Inhibition of the NFATc2/FKBP5 axis alleviates microglial neuroinflammation by regulating arachidonic acid metabolism in Parkinson's disease

Microglia-induced neuroinflammation is among the core pathological hallmarks of Parkinson's disease (PD). FKBP5, which has been implicated in stress-related disorders, is recognized as a key regulator of inflammatory responses. However, the role and mechanism of FKBP5 in PD remain unclear. In the present study, we revealed that reducing FKBP5 levels via shRNA targeting microglia or pharmacological inhibition with SAFit2 could mitigate motor impairment and dopamine neuronal loss,as well as reducearachidonic acid (AA) and proinflammatory factors (IL-6, TNF-α, and iNOS) levels in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Conversely, FKBP5 knockdown in 1-methyl-4-phenylpyridinium (MPP⁺)-treated BV2 microglia reduced inflammatory marker expression and targeted the inhibition of AA synthesis. Moreover, we revealed that NFATc2, a transcription factor of FKBP5, was significantly involved in AA generation and proinflammatory cytokine expression both in vivo and in vitro. In the MPP⁺-treated microglia, FKBP5 upregulation reversed the inhibition of AA signaling pathways induced by NFATc2 silencing. Furthermore, PD patients presented elevated mRNA expression of NFATc2 and FKBP5 in the peripheral blood, which were positively correlated with disease severity and serum AA levels, respectively. These findings highlight the involvement of the NFATc2/FKBP5 signaling pathway in AA-induced microglial neuroinflammation, indicating that NFATc2/FKBP5 may serve as PD biomarkers and targets for therapeutic interventions.

Arachidonic acid; FKBP5; NFATc2; Neuroinflammation; Parkinson’s disease.