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<p>Ozone (O<sub>3</sub>) is a significant global air pollutant. Recent epidemiological studies have established a correlation between O<sub>3</sub> exposure and an increased risk of neurological disorders. However, the underlying mechanisms by which O<sub>3</sub> induces cognitive deficits remain unclear. This study demonstrated that exposure to environmentally relevant O<sub>3</sub> levels resulted in significant cognitive impairment in mice. These deficits arose from hippocampal synaptic injury, characterized by reduced dendritic spine density, disrupted synaptic ultrastructure, and impaired long-term potentiation. Mechanistically, O<sub>3</sub> activated the liver complement pathway, leading to increased levels of complement component 3 (C3) and its subsequent release into the bloodstream. Furthermore, O<sub>3</sub> compromised the integrity of the blood–brain barrier, allowing peripheral C3 to infiltrate the hippocampus. Notably, C3 served as a key signal that triggered local pro-inflammatory microglial activation and enhanced their phagocytosis of excitatory synapses, ultimately resulting in synaptic loss and cognitive decline. Importantly, both the microglial inhibitor minocycline and liver-specific C3 knockdown suppressed pro-inflammatory microglial activation and restored synaptic plasticity and cognitive function. These findings systematically reveal a novel liver–brain axis in O<sub>3</sub> neurotoxicity, whereby peripheral C3 drives central microglial phagocytosis of excitatory synapses, offering new mechanistic insights and potential therapeutic targets for O<sub>3</sub>-related neurological diseases.</p>

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Ozone-induced cognitive deficits are mediated by the liver–brain axis: peripheral complement C3 triggers microglial synaptic phagocytosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月19日

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  • Yougang Wang,
  • Haomin Qi,
  • Weiran Dong,
  • Yushan Chen,
  • Desiré Nisubire,
  • Yan Zeng,
  • Jinquan Li

摘要

Ozone (O3) is a significant global air pollutant. Recent epidemiological studies have established a correlation between O3 exposure and an increased risk of neurological disorders. However, the underlying mechanisms by which O3 induces cognitive deficits remain unclear. This study demonstrated that exposure to environmentally relevant O3 levels resulted in significant cognitive impairment in mice. These deficits arose from hippocampal synaptic injury, characterized by reduced dendritic spine density, disrupted synaptic ultrastructure, and impaired long-term potentiation. Mechanistically, O3 activated the liver complement pathway, leading to increased levels of complement component 3 (C3) and its subsequent release into the bloodstream. Furthermore, O3 compromised the integrity of the blood–brain barrier, allowing peripheral C3 to infiltrate the hippocampus. Notably, C3 served as a key signal that triggered local pro-inflammatory microglial activation and enhanced their phagocytosis of excitatory synapses, ultimately resulting in synaptic loss and cognitive decline. Importantly, both the microglial inhibitor minocycline and liver-specific C3 knockdown suppressed pro-inflammatory microglial activation and restored synaptic plasticity and cognitive function. These findings systematically reveal a novel liver–brain axis in O3 neurotoxicity, whereby peripheral C3 drives central microglial phagocytosis of excitatory synapses, offering new mechanistic insights and potential therapeutic targets for O3-related neurological diseases.