Low-dose interleukin-2 reverses behavioral sensitization in multiple mouse models of headache disorders

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.

Low-Dose Interleukin-2 and Regulatory T Cell Treatments Attenuate Punctate and Dynamic Mechanical Allodynia in a Mouse Model of Sciatic Nerve Injury

“… 24 Here, we treated female Swiss Webster mice with daily ld-IL2 (1 µg/mouse/day, ip) or saline, starting 5 days before SNI and continuing till 21 days post-surgery. 18 Basal punctate and dynamic mechanical sensitivity was not altered by 5 days of ld-IL2 injections ( Figure 1 , SNI+saline versus SNI+IL2, Day 0). In saline-treated mice, the withdrawal threshold to von Frey filaments decreased to about 20% of the baseline value between 4–22 days post-SNI.…”

“…In a previous study, we have verified that the transferred cells contain 84% CD25 + CD4 + cells and 76% Foxp3 + CD25 + CD4 + cells. 18 …”

“…One in every 3 serial sections were used for individual immunohistochemistry experiments as described previously. 18 , 23 T cells were identified by the rat anti-CD3 antibody (clone 17A2, 1:200, eBioscience, San Diego, CA, USA) and Treg cells were identified with the chicken anti-EGFP antibody (1:1000, AVES Lab, Tigard, OR, USA) in tissues from DEREG mice. AlexaFluor 568- or 488-conjugated secondary antibodies (Invitrogen, Carlsbad, CA, USA) were used at 1:1000 dilution.…”

“… 15–17 Ld-IL2 effectively reverses behavioral sensitization in several mouse models of chronic headache disorders without altering basal nociceptive responses or inducing tolerance. 18 A recent study reports that ld-IL2 given soon after nerve injury mildly attenuates early punctate allodynia (< 2 weeks post-injury) through inhibition of the Th1 response at the injured nerve. 10 In this study, we investigated whether ld-IL2 treatment and Treg cell transfer are effective for the prolonged punctate and dynamic allodynia resulting from peripheral nerve injury.…”

Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition

“…Similar to humans, NTG produces a delayed allodynia in mice [35], as well as photophobia and altered meningeal blood flow [36,37]. Chronic intermittent administration of NTG is used to model chronic migraine [32,[38][39][40][41]. Although, compared to humans, much higher doses of NTG are required in rodents, the allodynia induced in mice is inhibited by migraine-specific medications, such as sumatriptan [35,38,42] and CGRP targeting drugs [32], as well as the migraine preventives propranolol and topiramate [43,44].…”