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Nitrated -Synuclein-Induced Alterations in Microglial Immunity Are Regulated by CD4⁺ T Cell Subsets¹

Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198

Microglial inflammatory neuroregulatory activities affect the tempo of nigrostriatal degeneration during Parkinson’s disease (PD). Such activities are induced, in part, by misfolded, nitrated -synuclein (N--syn) within Lewy bodies released from dying or dead dopaminergic neurons. Such pathobiological events initiate innate and adaptive immune responses affecting neurodegeneration. We posit that the neurobiological activities of activated microglia are affected by cell-protein and cell-cell contacts, in that microglial interactions with N--syn and CD4⁺ T cells substantively alter the microglial proteome. This leads to alterations in cell homeostatic functions and disease. CD4⁺CD25⁺ regulatory T cells suppress N--syn microglial-induced reactive oxygen species and NF-B activation by modulating redox-active enzymes, cell migration, phagocytosis, and bioenergetic protein expression and cell function. In contrast, CD4⁺CD25^– effector T cells exacerbate microglial inflammation and induce putative neurotoxic responses. These data support the importance of adaptive immunity in the regulation of Parkinson’s disease-associated microglial inflammation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Frances and Louie Blumkin Foundation, the Community Neuroscience Pride of Nebraska Research Initiative, the Alan Baer Charitable Trust (to H.E.G.), the University of Nebraska Medical Center Patterson Fellowship (to A.D.R.), and National Institutes of Health Grants 5P01NS31492, 2R37 NS36126, 2R01 NS034239, P20RR15635, U54NS43011, P01MH64570, and P01 NS43985 (to H.E.G.).

² Address correspondence and reprint requests to Dr. Howard E. Gendelman, Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, 985880 Nebraska Medical Center, Omaha, NE 68198-5880. E-mail address: hegendel{at}unmc.edu

³ Abbreviations used in this paper: PD, Parkinson’s disease; BVA, biological variance analysis; BVR B, biliverdin reductase B; CB, cathepsin B; ETC, electron transport chain; DA, dopaminergic; DAPI, 4',6-diamidino-2-phenylindole; FasL, Fas ligand; GLU 1, glutaredoxin 1; GSH, glutathione; HSP, heat shock protein; LB, Lewy body; MFI, mean fluorescence intensity; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; N--syn, nitrated--syn; qPCR, quantitative PCR; ROS, reactive oxygen species; SOD, superoxide dismutase; -syn, -synuclein; Teff, CD4⁺CD25^– effector T cell; Treg, CD4⁺CD25⁺ regulatory T cell; THX 1, thioredoxin 1; UPS, ubiquitin-proteasome system.

⁴ The online version of this article contains supplemental material.