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

Autor:	Doroshenko ER; Department of Immunology, University of Toronto, Toronto, ON, Canada., Drohomyrecky PC; Department of Immunology, University of Toronto, Toronto, ON, Canada., Gower A; Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada., Whetstone H; Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, ON, Canada., Cahill LS; Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, Canada., Ganguly M; Histology Core, The Centre for Phenogenomics, Toronto, ON, Canada., Spring S; Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, Canada., Yi TJ; Department of Immunology, University of Toronto, Toronto, ON, Canada.; Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada., Sled JG; Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada., Dunn SE; Department of Immunology, University of Toronto, Toronto, ON, Canada.; Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada.; Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 Feb 26; Vol. 12, pp. 570425. Date of Electronic Publication: 2021 Feb 26 (Print Publication: 2021).
DOI:	10.3389/fimmu.2021.570425
Abstrakt:	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 ( Cx3cr1 CreERT2 : Ppard fl/fl ). We observed that by 30 days of TAM treatment, Cx3cr1 CreERT2 : Ppard fl/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 Cx3cr1 CreERT2 : Ppard fl/fl mice presented with an exacerbated course of disease compared to TAM-treated Ppard fl/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 Cx3cr1 CreERT2 : Ppard fl/fl group compared to controls. In early EAE, a time when clinical scores and the infiltration of CD45 + leukocytes was equivalent between Cx3cr1 CreERT2 : Ppard fl/fl and Ppard fl/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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Doroshenko, Drohomyrecky, Gower, Whetstone, Cahill, Ganguly, Spring, Yi, Sled and Dunn.)
Databáze:	MEDLINE
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