Dendritic Cells Induce Clec5a-mediated Immune Modulation in MPTP-induced Parkinson's Disease Mouse Model.

Abstract

Background: Parkinson's disease (PD) is characterized by a progressive decline in dopaminergic neurons within the substantia nigra (SN). Although its underlying cause has yet to be fully elucidated, accumulating evidence suggests that neuroinflammation contributes substantially to disease development. Treatment strategies targeting neuroinflammation could improve PD outcomes. Monocyte-derived tolerogenic dendritic cells (tolDCs) modulate immune responses and induce regulatory T cells (Tregs) during various inflammatory diseases. However, the mechanisms underlying tolDC-mediated immunoregulation in PD remain unclear.

Methods: We investigated the immune modulatory role of tolDCs by analyzing gene expression patterns and identified that the C-type lectin domain family 5 member A (Clec5a) was highly induced in tolDCs. To assess its function, we generated Clec5a-knockdown tolDCs and measured cytokine production, including interleukin (IL)-10 and IL-6, forkhead box protein P3 (Foxp3)⁺ Treg induction, and nuclear factor kappa B (NF-κB) signaling activity. Furthermore, we evaluated the therapeutic effects of Clec5a-expressing dendritic cells (DCs) in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Dopaminergic neuron survival, α-synuclein (α-syn) accumulation, neuroinflammatory markers, and locomotor behavior were analyzed following DC administration.

Results: Clec5a-knockdown tolDCs exhibited reduced immunomodulatory function and IL-10 levels but enhanced IL-6 levels. In addition, these cells induced fewer Foxp3⁺ Tregs and showed significantly enhanced NF-κB signaling activity. In the MPTP-induced PD model, administration of Clec5a-expressing DCs ameliorated dopaminergic neuron loss and α-syn accumulation. Furthermore, Clec5a-expressing DCs reduced the number of CD45^highCD11b⁺CD86⁺ macrophages in the brain, reduced brain inflammatory cytokine expression, and improved locomotor activity.

Conclusions: These findings suggest that Clec5a plays a critical role in the immunomodulatory function of tolDCs. The administration of Clec5a-expressing DCs effectively reduced neuroinflammation and protected dopaminergic neurons in an MPTP-induced PD model. Therefore, Clec5a-expressing tolDCs may demonstrate therapeutic potential by managing PD symptoms by suppressing inflammatory responses associated with neurodegeneration.