Regulatory T cells and their derived cytokine, interleukin-35, reduce pain in experimental autoimmune encephalomyelitis.

Regulatory T cells and their derived cytokine, interleukin-35, reduce pain in experimental autoimmune encephalomyelitis.

Publication date: Jan 16, 2019

Sensory problems, such as neuropathic pain, are common and debilitating symptoms in multiple sclerosis (MS), an autoimmune inflammatory disorder of the central nervous system (CNS). Regulatory T (Treg) cells are critical for maintaining immune homeostasis, however, 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 immunised female mice. In EAE-induced female mice, adoptive transfer of Treg cells and spinal delivery of the Treg cell cytokine interleukin (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 were associated with upregulated IL-10 expression in CNS-infiltrating lymphocytes, and reduced monocyte infiltration in the trigeminal afferent pathway. Taken together, 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.SIGNIFICANCE STATEMENTPain is a highly prevalent symptom affecting the majority of multiple sclerosis (MS) patients and dramatically affects overall health-related quality-of-life, yet represents a research area that has been largely ignored. Here we identify, for the first time, a role for regulatory T cells and interleukin-35 in suppressing facial allodynia and facial grimacing in animals with experimental autoimmune encephalomyelitis (EAE). We demonstrate that spinal delivery of regulatory T cells and interleukin-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.

Duffy, S.S., Keating, B.A., Perera, C.J., Lees, J.G., Tonkin, R.S., Makker, P.G.S., Carrive, P., Butovsky, O., and Moalem-Taylor, G. Regulatory T cells and their derived cytokine, interleukin-35, reduce pain in experimental autoimmune encephalomyelitis. 17173. 2019 J Neurosci.



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