Abstract
Classical activation (M1 phenotype) and alternative activation (M2 phenotype) are the two polars of microglial activation states that can produce either neurotoxic or neuroprotective effects in the immune pathogenesis of Parkinson’s disease (PD). Exploiting the beneficial properties of microglia cells by modulating their polarization states provides great potential for the treatment of PD. However, the mechanism that regulates microglia polarization remains elusive. Here we demonstrated that Kir6.1-containing ATP-sensitive potassium (Kir6.1/K-ATP) channel switched microglia from the detrimental M1 phenotype toward the beneficial M2 phenotype. Kir6.1 knockdown inhibited M2 polarization and simultaneously exaggerated M1 microglial inflammatory responses, while Kir6.1 overexpression promoted M2 polarization and synchronously alleviated the toxic phase of M1 microglia polarization. Furthermore, we observed that the Kir6.1 deficiency dramatically exacerbated dopaminergic neuron death companied by microglia activation in mouse model of PD. Mechanistically, Kir6.1 deficiency enhanced the activation of p38 MAPK–NF-κB pathway and increased the ratio of M1/M2 markers in the substantia nigra compacta of mouse model of PD. Suppression of p38 MAPK in vivo partially rescued the deleterious effects of Kir6.1 ablation on microglia phenotype and dopaminergic neuron death. Collectively, our findings reveal that Kir6.1/K-ATP channel modulates microglia phenotypes transition via inhibition of p38 MAPK–NF-κB signaling pathway and Kir6.1/K-ATP channel may be a promising therapeutic target for PD.
Highlights
Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, is characterized by the progressive loss of dopaminergic (DA) neurons in substantia nigra compacta (SNc) and excessive reactive microgliosis[1]
To explore the underlying mechanism for Kir6.1/K-ATP channel-regulated microglia phenotype, we examined the expression of MAPK and NF-κB signaling pathway which and transforming growth factor-β (TGF-β) (h) in the substantia nigra compacta (SNc). i–l Kir6.1 deficiency enhanced the activation of p38 and NF-κB in the SNc
The expression of TNF-α, IL-1β and IL-6 were assessed by qPCR (a–c) or ELISA (d–f) in BV2 microglia. g Representative immunofluorescence staining of CD16/32 was visualized under microscopy. h The expression of M1 related biomarker CCR7 was detected by flow cytometry
Summary
Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, is characterized by the progressive loss of dopaminergic (DA) neurons in substantia nigra compacta (SNc) and excessive reactive microgliosis[1]. Activated microglia are observed in the vicinity of the degenerating neurons in the SNc of animal models as well as in PD patients[2,3]. Microglia-mediated neuroinflammation is an important component in PD pathogenesis. Simple anti-inflammatory strategy may not be efficacious in clinical therapy of PD. Microglia activation can be classified into two major phenotypes defined as ‘classical activation’ ( termed M1 phenotype) and ‘alternative activation’ (M2 phenotype)[4,5,6]. M1 microglia polarization is associated with the production and release of multiple pro-inflammatory cytokines[7,8]. The released factors generally act in tissue defense and promote the destruction of pathogens[9]
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