Nitrated {alpha}-synuclein-induced alterations in microglial immunity are regulated by CD4+ T cell subsets.
Microglial inflammatory neuroregulatory activities affect the tempo of nigrostriatal degeneration during Parkinson's disease (PD). Such activities are induced, in part, by misfolded, nitrated alpha-synuclein (N-alpha-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-alpha-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-alpha-syn microglial-induced reactive oxygen species and NF-kappaB 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.
Reynolds
Ashley D
AD
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, 68198, USA.
Stone
David K
DK
Mosley
R Lee
RL
Gendelman
Howard E
HE
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis / Q000276:immunology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010300:Parkinson Disease / Q000276:immunology; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D051844:alpha-Synuclein / Q000276:immunology* / Q000378:metabolism
D018925:Chemokines; D016328:NF-kappa B; D051844:alpha-Synuclein