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α/β‐Hydrolase Domain‐6 Regulates Macrophage Polarization and its Inhibition Protects Against LPS‐Induced Inflammation
Author(s) -
Schmitt Clémence,
Poursharifi Pegah,
Peyot MarieLine,
Madiraju S. R.,
Prentki Marc
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02545
Subject(s) - inflammation , macrophage polarization , lipopolysaccharide , tumor necrosis factor alpha , immunology , macrophage , medicine , biology , biochemistry , in vitro
The activated M1 macrophages exhibit pro‐inflammatory activity and contribute to diverse inflammatory disorders, such as microbial infection, sepsis, autoimmune diseases, and cardiometabolic disorders. Thus, targeting macrophage polarization towards an anti‐inflammatory M2 phenotype may provide a strategy to treat inflammatory diseases. Deletion of the monoacylglycerol lipase α/β‐hydrolase domain‐6 (ABHD6) demonstrated the therapeutic potential of targeting ABHD6 against obesity, type‐2‐diabetes, and other inflammatory disorders. However, the role of ABHD6 in macrophage activation/polarization under inflammatory conditions remains to be ascertained. Using macrophage cell lines, a pharmacological approach, and whole‐body ABHD6 KO mice, we investigated whether ABHD6 suppression is protective against lipopolysaccharide (LPS)‐induced inflammation. Pharmacological inhibition of ABHD6 activity with a potent inhibitor (KT203) in RAW264.7 and J774A.1 macrophages attenuates LPS‐induced expression of pro‐inflammatory cytokines ( Tnfa and Mcp1 ). In addition, ABHD6 inhibition results in decreased LPS‐induced secretion of TNFα and MCP1 from RAW264.7 macrophages. Interestingly, absence of ABHD6 activity promotes LPS‐primed macrophage polarization towards the M2 phenotype, as evidenced by the increased arginase‐1 ( Arg1 ) expression. Furthermore, whole‐body ABHD6 KO mice, compared to the wild‐type controls, show lower susceptibility to systemic LPS‐induced inflammation as indicated by a decline in plasma TNFα and MCP‐1 levels and reduced expression of pro‐inflammatory markers ( Cd68 and Il1b ) in peripheral blood mononuclear cells and lung tissue. Finally, ABHD6 KO mediated protection against acute LPS‐induced inflammation is more prominent in female versus male mice. Taken together, our data support a pro‐inflammatory role for ABHD6 under LPS‐induced condition. ABHD6 inhibition switches LPS‐induced macrophage polarization towards an anti‐inflammatory M2 state, and ABHD6 deletion in mice attenuates systemic response to LPS challenge. The results suggest the therapeutic potential of ABHD6 inhibition for the treatment of inflammation‐associated disorders.