2. Academic Validation
  3. ELOVL6 deficiency aggravates allergic airway inflammation through the ceramide-S1P pathway in mice

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

  • J Allergy Clin Immunol. 2023 Apr;151(4):1067-1080.e9. doi: 10.1016/j.jaci.2022.12.808.
Kazufumi Yoshida 1,  Yuko Morishima 2,  Satoshi Ano 3,  Hirofumi Sakurai 1,  Kenya Kuramoto 1,  Yoshiya Tsunoda 1,  Kai Yazaki 1,  Masayuki Nakajima 1,  Mingma Thering Sherpa 1,  Masashi Matsuyama 1,  Takumi Kiwamoto 1,  Yosuke Matsuno 1,  Yukio Ishii 1,  Akio Hayashi 4,  Takashi Matsuzaka 5,  Hitoshi Shimano 5,  Nobuyuki Hizawa 1
Affiliations

Affiliations

  • 1 Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
  • 2 Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan. Electronic address: mk01a231@md.tsukuba.ac.jp.
  • 3 Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Department of Respiratory Medicine, National Hospital Organization Kasumigaura Medical Center, Tsuchiura, Ibaraki, Japan.
  • 4 Exploratory Research Laboratories, Minase Research Institute, Ono Pharmaceutical Co Ltd, Mishima, Osaka, Japan; AMED-CREST, Japan Agency for Medical Research and Development (AMED), Chiyoda, Tokyo, Japan.
  • 5 Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; AMED-CREST, Japan Agency for Medical Research and Development (AMED), Chiyoda, Tokyo, Japan.
PMID: 36592705 DOI: 10.1016/j.jaci.2022.12.808
Abstract

Background: 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.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Asthma; DL-threo-dihydrosphingosine; ELOVL6; ceramide; fumonisin B1; palmitic acid; sphingosine-1-phosphate.

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