BACKGROUND AND PURPOSE: Microglia phenotype and phagocytic activity are deregulated in Parkinson's disease (PD). Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are neuroprotective in experimental PD, but their role in regulating microglial phenotype and phagocytosis has been poorly investigated. We addressed it by using the PPARγ agonist MDG548. EXPERIMENTAL APPROACH: Murine microglial cell line MMGT12 was stimulated with LPS and/or MDG548 and their effect on phagocytosis of fluorescent microspheres or necrotic neurons was investigated by flow cytometry. Cytokines and markers of microglia phenotype such as Mannose Receptor C-Type 1 (MRC1), Ym1 and CD68 were measured by ELISA and fluorescent immunohistochemistry. Levels of Beclin-1, recently shown to play a role in microglial phagocytosis, were measured by western blotting. In the In vivo MPTP-probenecid (MPTPp) model of PD in mice, MDG548 was tested on motor impairment, nigral neurodegeneration, microglial activation and phenotype. KEY RESULTS: MDG548, applied to LPS-stimulated microglia, increased the phagocytosis of both latex beads and necrotic cells, upregulated the expression of MRC1, CD68 and to a lesser extent IL-10, while counteracted the LPS-induced increase of TNF-α and iNOS. MDG548 also caused the induction of Beclin-1. The chronic MPTPp treatment in mice downregulated MRC1 and TGF-β and upregulated TNF-α and IL-1β immunoreactivity in activated CD11b-positive microglia, causing the death of nigral dopaminergic neurons. MDG548 arrested the MPTPp-induced cell death, enhanced MRC1 and restored cytokines levels. CONCLUSION AND IMPLICATIONS: This study adds a novel mechanism for PPARγ-mediated neuroprotection in PD, and suggests that boosting the phagocytic activity and anti-inflammatory markers may represent an effective disease-modifying approach.

Boosting phagocytosis and anti-inflammatory phenotype in microglia mediates neuroprotection by PPARγ agonist MDG548 in Parkinson's disease

Giovanna Mulas;Andrea Diana;Fabrizio Angius;Stefano Spolitu;Gabriella Simbula;Barbara Batetta;Saturnino Spiga;Anna R Carta
Ultimo
2018-01-01

Abstract

BACKGROUND AND PURPOSE: Microglia phenotype and phagocytic activity are deregulated in Parkinson's disease (PD). Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are neuroprotective in experimental PD, but their role in regulating microglial phenotype and phagocytosis has been poorly investigated. We addressed it by using the PPARγ agonist MDG548. EXPERIMENTAL APPROACH: Murine microglial cell line MMGT12 was stimulated with LPS and/or MDG548 and their effect on phagocytosis of fluorescent microspheres or necrotic neurons was investigated by flow cytometry. Cytokines and markers of microglia phenotype such as Mannose Receptor C-Type 1 (MRC1), Ym1 and CD68 were measured by ELISA and fluorescent immunohistochemistry. Levels of Beclin-1, recently shown to play a role in microglial phagocytosis, were measured by western blotting. In the In vivo MPTP-probenecid (MPTPp) model of PD in mice, MDG548 was tested on motor impairment, nigral neurodegeneration, microglial activation and phenotype. KEY RESULTS: MDG548, applied to LPS-stimulated microglia, increased the phagocytosis of both latex beads and necrotic cells, upregulated the expression of MRC1, CD68 and to a lesser extent IL-10, while counteracted the LPS-induced increase of TNF-α and iNOS. MDG548 also caused the induction of Beclin-1. The chronic MPTPp treatment in mice downregulated MRC1 and TGF-β and upregulated TNF-α and IL-1β immunoreactivity in activated CD11b-positive microglia, causing the death of nigral dopaminergic neurons. MDG548 arrested the MPTPp-induced cell death, enhanced MRC1 and restored cytokines levels. CONCLUSION AND IMPLICATIONS: This study adds a novel mechanism for PPARγ-mediated neuroprotection in PD, and suggests that boosting the phagocytic activity and anti-inflammatory markers may represent an effective disease-modifying approach.
2018
MPTP; MRC1; Parkinson; TNF-α; Microglia; Neuroinflammation; Phagocytosis
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11584/242848
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