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

Abstract

Peroxisome proliferator-activated receptor (PPAR)-d 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-d 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-d to the more severe CNS inflammatory response remained unclear. In this study, we studied the specific involvement of PPAR-d 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-d in DC in limiting Th cell priming during EAE.

The role of peroxisome proliferator-activated receptors (PPAR) in immune responses

“…In a murine EAE model, PPARδ deficiency augmented Th1 and Th17 polarization and inhibited Th2 and Treg differentiation, while the opposite results were induced with PPARδ activation [91][92][93]. Notably, mice lacking PPARδ expression only in the myeloid compartment also develop more severe EAE due to Th1/Th17 polarization of CD4 + T cells, highlighting the role of PPARδ in the crosstalk between innate and adaptive immune cells [94].…”

Recent Insights on the Role of PPAR-β/δ in Neuroinflammation and Neurodegeneration, and Its Potential Target for Therapy

“…Studies showed that PPAR-β/δ agonists, through a negative feedback loop, could reduce inflammation and damage of tissues in EAE models of MS (Polak et al 2005). The study by Drohomyrecky et al (2019) also demonstrated that mutant mice hypomorphic for PPAR-β/δ receptor showed a more severe course of inflammatory process in CNS, and this event could be revered by PPAR-β/δ agonists (Drohomyrecky et al 2019).…”

Peroxisome Proliferator-Activated Receptor-δ Deficiency in Microglia Results in Exacerbated Axonal Injury and Tissue Loss in Experimental Autoimmune Encephalomyelitis

“…For real-time PCR, RNA was isolated using an RNeasy Miniprep Kit (Qiagen). Total RNA (100 µg) was reverse transcribed to cDNA using SuperScript III reverse transcriptase (Invitrogen) and cDNA abundance was analyzed by real-time PCR using Roche SYBR Green I master mix and sequence specific primers as described previously (19).…”

“…Cross-sections (5 µm) were cut (Center for Phenogenomics, Toronto, ON) and dually stained with hematoxylin and eosin (H&E) and Luxol Fast Blue (LFB) to visualize inflammatory/demyelinating lesions. Inflammation and demyelination were scored as described previously (19). IHC for mouse SMI-31 (Biolegend, Cat# 801601, 1:5,000) and SMI-32 (Biolegend; Cat #801701, 1:5,000) antibodies was performed as previously described using the mouse-onmouse (M.O.M.)…”

“…Previously, it was reported that whole-body deficiency of PPAR-δ in mice resulted in the development of a more progressive form of EAE (16,17). However, it was difficult to discern how much microglia contributed to this phenotype, since PPAR-δ deficient mice exhibited a number of immune defects that operate upstream of microglia activation in EAE, including the enhanced production of IL-12p40 and IL-6 by spleen macrophages (16), increased lymphopenia and associated memory T cell formation (18), enhanced dendritic cell priming of T helper (Th) cells (19), and heightened IFN-γ and IL-17 production by Th cells (16,17).…”