Acute activation of bronchopulmonary vagal nociceptors by type I interferons

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 anex vivovagal 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 fromPirt-Cre;R26-GCaMP6 smice we found that applying IFN alpha or IFN beta 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 IFN beta was largely inhibited. The type 2 interferon, IFN gamma, also activated airway nerves and this was not inhibited by the IFNAR1 blocking antibody. The Janus kinase inhibitor GLPG0634 (1 mu m) virtually abolished the nerve activation caused by IFN beta. Consistent with the activation of vagal afferent C-fibers, infusing IFN beta 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 IFN beta (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.