Peroxisome proliferator‐activated receptor δ agonists inhibit T helper type 1 (Th1) and Th17 responses in experimental allergic encephalomyelitis

Abstract

SummaryMultiple sclerosis (MS) is a neurological disorder that affects more than a million people world-wide. The aetiology of MS is not known and there is no medical treatment available that can cure MS. Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated autoimmune disease model of MS. The pathogenesis of EAE/MS is a complex process involving activation of immune cells, secretion of inflammatory cytokines and destruction of myelin sheath in the central nervous system (CNS). Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptor transcription factors that regulate cell growth, differentiation and homeostasis. PPAR agonists have been used in the treatment of obesity, diabetes, cancer and inflammation. We and others have shown that PPARc, a and d agonists inhibit CNS inflammation and demyelination in the EAE model of MS. In this study we show that the PPARd agonists GW501516 and L165041 ameliorate MOGp35-55-induced EAE in C57BL/ 6 mice by blocking interferon (IFN)-c and interleukin (IL)-17 production by T helper type 1 (Th1) and Th17 cells. The inhibition of EAE by PPARd agonists was also associated with a decrease in IL-12 and IL-23 and an increase in IL-4 and IL-10 expression in the CNS and lymphoid organs. These findings indicate that PPARd agonists modulate Th1 and Th17 responses in EAE and suggest their use in the treatment of MS and other autoimmune diseases.

Retinoid X Receptor Agonists Modulate Foxp3+ Regulatory T Cell and Th17 Cell Differentiation with Differential Dependence on Retinoic Acid Receptor Activation

“…Agonists of PPARg and PPARd also ameliorate EAE through the inhibition of Th17 or Th1 differentiation (27)(28)(29). The PPARa agonist gemfibrozil, as well as fenofibrate, was shown to inhibit the clinical signs of EAE (35).…”

“…Previous studies demonstrated that direct PPARg agonists ameliorate experimental autoimmune encephalomyelitis (EAE), an animal model of the human CNS demyelinating diseases, by specifically inhibiting Th17 differentiation (27). PPARd agonists also ameliorate EAE by inhibiting both Th1 and Th17 differentiation (28,29). In contrast, the effects of PPAR on iTreg differentiation are controversial (30)(31)(32).…”

High-Affinity Peroxisome Proliferator-Activated Receptor β/δ-Specific Ligands with Pure Antagonistic or Inverse Agonistic Properties

“…Furthermore, PPAR␤/␦ also seems to modulate intestinal tumorigenesis (Peters et al, 2000;Barak et al, 2002;Di-Poi et al, 2002;Gupta et al, 2004;Wang et al, 2004;Burdick et al, 2006) and chemically induced skin carcinogenesis in different mouse models (Kim et al, 2004;Bility et al, 2008), as well as in tumor stroma organization (Abdollahi et al, 2007;Mü ller-Brü sselbach et al, 2007). PPAR␤/␦ also plays a key role in the differentiation and/or function of specific immune cells, including macrophages Odegaard et al, 2008) and Thelper cells (Kanakasabai et al, 2010). These observations indicate that PPAR␤/␦ may represent a drug target for the treatment of major human diseases.…”

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

“…However, recent studies showed that GW-0742, which is a specific agonist for, reduced EAE disease severity in a receptor-dependent manner (Polak et al, 2005). 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).…”