Low-Dose IL-2 Attenuates Neuropathic Pain via Treg Expansion in Rats

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Background: Neuropathic pain (NP) involves complex neuroimmune interactions. Regulatory T cells (Tregs) have been implicated in immune homeostasis, but their role in NP pathogenesis and therapeutic potential remains poorly understood. Aim: This study aimed to investigate the immunomodulatory effects of low-dose interleukin-2 (IL-2) on Treg populations and neuropathic pain behavior in a rat model of chronic constriction injury (CCI). Methods: CCI was induced in Sprague-Dawley rats, followed by daily intraperitoneal administration of low-dose IL-2 (5000 U/day) for three consecutive days, administered either three days prior to or following CCI. Pain behaviors were assessed by measuring mechanical withdrawal threshold and thermal withdrawal latency. Treg and T conventional (Tconv) cell subsets were quantified by flow cytometry in blood, spleen, dorsal root ganglia (DRG), and spinal cord. Functional markers (CD62L, ICOS) and serum IL-10 concentrations were also examined. Results: CCI increased T cell infiltration in the DRG, with limited endogenous Treg expansion. Low-dose IL-2 significantly elevated Treg proportions in blood, spleen, and DRG, without promoting Tconv expansion. In the DRG, IL-2-treated CCI rats showed a marked increase in Treg proportions, peaking at day 3 (20.73 ± 2.83% vs 6.74 ± 0.67% in controls) and remaining significantly elevated through day 21. IL-2 also enhanced Treg expression of ICOS and CD62L and increased serum IL-10 levels. Rats receiving IL-2 treatment demonstrated significant improvements in mechanical pain thresholds (61.53 ± 8.46% reduction) and thermal pain thresholds (52.74 ± 6.73% reduction) relative to controls on day 21. Preventive IL-2 injection (pre-CCI) was less effective than post-CCI administration. Conclusion: Low-dose IL-2 selectively augments functional Tregs and mitigates neuropathic pain through modulation of peripheral and neural immune responses. Further Treg-specific mechanistic validations are required to confirm its potential for translational clinical therapy.

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