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

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.