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

Abstract

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.

Anti-Inflammatory Action of Dietary Wild Olive (Acebuche) Oil in the Retina of Hypertensive Mice

“…PPARs are involved in the control of metabolic activities through differential regulation of glucose and lipid metabolism following activation by fatty acids [ 57 ], which makes them attractive targets for oil-mediated regulation. Moreover, PPARs can reduce excess inflammation by transcriptional regulation of a wide variety of genes, not only those related to inflammation but also those involved in metabolism, proliferation and differentiation pathways [ 58 ], and they can even regulate neurotoxic activities related to microglia activation [ 58 ]. PPAR expression and activation provides clear beneficial effects on different retinopathies of vascular origin [ 58 ].…”

“…Moreover, PPARs can reduce excess inflammation by transcriptional regulation of a wide variety of genes, not only those related to inflammation but also those involved in metabolism, proliferation and differentiation pathways [ 58 ], and they can even regulate neurotoxic activities related to microglia activation [ 58 ]. PPAR expression and activation provides clear beneficial effects on different retinopathies of vascular origin [ 58 ]. These pleiotropic effects have prompted the use of different PPAR agonists to treat various inflammatory retinopathies, including DR, oxygen-induced retinopathy and AMD [ 59 , 60 , 61 ].…”

Oligonol ameliorates liver function and brain function in the 5 × FAD mouse model: transcriptional and cellular analysis

“…We also found 20 decreased genes, including Ralbp1, related to mitochondrial function and decreased neuroinflammation; 131,132 Slc38a10, related to the upregulation of cell survival and the homeostasis of neurotransmitters such as GABA, dopamine, serotonin, and glutamate; 133 Ppard, associated with the protection of axonal injury and cell growth and the regulation of immune response; 134 Paqr3, related to the regulation of energy metabolism, and Golgi apparatus; 135 Fbxo7, related to the upregulation of pyramidal neuronal function with Pink1; 136,137 Myo9b, related to the maintenance of the dendrite morphology of neurons; 138 Abca7, associated with the downregulation of the phagocytosis process in glia, and the process of Alzheimer's disease; 139,140 Sbno2, related to the downregulation of interleukin-6 secretion, and the suppression of inflammation; 141,142 and Snrnp70, related to the inhibition of amyotrophic lateral sclerosis and motoneuronal degeneration 143,144 in the 5 × FAD mouse hippocampus after oligonol treatment.…”

The X factor in neurodegeneration

“…In contrast to SJL mice, where females show a more severe clinical course, there is no sex difference in EAE walking scores in C57BL/6 mice ( Palaszynski et al, 2004 ; Papenfuss et al, 2004 ). Yet, even in C57BL/6 mice, androgens exert anti-inflammatory effects on cytokines and peroxisome proliferator-activated receptor α (PPARα) in T lymphocytes in the immune system ( Doroshenko et al, 2021 ; Dunn et al, 2007 ; Zhang et al, 2012 ). Conversely, XY sex chromosome complement in the CNS confers a worse neurodegenerative response to immune-mediated injury ( Du et al, 2014 ).…”