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Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson’s Disease

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Abstract

Parkinson’s disease (PD) is a progressive movement disorder characterized by neuroinflammation and dopaminergic neurodegeneration in the brain. 1-methyl-4-phenylpyridinium (MPP+), a metabolite of the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces the release of inflammatory mediators from glial cells and neurons. Glia maturation factor (GMF), a brain proinflammatory protein, MPP+ , and mast cell-derived inflammatory mediators induce neurodegeneration which eventually leads to PD. However, the precise mechanisms underlying interaction between glial cells, neurons and mast cells in PD still remain elusive. In the present study, mouse bone marrow-derived mast cells (BMMCs) and mouse fetal brain-derived mixed glia/neurons, astrocytes and neurons were incubated with MPP+, GMF and mast cell-derived inflammatory mediators mouse mast cell protease-6 (MMCP-6), MMCP-7 or tryptase/brain-specific serine protease-4 (tryptase/BSSP-4). Inflammatory mediators released from these cells in the culture medium were quantitated by enzyme-linked immunosorbent assay. Neurodegeneration was quantified by measuring total neurite outgrowth following microtubule-associated protein-2 immunocytochemistry. MPP+-induced significant neurodegeneration with reduced total neurite outgrowth. MPP+induced the release of tryptase/BSSP-4 from the mouse mast cells, and tryptase/BSSP-4 induced chemokine (C-C motif) ligand 2 (CCL2) release from astrocytes and glia/neurons. Overall our results suggest that MPP+, GMF, MMCP-6 or MMCP-7 stimulate glia/neurons, astrocytes or neurons to release CCL2 and matrix metalloproteinase-3. Additionally, CD40L expression is increased in BMMCs after incubation with MPP+ in a co-culture system consisting of BMMCs and glia/neurons. We propose that mast cell interaction with glial cells and neurons during neuroinflammation can be explored as a new therapeutic target for PD.

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Acknowledgements

The Flow cytometry data presented herein were obtained at the Flow Cytometry Facility, which is a Carver College of Medicine/Holden Comprehensive Cancer Center core research facility at the University of Iowa, Iowa City, IA. The Facility is funded through user fees and the generous financial support of the Carver College of Medicine, Holden Comprehensive Cancer Center, and Iowa City Veteran’s Administration Medical Center. We thank Mr. Justin Fishbaugh, Technical Director, Flow Cytometry Facility for his help in Flow Cytometry data acquisition and analysis in this study.

Funding

This work was supported by Veteran Affairs Merit Award I01BX002477 and National Institutes of Health Grants AG048205 & NS073670 to AZ.

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Authors and Affiliations

  1. U.S. Department of Veterans Affairs, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, 65201, USA

    Duraisamy Kempuraj, Govindhasamy Pushpavathi Selvakumar, Ramasamy Thangavel, Mohammad Ejaz Ahmed, Sudhanshu Raikwar, Shankar Iyer & Asgar Zaheer

  2. Department of Neurology and the Center for Translational Neuroscience, School of Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, 65201, USA

    Duraisamy Kempuraj, Govindhasamy Pushpavathi Selvakumar, Smita Zaheer, Ramasamy Thangavel, Mohammad Ejaz Ahmed, Sudhanshu Raikwar, Raghav Govindarajan, Shankar Iyer & Asgar Zaheer

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  1. Duraisamy Kempuraj
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Correspondence to Asgar Zaheer.

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The Committee on the Ethics of Animal Experiments of the University of Iowa (Iowa City, IA) and the University of Missouri (Columbia, MO) approved the protocol.

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Kempuraj, D., Selvakumar, G.P., Zaheer, S. et al. Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson’s Disease. J Neuroimmune Pharmacol 13, 100–112 (2018). https://doi.org/10.1007/s11481-017-9766-1

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