ABHD6 suppression attenuates pro-inflammatory responses in mice and promotes anti-inflammatory polarization of macrophages during endotoxin stress
Bibliographic record
Abstract
α/β-hydrolase domain-containing-6 (ABHD6) hydrolyzes various lipids, including monoacylglycerols (MAGs). Pharmacological inhibition of ABHD6 with WWL70 is anti-inflammatory in animal models. However, because of the multiple substrates of ABHD6 and the off-target effects of WWL70, the precise role of ABHD6 in inflammation remains to be clarified. Here, we investigated the role of ABHD6 in lipopolysaccharide (LPS)-mediated inflammatory response, employing a more specific ABHD6 inhibitor, KT203, and ABHD6-KO mice. ABHD6-KO mice showed lower susceptibility to LPS-mediated systemic endotoxemia. Inhibition by KT203 or deletion of ABHD6 in LPS-stressed macrophages reduced the pro-inflammatory and elevated the anti-inflammatory markers. In RAW 264.7 macrophages, KT203 reduced LPS-induced morphological changes, migration and cytokine release. In vivo, KT203 treatment of LPS-exposed wild-type mice markedly curtailed circulating TNF-α levels. Analysis of cellular and secreted bioactive lipids in the LPS-treated RAW 264.7 macrophages revealed that KT203 markedly elevated the levels of various lipid species, in particular secreted docosahexaenoic acid (DHA)-derived MAG (1/2-docosahexaenoylglycerol (DHG)) and DHA-containing N-acylethanolamines and oxylipins. We further observed that 1-DHG, 2-arachidonoylglycerol, docosahexaenoylethanolamide and 17-hydroxydocosahexaenoic acid showed anti-inflammatory effects and PPARα agonism in LPS-treated RAW 264.7 macrophages. The data suggest that ABHD6 suppression results in the accumulation of various bioactive lipids, in particular DHA-containing MAG, N-acylethanolamines and oxylipins, which activate PPARα signaling pathway to curtail the inflammatory response of macrophages to LPS. Overall, the findings provide evidence for a mechanism involving MAG and possibly other lipid species/PPARα signaling, for the anti-inflammatory effects of ABHD6 suppression during endotoxemia. Thus, the inhibition of ABHD6 is a promising approach to mitigate inflammation.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".