MIF downregulation attenuates neuroinflammation via TLR4/MyD88/TRAF6/NF-κB pathway to protect dopaminergic neurons in Parkinson's disease model.

The progression of Parkinson's disease (PD) is closely associated with neuroinflammatory responses and microglial activation. Consequently, research targeting microglia-mediated neuroinflammation has garnered increasing attention. Macrophage migration inhibitory factor (MIF), a multifunctional cytokine, is implicated in neurodegenerative pathologies, including PD. However, its precise regulatory mechanisms in PD-associated microglial activation and neuroinflammatory cascades remain incompletely characterized. In this study, we observe that MIF exacerbates the pathogenesis of PD through its pro-inflammatory effect, and downregulation of MIF could ameliorate motor behavior deficits, attenuate neuroinflammation, and protect midbrain dopamine (DA) neurons in PD mice. Mechanistically, MIF downregulation attenuates neuroinflammation and exerts neuroprotection against microglia-induced neuronal injury and degeneration by regulating the TLR4/MyD88/TRAF6 signaling axis. In conclusion, this study elucidates the pivotal role of MIF in regulating neuroinflammation associated with PD, suggesting that MIF may be a potential therapeutic target for intervening in PD progression, and providing new strategies for PD treatment.