Multiple sclerosis (MS), a demyelinating autoimmune disease of the central nervous system (CNS), predominately affects females compared to males. Tumor necrosis factor (TNF), a pro-inflammatory cytokine, signaling through TNF receptor 1 contributes to inflammatory disease pathogenesis. In contrast, TNF receptor 2 signaling is neuroprotective. Current anti-TNF MS therapies are shown to be detrimental to patients due to pleiotropic effects on both pro- and anti-inflammatory functions. Using a non-pertussis toxin (nPTX) experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice, we systemically administered a TNFR2 agonist (p53-sc-mTNF_R2) to investigate behavioral and pathophysiological changes in both female and male mice. Our data shows that TNFR2 activation alleviates motor and sensory symptoms in females. However, in males, the agonist only alleviates sensory symptoms and not motor. nPTX EAE induction in TNFR2 global knockout mice caused exacerbated motor symptoms in females along with an earlier day of onset, but not in males. Our data demonstrates that TNFR2 agonist efficacy is sex-specific for alleviation of motor symptoms, however, it effectively reduces mechanical hypersensitivity in both females and males. Altogether, these data support the therapeutic promise TNFR2 agonism holds as an MS therapeutic and, more broadly, to treat central neuropathic pain.

多发性硬化症 (MS) 是一种中枢神经系统 (CNS) 脱髓鞘自身免疫性疾病，与男性相比，女性主要受到多发性硬化症 (MS) 的影响。肿瘤坏死因子 (TNF) 是一种促炎细胞因子，通过 TNF 受体 1 发出信号，有助于炎症性疾病的发病机制。相反，TNF 受体 2 信号传导具有神经保护作用。目前的抗 TNF MS 疗法由于对促炎和抗炎功能的多效性作用而被证明对患者有害。我们在 C57BL/6 小鼠中使用非百日咳毒素 (nPTX) 实验性自身免疫性脑脊髓炎 (EAE) 模型，系统地给予 TNFR2 激动剂 (p53-sc-mTNF _R2 )，以研究雌性和雄性小鼠的行为和病理生理变化。我们的数据显示 TNFR2 激活可减轻女性的运动和感觉症状。然而，对于男性来说，激动剂只能缓解感觉症状，不能缓解运动症状。在 TNFR2 全基因敲除小鼠中，nPTX EAE 诱导会导致雌性小鼠运动症状加剧，且发病时间提前，但雄性小鼠则不会。我们的数据表明，TNFR2 激动剂对于缓解运动症状的功效具有性别特异性，但它可以有效降低女性和男性的机械超敏反应。总而言之，这些数据支持 TNFR2 激动剂作为多发性硬化症治疗药物的治疗前景，更广泛地说，用于治疗中枢神经性疼痛。