Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospitals, 1211 Geneva 14, Switzerland; Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland.
Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland.
J Autoimmun. 2015 Jan;56:45-55. doi: 10.1016/j.jaut.2014.10.001. Epub 2014 Nov 10.
Perturbation of steroids pathways is linked to inflammation and chronic diseases, however the underlying mechanism remains unclear. Oxysterols, oxidized forms of cholesterol, are not only essential for bile synthesis and sterol transportation but have recently been shown to contribute to the immune response. In addition, serum oxysterols levels have been proposed as suitable candidate biomarkers for neurological diseases such as multiple sclerosis (MS). However how oxysterols modulate adaptive immunity is unknown and their functions in autoimmunity have not been investigated. The enzyme cholesterol 25 hydroxylase (Ch25h) is the rate limiting step to synthesize the oxysterol 7α,25-dihydroxycholesterol (7α,25-OHC) from cholesterol. We here report, using the MS murine model experimental autoimmune encephalomyelitis (EAE), that Ch25h deletion significantly attenuated EAE disease course by limiting trafficking of pathogenic CD4(+) T lymphocytes to the central nervous system (CNS). Mechanistically, we show a critical involvement for oxysterols in recruiting leukocytes into inflamed tissues and propose that 7α,25-OHC preferentially promotes the migration of activated CD44(+)CD4(+) T cells by binding the G protein-coupled receptor called Epstein-Barr virus induced gene 2 (EBI2). Collectively, our results support a pro-inflammatory role for oxysterols during EAE and identify oxysterols as a potential therapeutic target to treat autoimmune diseases.
甾体通路的干扰与炎症和慢性疾病有关，但潜在的机制尚不清楚。氧化固醇是胆固醇的氧化形式，不仅是胆汁合成和固醇运输所必需的，而且最近还被证明有助于免疫反应。此外，血清氧化固醇水平已被提议作为神经退行性疾病如多发性硬化症（MS）的合适候选生物标志物。然而，氧化固醇如何调节适应性免疫以及它们在自身免疫中的功能尚未被研究。胆固醇 25 羟化酶（Ch25h）是从胆固醇合成氧化固醇 7α，25-二羟胆固醇（7α，25-OHC）的限速酶。在这里，我们使用 MS 啮齿动物实验性自身免疫性脑脊髓炎（EAE）模型报告说，Ch25h 的缺失通过限制致病性 CD4+T 淋巴细胞向中枢神经系统（CNS）的迁移，显著减轻了 EAE 病程。从机制上讲，我们表明氧化固醇在招募白细胞进入炎症组织中起着关键作用，并提出 7α，25-OHC 通过结合称为 Epstein-Barr 病毒诱导基因 2（EBI2）的 G 蛋白偶联受体，优先促进激活的 CD44+CD4+T 细胞的迁移。总之，我们的结果支持氧化固醇在 EAE 期间的促炎作用，并将氧化固醇确定为治疗自身免疫性疾病的潜在治疗靶点。
