Low-dose IL-2 reverses stress-induced migraine-like pain through a TGF-β–dependent mechanism

Editor’s note: The research described below comes from a recipient of a 2026 MSC Travel Grant supporting travel to the 68th Annual Scientific Meeting of the American Headache Society. These grants reimburse travel expenses for those who have had their abstract for a presentation or poster accepted at a meeting. 

By Róli Simões, PhD, postdoc, Washington University in St. Louis.

What is the research gap that your study addresses?

Stress is one of the most common and clinically relevant triggers of migraine and is strongly associated with the transition to chronic pain states. However, the biological pathways that regulate how stress alters pain sensitivity remain insufficiently characterized. Emerging evidence implicates neuroimmune interactions in migraine, but the specific regulatory cytokine signals that control stress-induced sensitization have not been clearly established. This limits the development of targeted therapies for patients with stress-exacerbated migraine.

What is your research hypothesis?

We hypothesized that regulatory T cell–mediated immune signaling limits stress-induced migraine-like sensitization through specific anti-inflammatory cytokine pathways.

What methodology did you use to address your research hypothesis?

To test this, we used a mouse model of repeated restraint stress (2 hours/day for 3 consecutive days) to induce migraine-like sensitization. Facial mechanical sensitivity was assessed at baseline, during the acute sensitization phase, and after recovery. Following resolution of acute hypersensitivity, mice were challenged with migraine triggers, including a nitric oxide donor (SNP) and bright light stress, to evaluate latent sensitization (priming). Low-dose interleukin-2 (IL-2) was administered daily across the stress and early post-stress period to expand regulatory T cells. To define the cytokine mechanisms involved, separate groups of animals received neutralizing antibodies against IL-10, IFN-γ, or TGF-β in repeated dosing schedules following stress and behavioral testing.

What are the main results of your study?

Our study demonstrates that repeated stress induces robust migraine-like sensitization and hyperalgesic priming in mice. Treatment with low-dose IL-2 (LD-IL-2) reverses stress-induced hypersensitivity and prevents the development of chronic sensitization, indicating engagement of endogenous regulatory mechanisms. Functional cytokine neutralization experiments revealed that blockade of IL-10 or IFN-γ does not alter baseline or IL-2–mediated effects, suggesting these pathways are not major contributors in this model. In contrast, neutralization of TGF-β abolishes the protective effects of LD-IL-2 and exacerbates stress-induced hypersensitivity, identifying TGF-β as the key cytokine required for IL-2–mediated regulation of migraine-like pain.

What conclusions did you reach based on your results?

These findings identify a neuroimmune mechanism linking stress to migraine-like sensitization. Regulatory immune pathways suppress stress-induced pain, with TGF-β acting as a critical, non-redundant mediator of IL-2–driven protection. This highlights the IL-2/TGF-β axis as a promising therapeutic target for stress-related migraine.

What are the limitations of your study?

This study was conducted in a preclinical mouse model, which may not fully capture the complexity and heterogeneity of human migraine. While we identify TGF-β as a critical mediator of IL-2–driven protection, the precise cellular sources and spatial sites of TGF-β signaling (e.g., meningeal versus systemic) remain to be defined. In addition, although multiple cytokine pathways are engaged, their interactions and relative contributions require further investigation. Future studies will address these questions and evaluate the translational relevance of these findings in clinical populations.

What is the relevance of your study to migraine?

Migraine is strongly influenced by stress and characterized by abnormal pain sensitization. Our study identifies a neuroimmune mechanism linking stress exposure to migraine-like pain, demonstrating that regulatory immune pathways actively control sensitization. By establishing TGF-β as a critical mediator of IL-2–driven protection, these findings provide insight into how immune dysregulation contributes to stress-related migraine vulnerability. This work highlights the IL-2/TGF-β axis as a potential therapeutic target and supports the development of immunoregulatory strategies for patients with stress-exacerbated migraine.