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

Over 60% of women with endometriosis experience abdominopelvic pain alongside pain in other areas of the body, such as chronic back pain, fibromyalgia and chronic fatigue, vulvodynia, and migraine. Although the imbalance of proinflammatory mediators, including the complement component C5a, has been implicated in endometriosis-associated pain symptoms, the mechanisms causing widespread pain and the role of C5a remain unclear. Female mice with endometriotic lesions displayed widespread pain and increased plasma C5a levels, similarly, observed in women with endometriosis. We hypothesized Schwann cells involvement in endometriotic pain. Silencing the C5a surface receptor (C5aR1) in mouse Schwann cells abolished C5a-induced activation of NLRP1 inflammasome and the ensuing interleukin-1β (IL-1β) release. IL-1β, from Schwann cells, recruited macrophages in sciatic/trigeminal nerve trunks. Macrophages induced oxidative stress, targeting proalgesic TRPA1, causing widespread mechanical allodynia. This pathway, initiated by C5aR1, engages Schwann cell signaling, including NLRP1/IL-1β/macrophages/oxidative stress/TRPA1, sustaining pain in an endometriosis mouse model.