Department of Immunology, University of Toronto, Toronto, ON, Canada.
Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada.
Front Immunol. 2021 Feb 26;12:570425. doi: 10.3389/fimmu.2021.570425. eCollection 2021.
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 allele was driven by expression of a tamoxifen (TAM)-inducible CX3C chemokine receptor 1 promoter-Cre recombinase transgene (: ). We observed that by 30 days of TAM treatment, : mice exhibited Cre-mediated deletion primarily in microglia and this was accompanied by efficient knockdown of expression in these cells. Upon induction of EAE, TAM-treated : mice presented with an exacerbated course of disease compared to TAM-treated 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 : group compared to controls. In early EAE, a time when clinical scores and the infiltration of CD45 leukocytes was equivalent between : and mice, -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, -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.
过氧化物酶体增殖物激活受体 (PPAR)-δ 是一种核受体，其功能是维持代谢稳态、调节细胞生长，并限制免疫反应过程中过度炎症的发展。此前，我们报道过 PPAR-δ 缺陷小鼠在实验性自身免疫性脑脊髓炎 (EAE) 中表现出更严重的临床病程；然而，由于 PPAR-δ 缺陷小鼠表现出许多增强中枢神经系统炎症的免疫缺陷，使得难以描绘小胶质细胞在这种疾病表型中的作用。在此，我们通过使用表达他莫昔芬（TAM）诱导型 CX3C 趋化因子受体 1 启动子-Cre 重组酶转基因的 floxed 等位基因敲除小鼠（: ），专门研究了 PPAR-δ 在 EAE 中小胶质细胞中的作用。我们观察到，在用 TAM 处理 30 天后，: 小鼠主要在小胶质细胞中表现出 Cre 介导的缺失，并且这些细胞中 的表达被有效地敲低。在诱导 EAE 后，与 TAM 处理的 对照相比，TAM 处理的 : 小鼠表现出疾病加重的病程。EAE 小鼠脊髓和大脑的组织病理学和磁共振（MR）研究显示，与对照相比，TAM 处理的 : 组中 Iba-1 免疫反应性增加、轴突损伤和中枢神经系统组织丢失。在早期 EAE 中，即临床评分和 CD45 白细胞浸润在 : 和 小鼠之间相当的时间点，-缺陷小胶质细胞表现出更具反应性的表型，表现为最长突起长度缩短和与稳态小胶质细胞基因特征相关的基因表达降低。此外，-缺陷小胶质细胞中与活性氧生成、吞噬作用和脂质清除、M2 激活以及炎症促进相关的基因表达增加。因此，我们的研究结果表明，PPAR-δ 在小胶质细胞中对于限制神经炎症过程中的旁观者组织损伤具有重要作用。
