Selective blockade of the lyso-PS lipase ABHD12 stimulates immune responses in vivo.
Nat Chem Biol
; 14(12): 1099-1108, 2018 12.
Article
in En
| MEDLINE
| ID: mdl-30420694
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Urea
/
Brain
/
Enzyme Inhibitors
/
High-Throughput Screening Assays
/
Lymphocytic Choriomeningitis
/
Monoacylglycerol Lipases
Limits:
Adult
/
Animals
/
Female
/
Humans
Language:
En
Journal:
Nat Chem Biol
Journal subject:
BIOLOGIA
/
QUIMICA
Year:
2018
Document type:
Article
Affiliation country:
United States