Acute activation of bronchopulmonary vagal nociceptors by type I interferons
Bibliographic record
Abstract
Key points Type I interferon receptors are expressed by the majority of vagal C‐fibre neurons innervating the respiratory tract Interferon alpha and beta acutely and directly activate vagal C‐fibers in the airways. The interferon‐induced activation of C‐fibers occurs secondary to stimulation of type 1 interferon receptors Type 1 interferons may contribute to the symptoms as well as the spread of respiratory viral infections by causing coughing and other defensive reflexes associated with vagal C‐fibre activation Abstract We evaluated the ability of type I interferons to acutely activate airway vagal afferent nerve terminals in mouse lungs. Using single cell RT‐PCR of lung‐specific vagal neurons we found that IFNAR1 and IFNAR2 were expressed in 70% of the TRPV1‐positive neurons (a marker for vagal C‐fibre neurons) and 44% of TRPV1‐negative neurons. We employed an ex vivo vagal innervated mouse trachea‐lung preparation to evaluate the effect of interferons in directly activating airway nerves. Utilizing 2‐photon microscopy of the nodose ganglion neurons from Pirt‐Cre;R26‐GCaMP6s mice we found that applying IFNα or IFNβ to the lungs acutely activated the majority of vagal afferent nerve terminals. When the type 1 interferon receptor, IFNAR1, was blocked with a blocking antibody the response to IFNβ was largely inhibited. The type 2 interferon, IFNγ, also activated airway nerves and this was not inhibited by the IFNAR1 blocking antibody. The Janus kinase inhibitor GLPG0634 (1 μm) virtually abolished the nerve activation caused by IFNβ. Consistent with the activation of vagal afferent C‐fibers, infusing IFNβ into the mouse trachea led to defensive breathing reflexes including apneas and gasping. These reflexes were prevented by pretreatment with an IFN type‐1 receptor blocking antibody. Finally, using whole cell patch‐clamp electrophysiology of lung‐specific neurons we found that IFNβ (1000 U ml−1) directly depolarized the membrane potential of isolated nodose neurons, in some cases beyond to action potential threshold. This acute non‐genomic activation of vagal sensory nerve terminals by interferons may contribute to the incessant coughing that is a hallmark of respiratory viral infections.
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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) | 0.003 | 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".