Complement receptor C5aR1 signaling in sensory neuron-associated macrophages drives neuropathic pain

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.

Schwann Cell C5aR1 co-opts Inflammasome NLRP1 to Sustain Pain in a Mouse Model of Endometriosis

“…C5a has been implicated in various pain conditions, including post-operative 16 , in ammatory 17 , and neuropathic pain 24 . To date, although little is known about the association between the complement system components and endometriotic pain, uctuation of C5a plasma levels during the different disease stages of endometriosis has been documented in female patients 20,40 .…”

“…A considerable proportion of women with endometriosis-associated pain reported a neuropathic-like pain component 41 . Recently, it has been observed that neuropathic-like pain caused by peripheral nerve injury in mice was modulated by activation of neuron associated C5aR1+ macrophages 24 . In our study, results obtained with the C5aR1 inhibitor and transgenic MaFIA mice con rm that increases in plasma C5a and nerve trunk macrophages are essential for the development of endometriosis-associated pain-like responses.…”

“…Participants did not receive any form of compensation. The blood plasma samples derived from nineteen endometriosis diagnosed patients [female, median age 30 years (range ] and fteen healthy individuals [female, median age 27 years (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)]. Considering the exploratory nature of the blood sampling analyses, the sample size was not determined based on statistical considerations but enrolling all consecutive outpatients and healthy controls.…”

“…Macrophages play a pivotal role in neurogenesis processes occurring close to endometriotic lesions, suggesting their role in endometriosis-associated pain generation 21,22,23 . Activation of C5aR1 in endoneurial macrophages induces the NLRP3 in ammasome-dependent release of the pro-nociceptive mediator interleukin 1 (IL-1) β to maintain pain in a mouse model of peripheral nerve injury 24 . Recently, we showed that crosstalk between Schwann cells (SCs) and endoneurial resident monocytes/macrophages in peripheral nerves activates an oxidative stress pathway that elicits neuroin ammation and sustains chronic pain 25,26,27,28 .…”