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Polo-like kinase 2 (PLK2) is a serine/threonine protein kinase associated with the regulation of synaptic plasticity and centriole duplication. We identify PLK2 as a crucial early-response gene in lipopolysaccharide (LPS)-stimulated microglial cells. Knockdown or inhibition of PLK2 remarkably attenuates LPS-induced expression of proinflammatory factors in microglial cells by suppressing the inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ)-nuclear factor (NF)-κB signaling pathway. We identify heat shock protein 90 alpha (HSP90α), a regulator of IKKβ activity, as a novel PLK2 substrate. Knockdown or pharmacological inhibition of HSP90α abolishes PLK2-mediated activation of NF-κB transcriptional activity and microglial inflammatory activation. Furthermore, phosphoproteomic analysis pinpoints Ser252 and Ser263 on HSP90α as novel phosphorylation targets of PLK2. Lastly, conditional knockout of PLK2 in microglial cells dramatically ameliorates neuroinflammation and subsequent dopaminergic neuron loss in an intracranial LPS-induced mouse Parkinson's disease (PD) model. The present study reveals that PLK2 promotes microglial activation through the phosphorylation of HSP90α and subsequent activation of the IKKβ-NF-κB signaling pathway. [Display omitted] • LPS rapidly induces PLK2 expression in microglial cells • Inhibition of PLK2 suppresses LPS-induced microglial activation via NF-κB signaling • PLK2 activates NF-κB signaling through phosphorylating HSP90α • Knockout of PLK2 in microglia ameliorated neuroinflammation and dopaminergic neuron loss Cheng et al. demonstrated that PLK2 functions as a primary early-response gene playing significant roles in microglial activation. PLK2 phosphorylates HSP90α at Ser252 and Ser263, which subsequently modulates the IKKβ/NF-κB pathway and microglial activation. The authors also revealed that conditional knockout of PLK2 in microglial cells protects dopaminergic neurons from inflammatory damage. [ABSTRACT FROM AUTHOR]