Peroxisome proliferator-activated receptor-? agonists prevent experimental autoimmune encephalomyelitis

2002 ◽  
Vol 51 (6) ◽  
pp. 694-702 ◽  
Author(s):  
Douglas L. Feinstein ◽  
Elena Galea ◽  
Vitaliy Gavrilyuk ◽  
Celia F. Brosnan ◽  
Caroline C. Whitacre ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Peroxisome Proliferator ◽  
Autoimmune Encephalomyelitis ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Agonists ◽  
Experimental Autoimmune

α-Lipoic acid enhances endogenous peroxisome-proliferator-activated receptor-γ to ameliorate experimental autoimmune encephalomyelitis in mice

2013 ◽  
Vol 125 (7) ◽  
pp. 329-340 ◽  
Author(s):  
Kai-Chen Wang ◽  
Ching-Piao Tsai ◽  
Chao-Lin Lee ◽  
Shao-Yuan Chen ◽  
Gu-Jiun Lin ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Lipoic Acid ◽  
Inflammatory Cells ◽  
Treg Cells ◽  
Peroxisome Proliferator ◽  
Autoimmune Encephalomyelitis ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Experimental Autoimmune

ALA (α-lipoic acid) is a natural, endogenous antioxidant that acts as a PPAR-γ (peroxisome-proliferator-activated receptor-γ) agonist to counteract oxidative stress. Thus far, the antioxidative and immunomodulatory effects of ALA on EAE (experimental autoimmune encephalomyelitis) are not well understood. In this study, we found that ALA restricts the infiltration of inflammatory cells into the CNS (central nervous system) in MOG (myelin oligodendrocyte glycoprotein)-EAE mice, thus reducing the disease severity. In addition, we revealed that ALA significantly suppresses the number and percentage of encephalitogenic Th1 and Th17 cells and increases splenic Treg-cells (regulatory T-cells). Strikingly, we further demonstrated that ALA induces endogenous PPAR-γ centrally and peripherally but has no effect on HO-1 (haem oxygenase 1). Together, these data suggest that ALA can up-regulate endogenous systemic and central PPAR-γ and enhance systemic Treg-cells to inhibit the inflammatory response and ameliorate MOG-EAE. In conclusion, our data provide the first evidence that ALA can augment the production of PPAR-γ in vivo and modulate adaptive immunity both centrally and peripherally in EAE and may reveal further antioxidative and immunomodulatory mechanisms for the application of ALA in human MS (multiple sclerosis).

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

2021 ◽  
Vol 12 ◽  
Author(s):  
Ellinore R. Doroshenko ◽  
Paulina C. Drohomyrecky ◽  
Annette Gower ◽  
Heather Whetstone ◽  
Lindsay S. Cahill ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Axonal Injury ◽  
Reactive Oxygen Species Generation ◽  
Tissue Loss ◽  
Peroxisome Proliferator ◽  
Autoimmune Encephalomyelitis ◽  
Peroxisome Proliferator Activated Receptor ◽  
Expression Of Genes ◽  
Deficient Mice ◽  
Experimental Autoimmune

Peroxisome proliferator-activated receptor (PPAR)-δ is a nuclear receptor that functions to maintain metabolic homeostasis, regulate cell growth, and limit the development of excessive inflammation during immune responses. Previously, we reported that PPAR-δ-deficient mice develop a more severe clinical course of experimental autoimmune encephalomyelitis (EAE); however, it was difficult to delineate the role that microglia played in this disease phenotype since PPAR-δ-deficient mice exhibited a number of immune defects that enhanced CNS inflammation upstream of microglia activation. Here, we specifically investigated the role of PPAR-δ in microglia during EAE by using mice where excision of a floxed Ppard allele was driven by expression of a tamoxifen (TAM)-inducible CX3C chemokine receptor 1 promoter-Cre recombinase transgene (Cx3cr1CreERT2: Ppardfl/fl). We observed that by 30 days of TAM treatment, Cx3cr1CreERT2: Ppardfl/fl mice exhibited Cre-mediated deletion primarily in microglia and this was accompanied by efficient knockdown of Ppard expression in these cells. Upon induction of EAE, TAM-treated Cx3cr1CreERT2: Ppardfl/fl mice presented with an exacerbated course of disease compared to TAM-treated Ppardfl/fl controls. Histopathological and magnetic resonance (MR) studies on the spinal cord and brains of EAE mice revealed increased Iba-1 immunoreactivity, axonal injury and CNS tissue loss in the TAM-treated Cx3cr1CreERT2: Ppardfl/fl group compared to controls. In early EAE, a time when clinical scores and the infiltration of CD45+ leukocytes was equivalent between Cx3cr1CreERT2: Ppardfl/fl and Ppardfl/fl mice, Ppard-deficient microglia exhibited a more reactive phenotype as evidenced by a shorter maximum process length and lower expression of genes associated with a homeostatic microglia gene signature. In addition, Ppard-deficient microglia exhibited increased expression of genes associated with reactive oxygen species generation, phagocytosis and lipid clearance, M2-activation, and promotion of inflammation. Our results therefore suggest that PPAR-δ has an important role in microglia in limiting bystander tissue damage during neuroinflammation.

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