Targeting Complement C3a or C5a Receptor for Paclitaxel-Induced Peripheral Neuropathic Pain 9228

Description Cancer chemotherapy-induced peripheral neuropathy (CIPN) is a devastating pain syndrome without effective therapies. We previously reported that rodents deficient in complement C3, the central component of complement activation cascade, showed a significantly reduced degree of paclitaxel-induced mechanical allodynia (PIMA), suggesting that complement is integrally involved in the pathogenesis of paclitaxel-induced CIPN. However, the underlying mechanism was unclear. We found that administration of paclitaxel induced C3 activation in serum and upregulated the expression of C3a and C5a receptors (C3aR and C5aR) on macrophages, but not neurons, in mouse dorsal root ganglion (DRG). Administration of C3aR or C5aR antagonist (C3aRA, C5aRA) significantly alleviated PIMA in both male and female mice. C3aRA or C5aRA reduced paclitaxel-mediated macrophage infiltration in DRG, a key step in the development of CIPN. Western blot and immunohistochemistry studies showed that C3aRA or C5aRA suppressed paclitaxel-induced NF-κB activation and TNFα production in DRG. Finally, C3aRA or C5aRA upregulated the anti-inflammatory cytokine IL-10 in DRG. Taking together, administration of C3aRA or C5aRA mitigated paclitaxel CIPN in rodents through regulating neuroinflammatory signals. Targeting the C3aR or C5aR neuroimmune pathways could be a novel therapeutic approach to alleviate this debilitating pain syndrome. Funding Sources Supported by NIH K08 CA228039. Topic Categories Neuroimmunology (NEUR)