Regulation of Airway Vagal Afferent C‐fibers by Type I and Type II Interferons
Authors: Patil Mayur Jayanta , Undem Bradley 
Published: June 2021

During respiratory viral infections and inflammatory airway diseases, both type I and type II interferons are elevated in the respiratory tract. Interferons are known for their ability to orchestrate anti‐viral defenses and other immunological responses in the airways. Our objective was to address the hypothesis that interferons may also play an important heretofore under‐appreciated role in recruiting the nocifensive nervous system during viral infection and inflammatory disease. We previously noted in an RNAseq evaluation that receptors for both type I and type II interferons are richly expressed by capsaicin‐sensitive vagal nodose and jugular C‐fiber neurons (PLoS One. 2017 Oct 5;12). In this study we show that both type I and II interferons (a, b, and g)directly and rapidly stimulate vagal C‐fiber terminals in mouse lungs to evoke action potential discharge.MethodsWe used single cell RT‐PCR specifically of nodose neurons retrogradely labeled from the mouse lungs to detect the presence of type I and II interferon receptors in airway afferent C‐fibers. To study action potential discharge from C‐fiber terminals we isolated the lungs, vagus nerve, along with vagal sensory ganglia from Pirt‐cre;GCaMP6smice. The nodose ganglion was positioned beneath a 20X, 2‐Photon microscope objective that assessed the elevations in calcium that were caused by action potentials conducted from the terminals in the lungs to cell bodies in the nodose ganglion. We noted that this system is sensitive enough to detect a single conducted action potential. This allowed us to simultaneously monitor the action potentials arriving at hundreds of vagal ganglion neurons in response to interferons infused specifically into the trachea/lung compartment.ResultsThe interferon receptors (ifnar1, ifnar2, ifngr1 and ifngr2) were expressed in 60–70% of airway‐specific TRPV1‐positive nodose neurons. In our 2 Photon imaging of the nodose ganglion we found that within minutes of perfusing the trachea/lungs with type I or II interferons action potentials were discharged from more than 70% of capsaicin‐sensitive C‐fibers (approximately 4000 neurons evaluated in 4 experiments). Vehicle perfusion was without effect. Among the interferons studies the relative responsiveness of vagal C‐fibers was b> g> aConclusionsThis study supports the hypothesis that type I and II interferons, in addition to orchestrating the immune responses by regulating chemokine and cytokine gene expression, can also more acutely recruit the nervous system by activating visceral sensory nociceptors. If dysregulated this may contribute to the nocifensive reflexes and sensations including bronchospasm, mucus secretion, urge to cough, and dyspnea, that can accompany airway inflammatory diseases and viral infections in asthmatic subjects.Support or Funding InformationNIH RO1HL137807, and David Marsh Symposium Research Award (Johns Hopkins)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.