qPCR and western blot confirmed receptor expression in mouse sciatic nerves. Ex vivo electrophysiology assessed neural responses in control and treated nerves exposed to C3aR and C5aR1 agonist or agonist + antagonists. C3aR localized to the glial paranodal region of large-myelinated fibers, while C5aR1 is primarily in small unmyelinated fibers. C3aR activation enhanced large-fiber responses, reduced the refractory period, and increased excitability. The C3aR antagonist prevented these effects. In contrast, C5aR1 activation had minimal impact on conduction. These findings highlight distinct roles of C3aR and C5aR1 in peripheral nerves and suggest that Schwann cell C3aR regulates neuronal excitability. Targeting these pathways may help modulate nerve activity and inflammation in conditions like Guillain-Barré syndrome and diabetic neuropathy.