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<p>Lead (Pb) and hypertension (HTN) frequently coexist in the environment, yet the impact of their co-exposure on social impairment remains poorly understood. We found that co-exposure to Pb and hypertension significantly exacerbated social impairment in mice, accompanied by nuclear hyperchromasia and structural damage in the hypothalamic paraventricular nucleus (PVN). Moreover, co-exposure significantly exacerbated microglial polarization imbalance in the PVN, as reflected by elevated expression of the M1 markers iNOS and COX2, coupled with reduced expression of the M2 marker Arg-1. Crucially, co-exposure induced a profound downregulation of TREM2 in the PVN, whereas TREM2 overexpression through intracerebral stereotactic injection not only alleviated the M1/M2 imbalance and mitigated neuronal injury but also improved social behavior. Mechanistically, we demonstrate that TREM2 exerts its neuroprotective effects by sustaining the expression of insulin-like growth factor-1 (IGF-1). Notably, the therapeutic benefits of TREM2 overexpression were abolished by concurrent IGF-1 knockdown, confirming that IGF-1 acts as an obligatory downstream mediator of TREM2-regulated microglial polarization. Collectively, our findings demonstrate that the TREM2/IGF-1 axis serves as an essential pathway mediating microglial polarization and social impairment following co-exposure to Pb and hypertension, underscoring a viable therapeutic strategy for neurobehavioral disorders linked to environmental and vascular insults.</p>

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Co-exposure to lead and hypertension exacerbates social impairment in mice through TREM2/IGF-1 mediated microglial polarization in the PVN

  • 期刊论文

  • 发表日期：

    2026年7月3日

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  • Jialu Zhao,
  • Huiyuan Shi,
  • Linchang Yu,
  • Jian Sun,
  • Xiaoming Song,
  • Yuan Yu,
  • Licheng Yan,
  • Fan Shi,
  • Weixuan Wang,
  • Yanshu Zhang

摘要

Lead (Pb) and hypertension (HTN) frequently coexist in the environment, yet the impact of their co-exposure on social impairment remains poorly understood. We found that co-exposure to Pb and hypertension significantly exacerbated social impairment in mice, accompanied by nuclear hyperchromasia and structural damage in the hypothalamic paraventricular nucleus (PVN). Moreover, co-exposure significantly exacerbated microglial polarization imbalance in the PVN, as reflected by elevated expression of the M1 markers iNOS and COX2, coupled with reduced expression of the M2 marker Arg-1. Crucially, co-exposure induced a profound downregulation of TREM2 in the PVN, whereas TREM2 overexpression through intracerebral stereotactic injection not only alleviated the M1/M2 imbalance and mitigated neuronal injury but also improved social behavior. Mechanistically, we demonstrate that TREM2 exerts its neuroprotective effects by sustaining the expression of insulin-like growth factor-1 (IGF-1). Notably, the therapeutic benefits of TREM2 overexpression were abolished by concurrent IGF-1 knockdown, confirming that IGF-1 acts as an obligatory downstream mediator of TREM2-regulated microglial polarization. Collectively, our findings demonstrate that the TREM2/IGF-1 axis serves as an essential pathway mediating microglial polarization and social impairment following co-exposure to Pb and hypertension, underscoring a viable therapeutic strategy for neurobehavioral disorders linked to environmental and vascular insults.