Abstract：
Elongation of very-long-chain fatty acids protein 6 (ELOVL6), an enzyme regulating elongation of saturated and monounsaturated fatty acids with C12 to C16 to those with C18, has been recently indicated to affect various immune and inflammatory responses; however, the precise process by which ELOVL6-related lipid dysregulation affects allergic airway inflammation is unclear.
This study sought to evaluate the biological roles of ELOVL6 in allergic airway responses and investigate whether regulating lipid composition in the airways could be an alternative treatment for asthma.
Expressions of ELOVL6 and other isoforms were examined in the airways of patients who are severely asthmatic and in mouse models of asthma. Wild-type and ELOVL6-deficient (Elovl6-/-) mice were analyzed for ovalbumin-induced, and also for house dust mite-induced, allergic airway inflammation by cell biological and biochemical approaches.
ELOVL6 expression was downregulated in the bronchial epithelium of patients who are severely asthmatic compared with controls. In asthmatic mice, ELOVL6 deficiency led to enhanced airway inflammation in which lymphocyte egress from lymph nodes was increased, and both type 2 and non-type 2 immune responses were upregulated. Lipidomic profiling revealed that the levels of palmitic acid, ceramides, and sphingosine-1-phosphate were higher in the lungs of ovalbumin-immunized Elovl6-/- mice compared with those of wild-type mice, while the aggravated airway inflammation was ameliorated by treatment with fumonisin B1 or DL-threo-dihydrosphingosine, inhibitors of ceramide synthase and sphingosine kinase, respectively.
This study illustrates a crucial role for ELOVL6 in controlling allergic airway inflammation via regulation of fatty acid composition and ceramide-sphingosine-1-phosphate biosynthesis and indicates that ELOVL6 may be a novel therapeutic target for asthma.
This study sought to evaluate the biological roles of ELOVL6 in allergic airway responses and investigate whether regulating lipid composition in the airways could be an alternative treatment for asthma.
Expressions of ELOVL6 and other isoforms were examined in the airways of patients who are severely asthmatic and in mouse models of asthma. Wild-type and ELOVL6-deficient (Elovl6-/-) mice were analyzed for ovalbumin-induced, and also for house dust mite-induced, allergic airway inflammation by cell biological and biochemical approaches.
ELOVL6 expression was downregulated in the bronchial epithelium of patients who are severely asthmatic compared with controls. In asthmatic mice, ELOVL6 deficiency led to enhanced airway inflammation in which lymphocyte egress from lymph nodes was increased, and both type 2 and non-type 2 immune responses were upregulated. Lipidomic profiling revealed that the levels of palmitic acid, ceramides, and sphingosine-1-phosphate were higher in the lungs of ovalbumin-immunized Elovl6-/- mice compared with those of wild-type mice, while the aggravated airway inflammation was ameliorated by treatment with fumonisin B1 or DL-threo-dihydrosphingosine, inhibitors of ceramide synthase and sphingosine kinase, respectively.
This study illustrates a crucial role for ELOVL6 in controlling allergic airway inflammation via regulation of fatty acid composition and ceramide-sphingosine-1-phosphate biosynthesis and indicates that ELOVL6 may be a novel therapeutic target for asthma.
摘要：
背景：极长链脂肪酸蛋白6（ELOVL6）的延长，一种调节具有C12-C16的饱和和单不饱和脂肪酸向具有C18的脂肪酸延伸的酶，最近被表明影响各种免疫和炎症反应；然而，ELOVL6相关脂质失调影响过敏性气道炎症的确切过程尚不清楚.
目的：评估ELOVL6在过敏性气道反应中的生物学作用，并研究调节气道中的脂质成分是否可以作为哮喘的替代治疗方法。
方法：在重度哮喘患者和哮喘小鼠模型的气道中检测ELOVL6和其他亚型的表达。分析野生型（WT）和ELOVL6缺陷型（Elovl6-/-）小鼠的卵清蛋白（OVA）诱导，以及室内尘螨(HDM)诱导的，细胞生物学和生物化学方法引起的过敏性气道炎症。
结果：与对照组相比，重度哮喘患者的支气管上皮中ELOVL6表达下调。在哮喘小鼠中，ELOVL6缺乏导致增强的气道炎症，其中淋巴细胞从淋巴结流出增加，2型和非2型免疫反应均上调。脂质组学分析显示棕榈酸的水平，与WT小鼠相比，OVA免疫的Elovl6-/-小鼠的肺中的神经酰胺和鞘氨醇-1-磷酸（S1P）更高，虽然用伏马菌素B1或DL-苏二氢鞘氨醇治疗可改善加重的气道炎症，神经酰胺合成酶和鞘氨醇激酶的抑制剂，分别。
结论：本研究说明了ELOVL6通过调节脂肪酸组成和神经酰胺-S1P生物合成在控制过敏性气道炎症中的关键作用，提示ELOVL6可能是哮喘治疗的新靶点。
目的：评估ELOVL6在过敏性气道反应中的生物学作用，并研究调节气道中的脂质成分是否可以作为哮喘的替代治疗方法。
方法：在重度哮喘患者和哮喘小鼠模型的气道中检测ELOVL6和其他亚型的表达。分析野生型（WT）和ELOVL6缺陷型（Elovl6-/-）小鼠的卵清蛋白（OVA）诱导，以及室内尘螨(HDM)诱导的，细胞生物学和生物化学方法引起的过敏性气道炎症。
结果：与对照组相比，重度哮喘患者的支气管上皮中ELOVL6表达下调。在哮喘小鼠中，ELOVL6缺乏导致增强的气道炎症，其中淋巴细胞从淋巴结流出增加，2型和非2型免疫反应均上调。脂质组学分析显示棕榈酸的水平，与WT小鼠相比，OVA免疫的Elovl6-/-小鼠的肺中的神经酰胺和鞘氨醇-1-磷酸（S1P）更高，虽然用伏马菌素B1或DL-苏二氢鞘氨醇治疗可改善加重的气道炎症，神经酰胺合成酶和鞘氨醇激酶的抑制剂，分别。
结论：本研究说明了ELOVL6通过调节脂肪酸组成和神经酰胺-S1P生物合成在控制过敏性气道炎症中的关键作用，提示ELOVL6可能是哮喘治疗的新靶点。
