2. Academic Validation
  3. Selective blockade of the lyso-PS lipase ABHD12 stimulates immune responses in vivo

Selective blockade of the lyso-PS lipase ABHD12 stimulates immune responses in vivo

  • Nat Chem Biol. 2018 Dec;14(12):1099-1108. doi: 10.1038/s41589-018-0155-8.
Daisuke Ogasawara  # 1,  Taka-Aki Ichu  # 1,  Vincent F Vartabedian  # 2,  Jacqueline Benthuysen 1,  Hui Jing 1,  Alex Reed 3,  Olesya A Ulanovskaya 3,  Jonathan J Hulce 1,  Amanda Roberts 4,  Steven Brown 1,  Hugh Rosen 1,  John R Teijaro 5,  Benjamin F Cravatt 6
Affiliations

Affiliations

  • 1 Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • 2 Department of Immunology and Infectious Disease, The Scripps Research Institute, La Jolla, CA, USA.
  • 3 Abide Therapeutics, San Diego, CA, USA.
  • 4 Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
  • 5 Department of Immunology and Infectious Disease, The Scripps Research Institute, La Jolla, CA, USA. [email protected].
  • 6 Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. [email protected].
  • # Contributed equally.
PMID: 30420694 DOI: 10.1038/s41589-018-0155-8
Abstract

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.

Figures
Products