Peroxisome proliferator-activated receptor-δ acts within peripheral myeloid cells to limit th cell priming during experimental autoimmune encephalomyelitis

Paulina C. Drohomyrecky, Ellinore R. Doroshenko, Rainer Akkermann, Marina Moshkova, Tae Joon Yi, Fei L. Zhao, Jeeyoon Jennifer Ahn, Tracy L. McGaha, Kalipada Pahan, Shannon E. Dunn*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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 (LysMCre:Ppardfl/fl). We observed that LysMCre:Ppardfl/fl mice were more susceptible to EAE and developed a more severe course of this disease compared with Ppardfl/fl controls. The more severe EAE in LysMCre:Ppardfl/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 LysMCre:Ppardfl/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 LysMCre:Ppardfl/fl mice had a heightened capacity to prime myelin oligodendrocyte glycoprotein (MOG)-specific Th cells compared with Ppardfl/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.

Original languageEnglish (US)
Pages (from-to)2588-2601
Number of pages14
JournalJournal of Immunology
Volume203
Issue number10
DOIs
StatePublished - Nov 15 2019
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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