Loss of PHD3 rescues mice from Neuroinflammation and cognitive disorders induced by lipopolysaccharide or surgical trauma.

Authors

Ji Che, Yixu Deng, Xiang Zhang, Changsheng Shi, Zhiyong He, Jing Dong, Jun Zhang

Published in

Experimental neurology. Pages 115985. Aug 19, 2026. Epub Aug 19, 2026.

Abstract

Neuroinflammation is recognized as a contributing factor to cognitive disorders. Previous studies have demonstrated PHD3 drives microglia-mediated neuroinflammation. Present study aims to further clarify the role of PHD3 in both lipopolysaccharide (LPS)- and anesthesia/surgery (AS)-induced neuroinflammation and cognitive impairments.
Eight-week-old male wild-type and PHD3 knockout C57BL/6 J mice were used to establish LPS- and AS-induced neuroinflammation models. Cognitive function was evaluated using the Y-maze, open-field, and novel object recognition tests. Neuroinflammatory responses, microglial activation, synaptic proteins, and apoptosis-associated changes in the hippocampus and prefrontal cortex were assessed by Western blotting and immunofluorescence staining. Furthermore, an adeno-associated virus (AAV)-mediated conditional microglial PHD3 knockdown model was established to investigate the role of microglial-specific PHD3 in neuroinflammatory regulation.
PHD3 knockout significantly ameliorated LPS- and AS-induced cognitive deficits, accompanied by reduced expression of pro-inflammatory mediators TNF-α and IL-1β, and decreased the activation of NF-κB pathway in the hippocampus and prefrontal cortex. PHD3 deficiency also attenuated microglial activation, restored postsynaptic density protein 95 (PSD95) and Synapsin I ‌(SYN1) levels, and reduced neuronal proapoptotic activation. Mechanistically, conditional microglial PHD3 knockdown recaptured the anti-inflammatory effects observed in PHD3 knockout mice via reducing LPS-induced inflammatory cytokines production, suppressing IKK/IκBα/NF-κB signaling activation, and modulating expressions of microglial activation-associated markers iNOS/CD86 and CD206/Arg-1. In addition, conditional microglial PHD3 knockdown attenuated LPS-induced upregulation of HIF-1α rather than HIF-2α expression.
Our results demonstrate that PHD3 deficiency exerts neuroprotective effects against systemic inflammation-induced cognitive dysfunction by suppressing microglial activation, synaptic damages, and neuronal apoptosis may through NF-κB signaling. These findings suggest that PHD3 may represent a promising therapeutic target for inflammation-associated cognitive disorders.

PMID:
42617908
Bibliographic data and abstract were imported from PubMed on 20 Aug 2026.

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