Mast Cells Augment Neuroinflammation and Neurodegeneration

Abstract

Activated glial cells, and neurons express several proinflammatory mediators that are implicated in neuroinflammation and neurodegeneration in neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD) and Multiple sclerosis (MS). Mast cells are immune and inflammatory cells that are implicated in neuroinflammation by releasing several prestored and newly synthesized multifunctional cytokines, chemokines and neurotoxic mediators. Protease activated receptor‐2 (PAR‐2) expression is increased in neuroinflammatory conditions. PD is characterized by neurodegeneration of dopaminergic neurons in the brain. Here, we have investigated how mast cells can contribute to neuroinflammation, and to the pathogenesis of PD. We demonstrate that inflammatory mediators such as interleukin‐1beta (IL‐1β), tumor necrosis factor‐alpha (TNF‐α) and the chemokine (C‐C motif) ligand 2 (CCL2) were lower in the brains of mast cell deficient (MC‐KO) mice and glia maturation factor‐deficient (GMF‐KO) mice when compared to wild type mice brains after acute 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) administration. Further, we found that reconstitution of mast cells in MC‐KO mice increases neuroinflammation in the MPTP‐injected mice brains as compared to the MC‐KO brains without mast cell reconstitution. Our immunofluorescence staining revealed that the PAR‐2 expression is increased in MPTP‐injected mice brains as compared to control wild type mice brains without MPTP administration. We also show significantly increased PAR‐2 expression in the cultured primary mouse astrocytes and neurons incubated with 1‐methyl‐4‐phenylpyridinium (MPP+), inflammatory protein GMF, mouse mast cell protease‐6 (MMCP‐6), and MMCP‐7. We conclude that mast cells augment neuroinflammation and neurodegeneration in neurodegenerative diseases including PD and inhibition of mast cell activation could be a therapeutic option in neuroinflammatory and neurodegenerative disorders.Support or Funding InformationThis work was supported by Veteran Affairs Merit Award I01BX002477 and National Institutes of Health Grants AG048205 & NS073670 to Prof. Asgar ZaheerThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.