ELOVL6 deficiency aggravates allergic airway inflammation through the ceramide-S1P pathway in mice

Elongation of very-long-chain fatty acids protein 6 (ELOVL6), an enzyme regulating elongation of saturated and monounsaturated fatty acids with C12-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.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 severely asthmatic patients and mouse models of asthma. Wild-type (WT) and ELOVL6-deficient (Elovl6ELOVL6 expression was downregulated in the bronchial epithelium of severely asthmatic patients 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 (S1P) were higher in the lungs of OVA-immunized Elovl6This study illustrates a crucial role for ELOVL6 in controlling allergic airway inflammation via regulation of fatty acid composition and ceramide-S1P biosynthesis, and indicates that ELOVL6 may be a novel therapeutic target for asthma.