Peroxisome proliferator-activated receptor (PPAR)-δ is a fatty acid-activated transcription factor that regulates metabolic homeostasis, cell growth, and differentiation. Previously, we reported that mice with a global deficiency of PPAR-δ develop an exacerbated course of experimental autoimmune encephalomyelitis (EAE), highlighting a role for this nuclear receptor in limiting the development of CNS inflammation. However, the cell-specific contribution of PPAR-δ to the more severe CNS inflammatory response remained unclear. In this study, we studied the specific involvement of PPAR-δ in myeloid cells during EAE using mice that had Cre-mediated excision of floxed Ppard driven by the lysozyme M (LysM) promoter (LysM ^Cre :Ppard ^fl/fl). We observed that LysM ^Cre :Ppard ^fl/fl mice were more susceptible to EAE and developed a more severe course of this disease compared with Ppard ^fl/fl controls. The more severe EAE in LysM ^Cre :Ppard ^fl/fl mice was associated with an increased accumulation of pathogenic CD4⁺ T cells in the CNS and enhanced myelin-specific Th1 and Th17 responses in the periphery. Adoptive transfer EAE studies linked this EAE phenotype in LysM ^Cre :Ppard ^fl/fl mice to heightened Th responses. Furthermore, studies using an in vitro CD11b⁺ cell:Th cell coculture system revealed that CD11b⁺CD11c⁺ dendritic cells (DC) from LysM ^Cre :Ppard ^fl/fl mice had a heightened capacity to prime myelin oligodendrocyte glycoprotein (MOG)-specific Th cells compared with Ppard ^fl/fl counterparts; the effects of DC on Th1 cytokine production were mediated through production of the IL-12p40 homodimer. These studies revealed a role for PPAR-δ in DC in limiting Th cell priming during EAE.

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