α/β‐Hydrolase Domain‐6 Regulates Macrophage Polarization and its Inhibition Protects Against LPS‐Induced Inflammation

Abstract

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.