THE ROLE OF SCHWANN CELL SUBTYPES IN RODENT MODELS OF CHRONIC PAIN

Chronic pain is a common, complex, and distressing condition that has negative impacts on individuals and society. It frequently presents as a symptom that outlasts the cause, a disease or an injury, due to which it initiated. Recent findings underline the role of Schwann cells in sustaining chronic pain. However, as Schwann cells can be subdivided in myelinated, Remak, and nociceptive cells, it was not clear which subpopulations contribute to chronic pain (Abdo et al., 2019). The present study propose to identify which cell type(s) is implicated in chronic pain, and the molecular pathways that mediate the proalgesic functions of the Schwann cell subtype(s). \nOver 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-1b (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.