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<p>HIV-Tat and morphine synergistically exacerbate neuroinflammation and DNA damage, yet the mechanisms linking the DNA damage response (DDR), chromatin remodeling, and innate immune activation remain poorly understood. Here, we investigated how HIV-Tat and morphine alter DNA repair dynamics and cGAS–STING–AIM2 inflammasome signaling in microglia and cortical tissue and evaluated the efficacy of dimethyl fumarate (DMF) in mitigating these effects. HMC3 microglial cells were exposed to HIV-Tat (50 ng/mL) and morphine (10 µM) for 24 h or 5 days, with H2A.X knockdown performed prior to treatment. In vivo, doxycycline (DOX)-induced Tat transgenic mice received escalating morphine doses for 4 days, followed by DMF (30 mg/kg, i.p.) for 7 days. Postmortem frontal cortical tissues from HIV-positive and matched HIV-negative donors were analyzed for validation. Behavioral testing, immunostaining, qPCR, and Western blotting assessed DDR markers, KAT5 acetylation, histone modifications, and innate immune mediators. HIV-Tat and morphine significantly enhanced DDR activation in vitro and in vivo, as indicated by increased ATM and γH2AX and elevated KAT5 acetylation. Large Organized Chromatin Lysine (K) domains (LOCK) displayed reduced H3K9me3 and increased H3K9ac, reflecting chromatin relaxation and disrupted epigenetic control over DDR and inflammation. DOX+Morphine treatment upregulated ERCC1 and ERCC8 but downregulated ERCC2, ERCC3, and ERCC6, demonstrating impaired nucleotide excision repair, and these changes were closely associated with cGAS–STING activation and AIM2/NLRP3 inflammasome induction. H2A.X knockdown or DMF treatment suppressed ATM phosphorylation, restored H3K9me3, normalized ERCC expression, and attenuated inflammasome activation. DMF also rescued HIV-Tat ± morphine-induced deficits in novel object recognition. Postmortem cortical tissue confirmed γH2AX accumulation, reduced ERCC2/ERCC3, and altered histone signatures consistent with experimental findings. Together, these results demonstrate that HIV-Tat and morphine cooperatively disrupt LOCK chromatin and DDR through the ATM/γH2AX axis, and that DMF reverses these molecular and functional abnormalities, highlighting its therapeutic potential in mitigating HIV- and opioid-induced neuroinflammation and cognitive decline.</p><p></p>

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Epigenetic LOCK chromatin links H3K9 modifications to ATM–γH2AX signaling in HIV-Tat and opioid neuroinflammation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月5日

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  • Karthick Chennakesavan,
  • Malar Samikkannu,
  • Haylee R. Hammond,
  • Shainnel O. Eans,
  • Marc J. Kaufman,
  • Jay P. McLaughlin,
  • Thangavel Samikkannu

摘要

HIV-Tat and morphine synergistically exacerbate neuroinflammation and DNA damage, yet the mechanisms linking the DNA damage response (DDR), chromatin remodeling, and innate immune activation remain poorly understood. Here, we investigated how HIV-Tat and morphine alter DNA repair dynamics and cGAS–STING–AIM2 inflammasome signaling in microglia and cortical tissue and evaluated the efficacy of dimethyl fumarate (DMF) in mitigating these effects. HMC3 microglial cells were exposed to HIV-Tat (50 ng/mL) and morphine (10 µM) for 24 h or 5 days, with H2A.X knockdown performed prior to treatment. In vivo, doxycycline (DOX)-induced Tat transgenic mice received escalating morphine doses for 4 days, followed by DMF (30 mg/kg, i.p.) for 7 days. Postmortem frontal cortical tissues from HIV-positive and matched HIV-negative donors were analyzed for validation. Behavioral testing, immunostaining, qPCR, and Western blotting assessed DDR markers, KAT5 acetylation, histone modifications, and innate immune mediators. HIV-Tat and morphine significantly enhanced DDR activation in vitro and in vivo, as indicated by increased ATM and γH2AX and elevated KAT5 acetylation. Large Organized Chromatin Lysine (K) domains (LOCK) displayed reduced H3K9me3 and increased H3K9ac, reflecting chromatin relaxation and disrupted epigenetic control over DDR and inflammation. DOX+Morphine treatment upregulated ERCC1 and ERCC8 but downregulated ERCC2, ERCC3, and ERCC6, demonstrating impaired nucleotide excision repair, and these changes were closely associated with cGAS–STING activation and AIM2/NLRP3 inflammasome induction. H2A.X knockdown or DMF treatment suppressed ATM phosphorylation, restored H3K9me3, normalized ERCC expression, and attenuated inflammasome activation. DMF also rescued HIV-Tat ± morphine-induced deficits in novel object recognition. Postmortem cortical tissue confirmed γH2AX accumulation, reduced ERCC2/ERCC3, and altered histone signatures consistent with experimental findings. Together, these results demonstrate that HIV-Tat and morphine cooperatively disrupt LOCK chromatin and DDR through the ATM/γH2AX axis, and that DMF reverses these molecular and functional abnormalities, highlighting its therapeutic potential in mitigating HIV- and opioid-induced neuroinflammation and cognitive decline.