School of Medical Sciences, The University of New South Wales, UNSW Sydney, Sydney, New South Wales 2052, Australia, and.
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
J Neurosci. 2019 Mar 20;39(12):2326-2346. doi: 10.1523/JNEUROSCI.1815-18.2019. Epub 2019 Jan 16.
Sensory problems such as neuropathic pain are common and debilitating symptoms in multiple sclerosis (MS), an autoimmune inflammatory disorder of the CNS. Regulatory T (Treg) cells are critical for maintaining immune homeostasis, but their role in MS-associated pain remains unknown. Here, we demonstrate that Treg cell ablation is sufficient to trigger experimental autoimmune encephalomyelitis (EAE) and facial allodynia in immunized female mice. In EAE-induced female mice, adoptive transfer of Treg cells and spinal delivery of the Treg cell cytokine interleukin-35 (IL-35) significantly reduced facial stimulus-evoked pain and spontaneous pain independent of disease severity and increased myelination of the facial nociceptive pathway. The effects of intrathecal IL-35 therapy were Treg-cell dependent and associated with upregulated IL-10 expression in CNS-infiltrating lymphocytes and reduced monocyte infiltration in the trigeminal afferent pathway. We present evidence for a beneficial role of Treg cells and IL-35 in attenuating pain associated with EAE independently of motor symptoms by decreasing neuroinflammation and increasing myelination. Pain is a highly prevalent symptom affecting the majority of multiple sclerosis (MS) patients and dramatically affects overall health-related quality of life; however, this is a research area that has been largely ignored. Here, we identify for the first time a role for regulatory T (Treg) cells and interleukin-35 (IL-35) in suppressing facial allodynia and facial grimacing in animals with experimental autoimmune encephalomyelitis (EAE). We demonstrate that spinal delivery of Treg cells and IL-35 reduces pain associated with EAE by decreasing neuroinflammation and increasing myelination independently of motor symptoms. These findings increase our understanding of the mechanisms underlying pain in EAE and suggest potential treatment strategies for pain relief in MS.
感觉问题，如神经病理性疼痛，是多发性硬化症（MS）的常见且使人虚弱的症状，MS 是一种中枢神经系统的自身免疫性炎症性疾病。调节性 T（Treg）细胞对于维持免疫稳态至关重要，但它们在 MS 相关疼痛中的作用尚不清楚。在这里，我们证明 Treg 细胞消融足以触发免疫雌性小鼠的实验性自身免疫性脑脊髓炎（EAE）和面部触诱发痛。在 EAE 诱导的雌性小鼠中，Treg 细胞的过继转移和脊髓内给予 Treg 细胞细胞因子白细胞介素-35（IL-35）可显著减轻面部刺激诱发的疼痛和自发性疼痛，而不依赖于疾病严重程度，并增加面部伤害感受通路的髓鞘形成。鞘内 IL-35 治疗的效果依赖于 Treg 细胞，并且与 CNS 浸润淋巴细胞中 IL-10 表达的上调和三叉神经传入途径中单核细胞浸润的减少有关。我们提供了证据表明 Treg 细胞和 IL-35 通过减少神经炎症和增加髓鞘形成来减轻与 EAE 相关的疼痛，而与运动症状无关。疼痛是影响大多数多发性硬化症（MS）患者的高度普遍的症状，并严重影响整体健康相关的生活质量；然而，这是一个很大程度上被忽视的研究领域。在这里，我们首次确定调节性 T（Treg）细胞和白细胞介素-35（IL-35）在抑制实验性自身免疫性脑脊髓炎（EAE）动物的面部触诱发痛和面部抽搐方面的作用。我们证明，通过减少神经炎症和增加髓鞘形成，脊髓内给予 Treg 细胞和 IL-35 可减轻与 EAE 相关的疼痛，而与运动症状无关。这些发现增加了我们对 EAE 中疼痛机制的理解，并为 MS 中的疼痛缓解提供了潜在的治疗策略。
