Selective blockade of the lyso-PS lipase ABHD12 stimulates immune responses in vivo
| Autor: | Jacqueline R. Benthuysen, Vincent F. Vartabedian, Alex Reed, Hugh Rosen, Benjamin F. Cravatt, Amanda J. Roberts, Daisuke Ogasawara, Olesya A. Ulanovskaya, Hui Jing, Taka-Aki Ichu, Jonathan J. Hulce, John R. Teijaro, Steven D. Brown |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adult Chemokine Clone (cell biology) Lymphocytic Choriomeningitis Lymphocytic choriomeningitis Article Proinflammatory cytokine 03 medical and health sciences 0302 clinical medicine Immune system In vivo medicine Animals Humans Urea Enzyme Inhibitors Molecular Biology Innate immune system biology Dose-Response Relationship Drug Macrophages Brain Cell Biology medicine.disease Mice Mutant Strains Monoacylglycerol Lipases 3. Good health Cell biology High-Throughput Screening Assays Mice Inbred C57BL 030104 developmental biology Lysophosphatidylserine biology.protein lipids (amino acids peptides and proteins) Female Lysophospholipids 030217 neurology & neurosurgery |
| Zdroj: | Nature chemical biology |
| ISSN: | 1552-4469 1552-4450 |
| Popis: | ABHD12 metabolizes bioactive lysophospholipids, including lysophosphatidylserine (lyso-PS). Deleterious mutations in human ABHD12 cause the neurological disease PHARC, and ABHD12(−/−) mice display PHARC-like phenotypes, including hearing loss, along with elevated brain lyso-PS and features of stimulated innate immune cell function. Here, we develop a selective and in vivo-active inhibitor of ABHD12 termed DO264 and show that this compound elevates lyso-PS in mouse brain and primary human macrophages. Unlike ABHD12(−/−) mice, adult mice treated with DO264 exhibited minimal perturbations in auditory function. On the other hand, both DO264-treated and ABHD12(−/−) mice displayed heightened immunological responses to lymphocytic choriomeningitis virus (LCMV) clone 13 infection that manifested as severe lung pathology with elevated proinflammatory chemokines. These results reveal similarities and differences in the phenotypic impact of pharmacological versus genetic blockade of ABHD12 and point to a key role for this enzyme in regulating immunostimulatory lipid pathways in vivo. |
| Databáze: | OpenAIRE |
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