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

OBJECTIVE

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.