Regulatory T Cells and Their Derived Cytokine, Interleukin-35, Reduce Pain in Experimental Autoimmune Encephalomyelitis

Abstract

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.

Exogenous activation of tumor necrosis factor receptor 2 promotes recovery from sensory and motor disease in a model of multiple sclerosis

“…Therefore, it is possible that potential neuroprotective activities of TNFR2 in the PNS contribute to its analgesic effects. Further, a recent publication has shown that Tregs reduce pain in EAE via alleviation of neuroinflammation (Duffy et al, 2019). This is in line with our observation that TNFR2 agonism expands Tregs and may indicate that Treg-mediated effects contribute to the analgesic effect of EHD2-sc-mTNF R2 .…”

Neuraxial Cytokines in Pain States

“…As an example, intrathecal administration of recombinant IL-27 induced antinociception dependent on IL-10 during the maintenance phase of peripheral neuropathy (194). Also, intrathecal delivery of IL-35 in an experimental murine model of autoimmune encephalomyelitis (EAE) reduced pain behaviors (i.e., facial allodynia and grimacing), which was noted to occur through an upregulation of an inflammatory cytokine, IL-10 (195). IL-35 has been very recently highlighted as a candidate target for diabetic neuropathic pain (DNP) treatment (78).…”

Neuronal, stromal, and T-regulatory cell crosstalk in murine skeletal muscle

“…Nav1.8 is a voltage-gated ion channel that mediates action potential firing in nociceptive neurons, and humans with mutations in this ion channel show changes in pain sensitivity. Recent work has shown that Tregs can be potent regulators of pain in mouse models of sciatic nerve injury and experimental autoimmune neuritis (32,33), as well as in experimental autoimmune encephalitis (34). Tregs could modulate pain through several molecular mechanisms.…”