Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, State University of Campinas, SP, Brazil.
Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, State University of Campinas, SP, Brazil; Laboratory of Cytochemistry and Immunocytochemistry, Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas, Campinas, Brazil.
Mult Scler Relat Disord. 2023 Apr;72:104605. doi: 10.1016/j.msard.2023.104605. Epub 2023 Mar 6.
Obesity-induced insulin resistance (OIR) has been associated with an increased prevalence of neurodegenerative disorders such as multiple sclerosis. Obesity results in increased blood-brain barrier (BBB) permeability, specifically in the hypothalamic regions associated with the control of caloric intake. In obesity, the chronic state of low-grade inflammation has been implicated in several chronic autoimmune inflammatory disorders. However, the mechanisms that connect the inflammatory profile of obesity with the severity of experimental autoimmune encephalomyelitis (EAE) are poorly defined. In this study, we show that obese mice are more susceptible to EAE, presenting a worse clinical score with more severe pathological changes in the spinal cord when compared with control mice. Analysis of immune infiltrates at the peak of the disease shows that high-fat diet (HFD)- and control (chow)-fed groups do not present any difference in innate or adaptive immune cell compartments, indicating the increased severity occurs prior to disease onset. In the setting of worsening EAE in HFD-fed mice, we observed spinal cord lesions in myelinated regions and (blood brain barrier) BBB disruption. We also found higher levels of pro-inflammatory monocytes, macrophages, and IFN-γCD4 T cells in the HFD-fed group compared to chow-fed animals. Altogether, our results indicate that OIR promotes BBB disruption, allowing the infiltration of monocytes/macrophages and activation of resident microglia, ultimately promoting CNS inflammation and exacerbation of EAE.
肥胖引起的胰岛素抵抗（OIR）与神经退行性疾病（如多发性硬化症）的发病率增加有关。肥胖导致血脑屏障（BBB）通透性增加，特别是与控制热量摄入相关的下丘脑区域。在肥胖中，慢性低度炎症状态与几种慢性自身免疫性炎症疾病有关。然而，将肥胖的炎症特征与实验性自身免疫性脑脊髓炎（EAE）的严重程度联系起来的机制尚不清楚。在这项研究中，我们表明肥胖小鼠更容易发生 EAE，与对照小鼠相比，它们在脊髓中的临床评分更差，病理变化更严重。在疾病高峰期对免疫浸润物进行分析表明，高脂肪饮食（HFD）和对照（chow）喂养组在固有或适应性免疫细胞区室中没有任何差异，这表明在疾病发作之前就出现了更严重的情况。在 HFD 喂养小鼠的 EAE 恶化的情况下，我们观察到在有髓区域的脊髓损伤和（血脑屏障）BBB 破坏。与 chow 喂养动物相比，我们还发现 HFD 喂养组中促炎单核细胞、巨噬细胞和 IFN-γCD4 T 细胞水平更高。总之，我们的结果表明 OIR 促进了 BBB 破坏，允许单核细胞/巨噬细胞的浸润和驻留小胶质细胞的激活，最终促进中枢神经系统炎症和 EAE 的恶化。
