Abstract
Headache disorders are highly prevalent and debilitating, with limited treatment options. Previous studies indicate that many proinflammatory immune cells contribute to headache pathophysiology. Given the well-recognized role of regulatory T (Treg) cells in maintaining immune homeostasis, we hypothesized that enhancing Treg function may be effective to treat multiple headache disorders. In a mouse model of chronic migraine, we observed that repeated nitroglycerin (NTG, a reliable trigger of migraine in patients) administration doubled the number of CD3 T cells in the trigeminal ganglia without altering the number of Treg cells, suggesting a deficiency in Treg-mediated immune homeostasis. We treated mice with low-dose interleukin-2 (ld-IL2) to preferentially expand and activate endogenous Treg cells. This not only prevented the development of NTG-induced persistent sensitization but also completely reversed the established facial skin hypersensitivity resulting from repeated NTG administration. The effect of ld-IL2 was independent of mouse sex and/or strain. Importantly, ld-IL2 treatment did not alter basal nociceptive responses, and repeated usage did not induce tolerance. The therapeutic effect of ld-IL2 was abolished by Treg depletion and was recapitulated by Treg adoptive transfer. Furthermore, treating mice with ld-IL2 1 to 7 days after mild traumatic brain injury effectively prevented as well as reversed the development of behaviors related to acute and chronic post-traumatic headache. In a model of medication overuse headache, Ld-IL2 completely reversed the cutaneous hypersensitivity induced by repeated administration of sumatriptan. Collectively, this study identifies ld-IL2 as a promising prophylactic for multiple headache disorders with a mechanism distinct from the existing treatment options.