Miao Lin, Wang Haowei, Yang Xue, Xu Lisha, Xu Ruike, Teng Hanxin, Zhang Yue, Zhao Yingjie, Yang Genmeng, Zeng Xiaofeng
NHC Key Laboratory of Drug Addiction Medicine, School of Forensic Medicine, Kunming Medical University, Kunming, China.
Department of Pathogen Biology and Immunology, School of Basic Medical Science, Kunming Medical University, Kunming, China.
Inflammation. 2025 Feb 19. doi: 10.1007/s10753-025-02266-9.
Human immunodeficiency virus (HIV)-infected individuals who abuse methamphetamine (METH) exhibit more severe neurotoxicity and cognitive impairment. Pyroptosis, a programmed cell death pathway mediated by the inflammasome, has been implicated in various neurological diseases. This study aimed to elucidate the role of the AIM2 inflammasome in METH- and HIV-1 Tat-induced pyroptosis in human brain tissue and in vitro models.
Postmortem brain tissue from HIV-infected individuals with a history of METH abuse was analyzed for pyroptosis markers and AIM2 inflammasome components using immunohistochemistry, immunofluorescence, and Western blotting. BV2 microglial cells were lentivirally transduced to knockdown AIM2 expression. DNA damage was assessed using Western blotting and the comet assay. Expression of pyroptosis-related proteins was evaluated by electron microscopy, Western blotting, and immunofluorescence. Cell viability was measured using the CCK8 assay.
Elevated levels of pyroptosis markers and AIM2 inflammasome components were observed in brain tissue from HIV-infected METH users. METH and Tat synergistically induced pyroptosis in BV2 cells in a time- and concentration-dependent manner, accompanied by DNA damage and activation of the AIM2 inflammasome. Knockdown of AIM2 significantly reduced the expression of pyroptosis-related proteins.
METH and HIV-1 Tat proteins synergistically induce microglial pyroptosis by activating the AIM2 inflammasome through dsDNA damage. These findings suggest that targeting the AIM2 inflammasome may be a promising therapeutic strategy for HIV-associated neurocognitive disorder (HAND).
滥用甲基苯丙胺（METH）的人类免疫缺陷病毒（HIV）感染者表现出更严重的神经毒性和认知障碍。细胞焦亡是一种由炎性小体介导的程序性细胞死亡途径，与多种神经疾病有关。本研究旨在阐明AIM2炎性小体在METH和HIV-1 Tat诱导的人脑组织和体外模型细胞焦亡中的作用。
使用免疫组织化学、免疫荧光和蛋白质免疫印迹法，对有METH滥用史的HIV感染者的尸检脑组织进行细胞焦亡标志物和AIM2炎性小体成分分析。用慢病毒转导BV2小胶质细胞以敲低AIM2表达。使用蛋白质免疫印迹法和彗星试验评估DNA损伤。通过电子显微镜、蛋白质免疫印迹法和免疫荧光评估细胞焦亡相关蛋白的表达。使用CCK8试验测量细胞活力。
在HIV感染的METH使用者的脑组织中观察到细胞焦亡标志物和AIM2炎性小体成分水平升高。METH和Tat以时间和浓度依赖性方式协同诱导BV2细胞发生细胞焦亡，伴有DNA损伤和AIM2炎性小体的激活。敲低AIM2可显著降低细胞焦亡相关蛋白的表达。
METH和HIV-1 Tat蛋白通过dsDNA损伤激活AIM2炎性小体，协同诱导小胶质细胞焦亡。这些发现表明，靶向AIM2炎性小体可能是治疗HIV相关神经认知障碍（HAND）的一种有前景的治疗策略。
