Glia Maturation Factor and Mast Cell-Dependent Expression of Inflammatory Mediators and Proteinase Activated Receptor-2 in Neuroinflammation

Article type: Research Article

Authors: Kempuraj, Duraisamy^{a; b; *} | Selvakumar, Govindhasamy Pushpavathi^{a; b} | Thangavel, Ramasamy^{a; b} | Ahmed, Mohammad Ejaz^{a; b} | Zaheer, Smita^b | Kumar, Keerthana Kuppamma^b | Yelam, Anudeep^b | Kaur, Harleen^b | Dubova, Iuliia^b | Raikwar, Sudhanshu P.^{a; b} | Iyer, Shankar S.^{a; b} | Zaheer, Asgar^{a; b; *}

Affiliations: [a] Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA | [b] Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA

Correspondence: [*] Correspondence to: Duraisamy Kempuraj, PhD, Assistant Research Professor, Department of Neurology, and Center for Translational Neuroscience, University of Missouri, School of Medicine, 1 Hospital Drive, Columbia, MO 65211, USA. Tel.: +1 573 882 6573; E-mail: [email protected] and Asgar Zaheer, PhD, Professor, Department of Neurology, Director, Center for Translational Neuroscience, University of Missouri, School of Medicine, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO 65211, USA. Tel.: +1 573 882 5386; E-mail: [email protected].

Abstract: Parkinson’s disease (PD) is characterized by the presence of inflammation-mediated dopaminergic neurodegeneration in the substantia nigra. Inflammatory mediators from activated microglia, astrocytes, neurons, T-cells and mast cells mediate neuroinflammation and neurodegeneration. Administration of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induces PD like motor deficits in rodents. 1-methyl-4-phenylpyridinium (MPP+), a toxic metabolite of MPTP activates glial cells, neurons and mast cells to release neuroinflammatory mediators. Glia maturation factor (GMF), mast cells and proteinase activated receptor-2 (PAR-2) are implicated in neuroinflammation. Alpha-synuclein which induces neurodegeneration increases PAR-2 expression in the brain. However, the exact mechanisms are not yet understood. In this study, we quantified inflammatory mediators in the brains of MPTP-administered wild type (Wt), GMF-knockout (GMF-KO), and mast cell knockout (MC-KO) mice. Additionally, we analyzed the effect of MPP+, GMF, and mast cell proteases on PAR-2 expression in astrocytes and neurons in vitro. Results show that the levels of interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and the chemokine (C-C motif) ligand 2 (CCL2) were lesser in the brains of GMF-KO mice and MC-KO mice when compared to Wt mice brain after MPTP administration. Incubation of astrocytes and neurons with MPP+, GMF, and mouse mast cell protease-6 (MMCP-6) and MMCP-7 increased the expression of PAR-2. Our studies show that the absence of mast cells and GMF reduce the expression of neuroinflammatory mediators in the brain. We conclude that GMF along with mast cell interactions with glial cells and neurons during neuroinflammation can be explored as a new therapeutic target for PD and other neuroinflammatory disorders.

Keywords: Astrocytes, cytokines, glia maturation factor, mast cells, mouse mast cell proteases, Parkinson’s disease, PAR-2

DOI: 10.3233/JAD-180786

Journal: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1117-1129, 2018