Peroxisome Proliferator-Activated Receptor-δ Deficiency in Microglia Results in Exacerbated Axonal Injury and Tissue Loss in Experimental Autoimmune Encephalomyelitis release_h5ldwefkpfbf7gapcwvfyu6b5i

by Ellinore R. Doroshenko, Paulina C. Drohomyrecky, Annette Gower, Heather Whetstone, Lindsay S. Cahill, Milan Ganguly, Shoshana Spring, Tae Joon Yi, John G. Sled, Shannon E. Dunn

Published in Frontiers in Immunology by Frontiers Media SA.

2021   Volume 12, p570425


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 <jats:italic>Ppard</jats:italic> allele was driven by expression of a tamoxifen (TAM)-inducible CX3C chemokine receptor 1 promoter-Cre recombinase transgene (<jats:italic>Cx3cr1</jats:italic><jats:sup>CreERT2</jats:sup>: <jats:italic>Ppard</jats:italic><jats:sup>fl/fl</jats:sup>). We observed that by 30 days of TAM treatment, <jats:italic>Cx3cr1</jats:italic><jats:sup>CreERT2</jats:sup>: <jats:italic>Ppard</jats:italic><jats:sup>fl/fl</jats:sup> mice exhibited Cre-mediated deletion primarily in microglia and this was accompanied by efficient knockdown of <jats:italic>Ppard</jats:italic> expression in these cells. Upon induction of EAE, TAM-treated <jats:italic>Cx3cr1</jats:italic><jats:sup>CreERT2</jats:sup>: <jats:italic>Ppard</jats:italic><jats:sup>fl/fl</jats:sup> mice presented with an exacerbated course of disease compared to TAM-treated <jats:italic>Ppard</jats:italic><jats:sup>fl/fl</jats:sup> 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 <jats:italic>Cx3cr1</jats:italic><jats:sup>CreERT2</jats:sup>: <jats:italic>Ppard</jats:italic><jats:sup>fl/fl</jats:sup> group compared to controls. In early EAE, a time when clinical scores and the infiltration of CD45<jats:sup>+</jats:sup> leukocytes was equivalent between <jats:italic>Cx3cr1</jats:italic><jats:sup>CreERT2</jats:sup>: <jats:italic>Ppard</jats:italic><jats:sup>fl/fl</jats:sup> and <jats:italic>Ppard</jats:italic><jats:sup>fl/fl</jats:sup> mice, <jats:italic>Ppard</jats:italic>-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, <jats:italic>Ppard</jats:italic>-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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