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The Role of Myeloid Peroxisome Proliferator-activated Receptor Delta in Experimental Autoimmune Encephalomyelitis

Drohomyrecky, PC;

Peroxisome proliferator-activated receptor δ (PPAR-δ) is a nuclear receptor that regulates whole body metabolic homeostasis, cell growth and differentiation. Previously our lab reported that mice lacking PPAR-δ (Ppardmut) developed more severe experimental autoimmune encephalomyelitis (EAE), with more proinflammatory T helper (Th) cells and macrophages. To elucidate the role of peripheral myeloid cells to this disease phenotype, EAE was induced in mice with a myeloid-specific PPAR-δ-deficiency (LysMCre:Ppardfl/fl). These mice developed more severe EAE compared to Ppardfl/fl controls, with an increased accumulation of pathogenic IL-17+CD4+ T cells in the CNS at the peak of EAE. Adoptive transfer studies and radiation bone marrow chimeras pointed to peripheral myeloid cells as the driver of this disease phenotype, substantiated by enhanced splenic myelin-specific Th1 and Th17 responses in LysMCre:Ppardfl/fl mice. Using a CD11b+:Th cell coculture system, CD11b+ cells from LysMCre:Ppardfl/fl mice were found to better at priming myelin-specific Th cells relative to Ppardfl/fl CD11b+ cells. The driver of this effect was predominantly increased expression of IL-12p40 and higher secretion of IL-12p40 homodimer and IL-23 by LysMCre:Ppardfl/fl CD11b+CD11c+ cells. These results thus identified a novel role for PPAR-δ in DCs in the regulation of Th cell priming during EAE. To evaluate the contribution of PPAR-δ in microglia in EAE, we used mice with a microglia-specific PPAR-δ-deficiency (Cx3cr1CreERT2:Ppardfl/fl), where tamoxifen (TAM)-treated mice exhibited microglial specific Ppard knockdown at 30 days. TAM-treated Cx3cr1CreERT2:Ppardfl/fl mice experienced worse EAE relative to TAM-treated Ppardfl/fl controls. Histopathology and magnetic resonance studies revealed increased Iba-1 immunoreactivity, axonal injury, and CNS atrophy in TAM-treated Cx3cr1CreERT2:Ppardfl/fl mice compared to controls. In early EAE, Cx3cr1CreERT2: Ppardfl/fl and Ppardfl/fl groups, Ppard-deficient microglia exhibited a more reactive phenotype as evidenced by a shorter maximum process length, lower expression of microglial genes associated with homeostasis, and higher expression of genes associated with reactive oxygen species generation, phagocytosis and lipid clearance, M2-activation, and inflammation. Our results therefore suggest that PPAR-δ is important in limiting the pro-inflammatory activities of microglia during EAE. Together, these studies expand upon the existing understanding of PPAR-δ in the immune system and are the first studies to evaluate the cell-specific roles of PPAR-δ in EAE.