Adenylyl Cyclase 6 Mediates Inhibition of TNF in the Inflammatory Reflex
Why this work is in the frame
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Bibliographic record
Abstract
Macrophage cytokine production is reflexively mediated by neural circuits. One example is the inflammatory reflex, defined by electrical signals traveling in the vagus nerve and signaling through splenic choline acetyltransferase+ T cells. Lymphocyte acetylcholine is the ligand for alpha7 nicotinic acetylcholine receptors (α7nAChR) on macrophages that suppress TNF release. Here, we observed that electrical vagus nerve stimulation of the inflammatory reflex with a duration of 0.1s - 60s significantly reduced systemic TNF release in endotoxemia. This suppression of TNF was sustained for more than 24 hours, but abolished in mice deficient in the α7nAChR subunit. Exposure of primary human macrophages and murine RAW 264.7 macrophage-like cells to selective ligands for α7nAChR for one hour in vitro attenuated TNF production for up to 24 hours in response to endotoxin. Pharmacological inhibition of adenylyl cyclase (AC) and knockdown of adenylyl cyclase 6 (AC6) or c-FOS abolished cholinergic mediated suppression of endotoxin-induced TNF release. These findings indicate that action potentials in the inflammatory reflex trigger an extended change in macrophage activation behavior that requires AC and phosphorylation of cAMP response element binding protein (CREB). This has significant implications for mechanisms of bioelectronic therapies to treat inflammatory diseases.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 it