Multi-omics profiling suggests deep brain stimulation-associated expansion of CLIC3+ NK cells attenuates neuroinflammation in Parkinson's disease

Deep brain stimulation (DBS) alleviates Parkinson's disease (PD) symptoms, but its immunomodulatory mechanisms remain elusive. Through integrating microarray (GSE23676), single cell/nucleus RNA-seq (GSE184950, GSE202210, GSE223138, GSE243639; after quality control (mitochondrial gene content <25%, gene number >200) 616,076 high-quality cells were included), and GWAS data, we identified CLIC3 as a DBS-associated, potential protective implications in PD. CLIC3 was selectively up-regulated in a distinct natural killer cell subset (NK_CLIC3), which secreted TGFB1 to restrain neuroinflammation. CellChat and immunohistochemistry revealed that NK_CLIC3 cells communicated with PD-relevant neuronal populations: excitatory (SLC18A2+), inhibitory (SLC18A2+), oligodendrocyte (SLC18A2+), and astrocytic (SLC18A2+) cells via THY1–ADGRE5 and GZMA–PARD3 axes. Immune infiltration analysis (GSE114517; n = 75) suggested NK infiltration and deficient M2 macrophage recruitment in PD brains, underscoring an inadequate anti-inflammatory response. We further isolated CLIC3-positive NK cells (from a healthy donor) by fluorescence-activated cell sorting (FACS) and confirmed their ability to degrade α-synuclein, the pathological protein in Parkinson's disease, supporting the potential NK(CLIC3+) cells' protective function in PD. Our findings suggest DBS may expand NK_CLIC3 cells to suppress neuroinflammation through TGFB1 mediated immune–neuronal crosstalk, positioning CLIC3 as a prospective therapeutic target for PD.