Complement receptor C5aR1 signaling in sensory neuron-associated macrophages drives neuropathic pain
Quadros, A. U.; Maganin, A. G. d. M.; Silva, E. A.; Damasceno, S.; Cavallini, M. C. M.; Davoli-Ferreira, M.; Lopes, A. H.; Sagar, D. R.; Brandolini, L.; Lee, S. H.; Alves-Filho, J. C.; Cunha, F.; Berta, T.; Koehl, J.; Alegretti, M.; Chapman, V.; Cunha, T. M.
Show abstract
Neuroimmune interactions across the pain pathway play a predominant role in the development of neuropathic pain. Previous reports demonstrated that complement driven effector systems including the C5a/C5aR1 axis contribute to these neuro-immune mechanisms. However, the cellular and molecular mechanisms underlying C5a/C5aR1 signaling-mediated neuropathic pain development remain ill-identified. Here we show that neuropathic pain following peripheral nerve injury was attenuated in C5aR1-deficient male and female mice as well as in wild type mice treated with a selective allosteric C5aR1 antagonist. Using two complementary cell-specific C5aR1 knockout mouse strains, we identified C5a/C5aR1 driven-activation of sensory neuron-associated macrophages (sNAMs) located in the sensory ganglia as the key site of peripheral nerve injury-induced neuropathic pain, whereas activation of macrophages of the local of peripheral nerve injury was not involved. Mechanistically, we uncovered IL-1b the main mediator of pain hypersensitivity in response to C5aR1 signaling in sNAMs. Our findings highlight a crucial role of C5a/C5aR1 axis activation in sNAMs for the development of neuropathic pain and identify this pathway as a promising novel target for neuropathic pain therapy.
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