Immunity, inflammation and disease · 2026
Impaired IL-35/Treg Axis Facilitates Neuropathic Pain Via TNF-α, TLR4, and HMGB1 Activation.
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You Pingdi, Shen Lirui, Huang Zhixiong, Yuan Cuihua, Wei Cuihua, Lin Sunzhi, Wang Bili, Chen Yongwu
Аннотация
BACKGROUND: Neuropathic pain (NP) is a chronic condition characterized by persistent pain due to dysfunction in the peripheral or central nervous system. Recent studies suggest immune dysregulation, particularly involving regulatory T cells (Tregs) and inflammatory mediators, plays a significant role in NP. Interleukin-35 (IL-35), an anti-inflammatory cytokine secreted by Tregs, has shown potential immunosuppressive effects, but its role in NP remains unclear. This study aimed to investigate the expression and regulatory role of IL-35 on Treg-mediated immune modulation and inflammatory responses in a rat model of neuropathic pain.
METHODS: A total of 18 male Sprague-Dawley rats were randomly assigned to Control, Sham, and Neuropathic Pain (NP) groups. The NP model was established using chronic constriction injury (CCI) of the sciatic nerve. Pain behaviors were assessed by measuring mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) at multiple time points post-surgery. IL-35 levels in serum were detected via ELISA. Flow cytometry was used to evaluate CD4⁺ and CD8⁺ T cell populations. Histopathological analysis of spinal cord tissue was performed using HE staining. Expression of IL-35, TNF-α, TLR4, and HMGB1 in spinal cord tissues was evaluated by immunohistochemistry, Western blotting, and RT-PCR.
RESULTS: Rats in the NP group exhibited significantly reduced MWT and TWL, confirming successful model establishment. Serum IL-35 levels and CD4⁺ T cell counts were significantly decreased, whereas CD8⁺ T cell counts were increased compared to controls (p < 0.05). Histopathology revealed neuronal degeneration in the NP group's spinal dorsal horn. In spinal cord tissue, IL-35 protein and mRNA levels were significantly downregulated, while TNF-α, TLR4, and HMGB1 were upregulated at both protein and mRNA levels (p < 0.05).
CONCLUSION: IL-35 expression is diminished in neuropathic pain and correlates with reduced Treg-mediated immunosuppressive function and increased neuroinflammation. The data suggest IL-35 mitigates neuropathic pain through modulation of T cell responses and suppression of TNF-α, TLR4, and HMGB1 signaling pathways. IL-35 may serve as a potential therapeutic target for neuropathic pain management.
METHODS: A total of 18 male Sprague-Dawley rats were randomly assigned to Control, Sham, and Neuropathic Pain (NP) groups. The NP model was established using chronic constriction injury (CCI) of the sciatic nerve. Pain behaviors were assessed by measuring mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) at multiple time points post-surgery. IL-35 levels in serum were detected via ELISA. Flow cytometry was used to evaluate CD4⁺ and CD8⁺ T cell populations. Histopathological analysis of spinal cord tissue was performed using HE staining. Expression of IL-35, TNF-α, TLR4, and HMGB1 in spinal cord tissues was evaluated by immunohistochemistry, Western blotting, and RT-PCR.
RESULTS: Rats in the NP group exhibited significantly reduced MWT and TWL, confirming successful model establishment. Serum IL-35 levels and CD4⁺ T cell counts were significantly decreased, whereas CD8⁺ T cell counts were increased compared to controls (p < 0.05). Histopathology revealed neuronal degeneration in the NP group's spinal dorsal horn. In spinal cord tissue, IL-35 protein and mRNA levels were significantly downregulated, while TNF-α, TLR4, and HMGB1 were upregulated at both protein and mRNA levels (p < 0.05).
CONCLUSION: IL-35 expression is diminished in neuropathic pain and correlates with reduced Treg-mediated immunosuppressive function and increased neuroinflammation. The data suggest IL-35 mitigates neuropathic pain through modulation of T cell responses and suppression of TNF-α, TLR4, and HMGB1 signaling pathways. IL-35 may serve as a potential therapeutic target for neuropathic pain management.