PDF(Pubmed)
Abstract：
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-mTNFR2) 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.
摘要：
多发性硬化症（MS），中枢神经系统（CNS）的脱髓鞘性自身免疫性疾病，与男性相比，女性主要受影响。肿瘤坏死因子(TNF),一种促炎细胞因子，通过TNF受体1的信号传导有助于炎性疾病的发病机制。相比之下,TNF受体2信号传导是神经保护性的。由于对促炎和抗炎功能的多效性作用，目前的抗TNFMS疗法对患者有害。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，我们全身给药TNFR2激动剂(p53-sc-mTNFR2),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激活可缓解女性的运动和感觉症状。然而,在男性中，激动剂仅缓解感觉症状，而不是运动。nPTXEAE在TNFR2全球基因敲除小鼠中的诱导导致雌性运动症状加剧，并且发病日期较早，但不是男性。我们的数据表明，TNFR2激动剂疗效是性别特异性的运动症状缓解，然而,它有效地降低了女性和男性的机械性超敏反应。总之,这些数据支持TNFR2激动作用作为MS治疗剂的治疗前景，更广泛地说，治疗中枢神经性疼痛。
