Abstract
Microglial activation is an important contributor to the pathogenesis of Parkinson’s disease (PD). Microglia are tightly and efficiently regulated by immune checkpoints, including CD200-CD200R1 and CX3CL1-CX3CR1. Understanding the involvement of these checkpoints in disease progression provides important insights into how microglial activation contributes to PD pathology. However, so far, studies have produced seemingly conflicting results. In this study, we demonstrate that CD200R1 expression is down-regulated at both early and late stage of PD model, and CX3CR1 expression is down-regulated in early stage and recovered in late stage. In primary cultured microglia, CD200R1 and CX3CR1 expressions are both directly regulated by LPS or α-synuclein, and CD200R1 expression is more sensitively regulated than CX3CR1. In addition, CD200 knockout causes an increase in proinflammatory cytokine production and microglial activation in the midbrain. Remarkably, DA neurons in the substantial nigra are degenerated in CD200-/- mice. Finally, activation of the CD200R with CD200Fc alleviates the neuroinflammation in microglia. Together, these results suggest that immune checkpoints play distinct functional roles in different stage of PD pathology, and the CD200-CD200R1 axis plays a significant role in nigrostriatal neuron viability and function.
Highlights
Parkinson’s disease (PD) is a neurological disorder characterized by the classical motor features of parkinsonism associated with Lewy bodies and the loss of dopaminergic neurons in the substantia nigra (SN) [1]
The mice were sacrificed at 9 h and 10 m post injection to analyze changes in microglial activation, cytokine production, and CD200R1 and CX3CR1 expression in the midbrain
These results indicate that CD200-CD200R1 is involved in both the early and late stages of LPS-induced neuroinflammation and that CX3CL1-CX3CR1 is only involved in the early stage
Summary
Parkinson’s disease (PD) is a neurological disorder characterized by the classical motor features of parkinsonism associated with Lewy bodies and the loss of dopaminergic neurons in the substantia nigra (SN) [1]. Disease progression-dependent expression of CD200R1 and CX3CR1 in PD exacerbated neuroinflammation and neurodegeneration in PD models [9, 10]. Chen et al found that a CD200R1blocking antibody injected into the striatum exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of 6-OHDA-induced PD [11]. These findings provide insights into the essential roles of these immune checkpoints in microglial activation of PD. CD200 has been reported to be upregulated and downregulated in LPS, spinal cord injury and PD models [20, 23] These conflicting findings have raised concerns about the model-specific or disease progressiondependent expression and function of these checkpoints
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