α/β‐Hydrolase Domain‐6 Regulates Macrophage Polarization and its Inhibition Protects Against LPS‐Induced Inflammation
Bibliographic record
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".