Nicotinic acetylcholine receptor silent agonists modulate inflammation
Bibliographic record
Abstract
Nicotinic acetylcholine receptors (nAChRs) have been increasingly studied for their immune regulatory properties. nAChRs are best known to function as ligand‐gated ion channels in neurons, however, recent evidence suggests that nicotine modulates inflammation by desensitizing non‐neuronal nAChRs, rather than by inducing channel opening. The objective of this study was to determine whether nAChR‐dependent anti‐inflammatory properties are due to channel desensitization. To this end, we made use of various nAChR ligands, including: 1) nicotine, a nAChR non‐selective agonist that also desensitizes the receptors; 2) AR‐R17779, an α7 nAChR subtype‐selective agonist; 3) α‐bungarotoxin, an α7 and α9 nAChR‐selective competitive antagonist, 4) mecamylamine, a non‐selective and non‐competitive antagonist; 5) N,N‐diethyl‐N’‐phenylpiperazine (DEPP)‐based silent agonists that selectively induce the desensitized state of α7 nAChR while producing little or no channel opening. We first evaluated the effects of these various nAChR ligands on the modulation of mouse and human monocyte/macrophage numbers, phenotype and cytokine production. Monocyte phenotype, cellular viability, proliferation and cytokine production were assessed by flow cytometry. In bone marrow‐derived monocyte/macrophage (BMDM) cell cultures, nicotine, mecamylamine and silent agonists reduced pro‐inflammatory monocyte numbers by affecting their viability and proliferation. The silent agonists also significantly reduced both LPS‐ and ATP‐induced cytokine production by mouse BMDMs. In human peripheral blood mononuclear cells (PBMCs), the silent agonists tested had modest effects on monocyte numbers and phenotype. However, LPS‐ and ATP‐induced cytokine production by human blood‐derived immune cells (PBMCs and whole blood) was inhibited by silent agonists. Taken together, our results suggest that nAChRs modulate pro‐inflammatory monocyte numbers and function via receptor desensitization rather than channel opening. nAChR silent agonists may thus be a novel source of anti‐inflammatory compounds that could be used for the treatment of inflammatory disorders. Support or Funding Information This work was supported by the MS Society of Canada, the New Brunswick Health Research Foundation and NIH. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.002 | 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".