ACVR1 drives neuropathic pain by regulating NLRP3-Induced neuronal pyroptosis through the p38 and Smad1/5/8 pathways

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology Pub Date : 2025-04-16 DOI:10.1016/j.neuropharm.2025.110469

Xiaoxu Zhang , Yuxin Miao , Zongxiao Li , Haoyue Xu , Zejun Niu

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Abstract

Background

Neuropathic pain is characterized by sustained pain hypersensitivity caused by nerve injury. The molecular mechanisms underlying this condition remain poorly understood. This study aims to elucidate the role of ACVR1 and its downstream pathways in mediating neuropathic pain through neuronal pyroptosis and neuroinflammation.

Methods

A spared nerve injury (SNI) model was established both in male and female mouse to induce neuropathic pain. Behavioral tests, Western blot, PCR, and immunofluorescence were used to assess the expression of ACVR1, p-Smad1/5/8, p-p38, and pyroptosis-related proteins (NLRP3, Caspase-1, and GSDMD-N). ACVR1, p38, and Smad1/5/8 were pharmacologically inhibited to evaluate their roles in neuropathic pain and pyroptosis.

Results

Behavioral analysis confirmed successful SNI model establishment, marked by reduced paw withdrawal thresholds (PWT). Protein and mRNA expression analysis revealed significant upregulation of ACVR1, p-Smad1/5/8, and p-p38 in the spinal cord, particularly in neurons. Furthermore, SNI enhanced pyroptosis-related protein expression, including NLRP3, Caspase-1, GSDMD-N, IL-1β and IL-18. Inhibition of ACVR1 alleviated mechanical allodynia, reduced neuronal pyroptosis, and decreased serum IL-1β and IL-18 levels. Similarly, p38 inhibition mitigated NLRP3-induced pyroptosis without altering ACVR1 expression. In contrast, Smad1/5/8 inhibition by DMH-1 effectively reduced pyroptosis and inflammation via NLRP3 but had no effect on p38 phosphorylation. Combined p38 and Smad1/5/8 pathway inhibition synergistically decreased pyroptosis-related protein expression, highlighting their interactive roles in ACVR1-mediated neuropathic pain.

Conclusion

These findings suggest that ACVR1 exacerbates neuropathic pain by activating neuronal pyroptosis and neuroinflammation via the p38 and Smad1/5/8 pathways. Targeting ACVR1 and its downstream signaling pathways may offer novel therapeutic strategies for neuropathic pain.

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ACVR1通过p38和Smad1/5/8通路调控nlrp3诱导的神经元焦亡，从而驱动神经性疼痛

背景神经性疼痛的特征是由神经损伤引起的持续疼痛超敏反应。这种情况的分子机制仍然知之甚少。本研究旨在阐明ACVR1及其下游通路通过神经元焦亡和神经炎症介导神经性疼痛的作用。方法分别建立雄性和雌性小鼠sa神经损伤模型，诱导神经性疼痛。采用行为试验、Western blot、PCR和免疫荧光检测ACVR1、p-Smad1/5/8、p-p38和焦热相关蛋白（NLRP3、Caspase-1和GSDMD-N）的表达。药理抑制ACVR1、p38和Smad1/5/8在神经性疼痛和焦亡中的作用。结果行为学分析证实SNI模型建立成功，其特征是爪脱阈值（PWT）降低。蛋白和mRNA表达分析显示，ACVR1、p-Smad1/5/8和p-p38在脊髓中显著上调，尤其是在神经元中。此外，SNI还增强了NLRP3、Caspase-1、GSDMD-N、IL-1β和IL-18等焦解热相关蛋白的表达。抑制ACVR1可减轻机械性异常痛，减少神经元焦亡，降低血清IL-1β和IL-18水平。同样，p38抑制减轻了nlrp3诱导的焦亡，而不改变ACVR1的表达。相比之下，DMH-1抑制Smad1/5/8可通过NLRP3有效减少焦亡和炎症，但对p38磷酸化无影响。p38和Smad1/5/8通路联合抑制协同降低了焦热相关蛋白的表达，突出了它们在acvr1介导的神经性疼痛中的相互作用。结论ACVR1通过p38和Smad1/5/8通路激活神经元焦亡和神经炎症，加重了神经性疼痛。靶向ACVR1及其下游信号通路可能为神经性疼痛提供新的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuropharmacology 医学-神经科学

CiteScore

10.00

自引率

4.30%

发文量

288

审稿时长

45 days

期刊介绍： Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).