Inhibition of C5aR1 as a promising approach to treat taxane-induced neuropathy

: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of several antitumor agents resulting in progressive and often irreversible damage of peripheral nerves. In addition to their known anticancer effects, taxanes, including paclitaxel, can also induce peripheral neuropathy by activating microglia and astrocytes, which release pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β), and chemokine (C-C motif) ligand 2 (CCL-2). All these events contribute to the maintenance of neuropathic or inflammatory response. Complement component 5a (C5a)/C5a receptor 1 (C5aR1) signaling was very recently shown to play a crucial role in paclitaxel-induced peripheral neuropathy. Our recent findings highlighted that taxanes have the previously unreported property of binding and activating C5aR1, and that C5aR1 inhibition by DF3966A is effective in preventing paclitaxel-induced peripheral neuropathy (PIPN) in animal models. Here, we investigated if C5aR1 inhibition maintains efficacy in reducing PIPN in a therapeutic setting. Furthermore, we characterized the role of C5aR1 activation by paclitaxel and the CIPN-associated activation of nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome. Our results clearly show that administration of the C5aR1 inhibitor strongly reduced cold and mechanical allodynia in mice when given both during the onset of PIPN and when neuropathy is well established. C5aR1 activation by paclitaxel was found to be a key event in the induction of inflammatory factors in spinal cord, such as TNF-α, ionized calcium-binding adapter molecule 1 (Iba-1), and glial fibrillary acidic protein (GFAP). In addition, C5aR1 inhibition significantly mitigated paclitaxel-induced inflammation and inflammasome activation by reducing IL-1β and NLRP3 expression at both sciatic and dorsal root ganglia level, confirming the involvement of inflammasome in PIPN. Moreover, paclitaxel-induced upregulation of C5aR1 was significantly reduced by DF3966A treatment in central nervous system. Lastly, the antinociceptive effect of C5aR1 inhibition was confirmed in an in vitro model of sensory neurons in which we focused on receptor channels usually activated upon neuropathy. In conclusion, C5aR1 inhibition is proposed as a therapeutic option with the potential to exert long-term protective effect on PIPN-associated neuropathic pain and inflammation.