Objective: To determine whether M1 microglial signaling via FAM19A3, CHI3L1, and VILIP-1 contributes to neuroinflammation, neuronal degeneration, and behavioral dysfunction in a Parkinson’s disease, and to evaluate the modulatory effects of IL-37.

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by dopaminergic neuron loss and α-synuclein aggregation. Beyond motor deficits, PD frequently involves neuropsychiatric symptoms such as depression, anxiety, and cognitive decline. Increasing evidence implicates neuroinflammation and microglial activation in PD pathogenesis. Activated pro-inflammatory (M1) microglia release mediators including CHI3L1 and VILIP-1, which are linked to neuronal injury. FAM19A3 may regulate these responses, whereas the anti-inflammatory cytokine IL-37 could hinder excessive microglial activation.

Method: PD-like pathology was induced in male Wistar rats by stereotaxic lipopolysaccharide injection into the substantia nigra; controls received PBS. Rats were grouped as control (n=10), early PD (40 days, n=20), and long-term PD (80 days, n=20), with PD groups further divided into untreated and IL-37-treated subgroups (n=10). IL-37 was administered intraperitoneally for seven days. Motor coordination and depressive-like behavior were assessed using rotarod and tail suspension tests. Biological samples were analyzed for FAM19A3, CHI3L1, VILIP-1, α-synuclein, and inflammatory cytokines, while dopaminergic neuron loss, microglial activation, and protein aggregation were assessed via immunohistochemistry and immunofluorescence.

Results: Early LPS-induced M1 activation increased FAM19A3, CHI3L1, and VILIP-1 levels in tissue and CSF, accompanied by α-synuclein accumulation, neuronal injury, and mild motor and behavioral deficits. Long-term PD showed sustained neuroinflammation, higher biomarker expression, greater dopaminergic neuron loss, and more severe behavioral impairment. IL-37 treatment reduced microglial activation and inflammatory mediators, reduced dopaminergic neuron loss, and improved behavioral outcomes.

Conclusion: M1 microglial signaling via FAM19A3, CHI3L1, and VILIP-1 links neuroimmune dysregulation with neuronal degeneration and behavioral dysfunction in PD. IL-37 may attenuate these inflammatory pathways and represents a potential therapeutic strategy for PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/microglial-inflammatory-signaling-mediates-neuroimmune-dysregulation-and-behavioral-dysfunction-in-a-parkinsons-disease-model/