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J Immunol. 2019 Nov 15;203(10):2588-2601. doi: 10.4049/jimmunol.1801200. Epub 2019 Oct 2.

Peroxisome Proliferator-Activated Receptor-δ Acts within Peripheral Myeloid Cells to Limit Th Cell Priming during Experimental Autoimmune Encephalomyelitis.

Author information

1
Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
2
Toronto General Hospital Research Institute, Toronto, Ontario M5G 2C4, Canada.
3
Princess Margaret Cancer Centre, Toronto, Ontario M5G 2M9, Canada.
4
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612.
5
Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Shannon.Dunn@unityhealth.to.
6
Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada; and.
7
Women's College Research Institute, Toronto, Ontario M5G 1N8, Canada.

Abstract

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.

PMID:
31578267
DOI:
10.4049/jimmunol.1801200

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