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.
Highlights
Multiple sclerosis (MS) is a chronic, autoimmune-based neurodegenerative disease that affects more than 2.5 million people worldwide [1]
Activation of microglia and the release of pro-inflammatory mediators by these cells is important in mediating neuroinflammation and tissue damage in EAE and MS [37]
To gain insights into these growth deficits, after 2 passages, microglia were re-plated at a specific density and the proliferation of these cells to macrophage colonystimulating factor (M-CSF) was assessed by BrdU incorporation and CFSE-dilution assays
Summary
Multiple sclerosis (MS) is a chronic, autoimmune-based neurodegenerative disease that affects more than 2.5 million people worldwide [1]. In EAE, microglia sense immune cell infiltration and damage in the CNS via expression of cytokine receptors and purinergic receptors and, in response to these cues, adopt a more active phenotype [9] As part of this activation process, microglia retract their processes, proliferate [10], and upregulate the phagocytic and antigen presenting machinery and expression of inducible nitric oxide synthase (iNOS) and proinflammatory mediators [6, 11]. In addition to these pro-inflammatory activities, microglia are crucial for healing within lesions via the phagocytic clearance of myelin debris [12]. Microglia and macrophage production of ROS and reactive nitrogen species are major contributors to neurodegeneration in EAE and MS [13, 14]
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