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Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.
小胶质细胞通过角鲨烯后甾醇合成促进脱髓鞘病变的修复。
- 影响因子:25.02
- DOI:10.1038/s41593-020-00757-6
- 作者列表:"Berghoff SA","Spieth L","Sun T","Hosang L","Schlaphoff L","Depp C","Düking T","Winchenbach J","Neuber J","Ewers D","Scholz P","van der Meer F","Cantuti-Castelvetri L","Sasmita AO","Meschkat M","Ruhwedel T","Möbius W","Sankowski R","Prinz M","Huitinga I","Sereda MW","Odoardi F","Ischebeck T","Simons M","Stadelmann-Nessler C","Edgar JM","Nave KA","Saher G
- 发表时间:2021-01-01
Abstract
:The repair of inflamed, demyelinated lesions as in multiple sclerosis (MS) necessitates the clearance of cholesterol-rich myelin debris by microglia/macrophages and the switch from a pro-inflammatory to an anti-inflammatory lesion environment. Subsequently, oligodendrocytes increase cholesterol levels as a prerequisite for synthesizing new myelin membranes. We hypothesized that lesion resolution is regulated by the fate of cholesterol from damaged myelin and oligodendroglial sterol synthesis. By integrating gene expression profiling, genetics and comprehensive phenotyping, we found that, paradoxically, sterol synthesis in myelin-phagocytosing microglia/macrophages determines the repair of acutely demyelinated lesions. Rather than producing cholesterol, microglia/macrophages synthesized desmosterol, the immediate cholesterol precursor. Desmosterol activated liver X receptor (LXR) signaling to resolve inflammation, creating a permissive environment for oligodendrocyte differentiation. Moreover, LXR target gene products facilitated the efflux of lipid and cholesterol from lipid-laden microglia/macrophages to support remyelination by oligodendrocytes. Consequently, pharmacological stimulation of sterol synthesis boosted the repair of demyelinated lesions, suggesting novel therapeutic strategies for myelin repair in MS.
摘要
: 多发性硬化症 (MS) 中发炎的脱髓鞘病变的修复需要小胶质细胞/巨噬细胞清除富含胆固醇的髓磷脂碎片,并从促炎性病变环境转变为抗炎性病变环境。随后,少突胶质细胞增加胆固醇水平,作为合成新髓鞘膜的先决条件。我们假设病变的消退是由受损的髓磷脂和少突胶质固醇合成引起的胆固醇的命运调节的。通过整合基因表达谱,遗传学和综合表型,我们发现,自相矛盾的是,吞噬髓磷脂的小胶质细胞/巨噬细胞中的固醇合成决定了急性脱髓鞘病变的修复。小胶质细胞/巨噬细胞不产生胆固醇,而是合成直接的胆固醇前体-去甾醇。去甾醇激活肝X受体 (LXR) 信号以解决炎症,为少突胶质细胞分化创造允许的环境。此外,LXR靶基因产物促进脂质和胆固醇从充满脂质的小胶质细胞/巨噬细胞流出,以支持少突胶质细胞的髓鞘再生。因此,固醇合成的药理学刺激促进了脱髓鞘病变的修复,这表明MS中髓鞘修复的新治疗策略。
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METHODS::Purpose: To report on ocular Vogt-Koyanagi-Harada (VKH)-like syndrome under vemurafenib treatment for metastatic melanoma.Design: A case report.Method: Description of clinical and imaging manifestations including fundus photography, fluorescein, and indocyanine green angiography.Results: A 46-year-old Thai female was diagnosed with metastatic melanoma of the skin and had been treated with multiple surgical excisions, radiotherapy, and vemurafenib (initial dose 480 mg orally twice daily, subsequently increased to maximum dose of 960 mg twice daily). After 6 months of vemurafenib use, she complained of bilateral redness and photophobia and was diagnosed with bilateral anterior uveitis, which was topically treated. Two weeks later, her visual acuity (VA) sharply deteriorated to 20/80 and counting fingers. Ocular examination at that stage stronly resembled acute VKH disease. She exhibited intraocular inflammation, and her fundus examination revealed bilateral optic disc swelling and serous retinal detachment. Fluorescein angiogram showed disc leakage and multiple pinpoint hyperfluorescence leakage spots and indocyanine green demonstrated multiple hypofluorescent spots. Oral prednisolone 30 mg/day was commenced while vemurafenib medication was ceased. Three weeks later, her vision improved, and serous retinal detachment subsided. However, her cutaneous melanoma recurred.Conclusions: Vemurafenib, a potential adjunct treatment for metastatic melanoma, was complicated by the development of panuveitis, papillitis, and multiple serous detachments. These ocular symptoms were similar to the presentation of acute VKH syndrome.
METHODS::Comprehensive reviews of the clinical characteristics and pathogenesis of Aicardi-Goutières syndrome (AGS), particularly its contextualization within a putative type I interferonopathy framework, already exist. However, recent reports of attempts at treatment suggest that an assessment of the field from a therapeutic perspective is warranted at this time. Here, we briefly summarize the neurological phenotypes associated with mutations in the seven genes so far associated with AGS, rehearse current knowledge of the pathology as it relates to possible treatment approaches, critically appraise the potential utility of therapies, and discuss the challenges in assessing clinical efficacy. WHAT THIS PAPER ADDS: Progress in understanding AGS disease pathogenesis has led to the first attempts at targeted treatment. Further rational therapies are expected to become available in the short- to medium-term.
METHODS::Purpose: To report the efficacy of adalimumab in a case of chronic Vogt-Koyanagi-Harada (VKH) disease refractory to conventional corticosteroids and immunosuppressive therapy and complicated by central serous chorioretinopathy (CSC).Case report: A 66-year-old woman diagnosed with VKH was treated with intravenous corticosteroids followed by oral corticosteroids and cyclosporine. However, systemic corticosteroids could not be tapered because of recurrent ocular inflammation and systemic complications (diabetes mellitus, moon face, bone weakness), while CSC appeared in both eyes. A diagnosis of chronic VKH resistant to medications complicated by corticosteroid-induced CSC was made. Systemic corticosteroids and cyclosporine were tapered and adalimumab initiated. Bilateral ocular inflammation and CSC were gradually reduced and visual acuity improved without any adverse effect. Twelve months after starting adalimumab monotherapy, no signs of active VKH and CSC were present.Conclusions: Adalimumab is one of the effective therapeutic options for refractory VKH disease complicated with corticosteroid-induced adverse effects.
神经系统自身免疫性疾病是以自身免疫细胞、免疫分子等攻击神经系统为主要致病机制的自身免疫性疾病。在免疫反应中,作用于神经系统自身抗原的致病抗体统称为神经系统自身抗体。