Peroxisome proliferator–activated receptor δ limits the expansion of pathogenic Th cells during central nervous system autoimmunity

Abstract

Peroxisome proliferator–activated receptors (PPARs; PPAR-α, PPAR-δ, and PPAR-γ) comprise a family of nuclear receptors that sense fatty acid levels and translate this information into altered gene transcription. Previously, it was reported that treatment of mice with a synthetic ligand activator of PPAR-δ, GW0742, ameliorates experimental autoimmune encephalomyelitis (EAE), indicating a possible role for this nuclear receptor in the control of central nervous system (CNS) autoimmune inflammation. We show that mice deficient in PPAR-δ (PPAR-δ−/−) develop a severe inflammatory response during EAE characterized by a striking accumulation of IFN-γ+IL-17A− and IFN-γ+IL-17A+ CD4+ cells in the spinal cord. The preferential expansion of these T helper subsets in the CNS of PPAR-δ−/− mice occurred as a result of a constellation of immune system aberrations that included higher CD4+ cell proliferation, cytokine production, and T-bet expression and enhanced expression of IL-12 family cytokines by myeloid cells. We also show that the effect of PPAR-δ in inhibiting the production of IFN-γ and IL-12 family cytokines is ligand dependent and is observed in both mouse and human immune cells. Collectively, these findings suggest that PPAR-δ serves as an important molecular brake for the control of autoimmune inflammation.

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

“…In addition, GW-501516 and L-165041 can inhibit EAE by reducing IFN-γ and IL-17 secretion, suggesting a possible regulatory function for PPARβ/δ in T-cell differentiation (Kanakasabai et al, 2010). The critical role of PPARβ/δ in T cells is further confirmed by the observation that PPARβ/δ -/-mice exhibited higher EAE severity than wild type mice concomitant with increased IFN-γ-and IL-17-producing CD4 + T cells (Dunn et al, 2010). PPARβ/δ -/-naïve CD4 + T cells are more prone to Th17 differentiation and hyper-responsive to TCR stimulation, as evidenced by the increased proliferation observed in these cells.…”

MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4

“…Induction of cell death in the CNS triggers a cascade of continuous (secondary) neurodegeneration, resulting in a substantially higher degree of tissue loss than could have been predicted from the severity of the initial damage (1). While the role of T cells in mediating autoimmune neuroinflammation has been studied intensively (2)(3)(4)(5)(6)(7), their role in neurodegeneration and neuroprotection is still a matter of debate. T cell inflammation associated with CNS injury was largely viewed as detrimental (8,9).…”

Antagonizing Peroxisome Proliferator–Activated Receptor α Activity Selectively Enhances Th1 Immunity in Male Mice

“…ELISA kits (eBioscience). PMA/ ionomycin stimulations and cell surface and intracellular cytokine stainings were performed as described previously (19,20). Intranuclear staining for transcription factors was performed using the Foxp3 Transcription Factor Staining Buffer Set (eBioscience).…”