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CD200R1 loss in CNS-associated macrophages triggers T cell-driven neurodegeneration in Parkinson’s disease

ABSTRACT: Immune dysregulation is increasingly recognized as a key contributor to Parkinson’s disease (PD) pathogenesis. While microglia are established central nervous system (CNS) immune regulators, the role of CNS-associated macrophages (CAMs) and their upstream modulation by immune checkpoints remains poorly defined. Here, we identify CD200R1, a myeloid-specific inhibitory receptor, as a checkpoint selectively expressed by embryonically derived CAMs at CNS borders. CD200R1 deletion reprograms CAMs toward a proinflammatory, antigen-presenting state enriched in interferon and pyroptosis-related gene signatures. In α-synuclein–based PD models, CD200R1 loss exacerbates dopaminergic neurodegeneration, enhances CD8⁺ T cell infiltration, and promotes formation of tertiary microglial–T cell nodules. Mechanistically, it activates the caspase-8/GSDMD pyroptosis pathway in CAMs, creating a permissive environment for pathogenic T cells. Pyroptosis blockade with disulfiram attenuates T cell infiltration and neurodegeneration. Notably, pharmacological activation of CD200R1 via CD200Fc suppresses CAM activation and confers neuroprotection. These findings define a border-specific immune checkpoint that governs CAM–T cell crosstalk and represents a tractable therapeutic target in PD.

ORGANISM(S): Mus musculus

PROVIDER: GSE304505 | GEO | 2025/08/09

REPOSITORIES: GEO

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CD200R1 loss in CNS-associated macrophages triggers T cell-driven neurodegeneration in Parkinson’s disease

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