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Recently, we demonstrated a vital role for lysophosphatidic acid in stimulating the primary autonomic oxygen chemoreceptors, the carotid bodies, in parasympathetic\u2010mediated asthmatic airway hyperresponsiveness. However, the cacophony of stimulatory factors and cellular mechanisms of carotid body activation are unknown. Therefore, we set out to determine the intracellular signalling involved in carotid body\u2010mediated sensing of asthmatic blood\u2010borne inflammatory mediators. We employed a range of <jats:italic>in vitro<\/jats:italic> and rat <jats:italic>in situ<\/jats:italic> preparations, site\u2010directed mutagenesis, patch\u2010clamp, nerve recordings and pharmacological inhibition to assess cellular signalling. We show that the carotid bodies are also sensitive to asthma\u2010associated prototypical Th2 cytokines which elicit sensory nerve excitation. This provides additional asthmatic ligands contributing to the previously established reflex arc resulting in efferent vagal activity and asthmatic bronchoconstriction. This novel sensing role for the carotid body is mediated by a PKC\u03b5\u2010dependent stimulation of transient receptor potential vanilloid 1 (TRPV1), likely via TRPV1 phosphorylation at sites T704 and S502. Importantly, carotid body oxygen sensing was unaffected by blocking either PKC\u03b5 or TRPV1. Further, we demonstrate that systemic PKC\u03b5 blockade reduces asthmatic respiratory distress in response to allergen and airway hyperresponsiveness. These discoveries support an inflammation\u2010dependent, oxygen\u2010independent function for the carotid body and suggest that targeting PKC\u03b5 provides a novel therapeutic option to abate allergic airway disease without altering life\u2010saving autonomic hypoxic reflexes.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp280749","type":"journal-article","created":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T18:54:49Z","timestamp":1605207289000},"page":"1335-1354","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["PKC\u03b5 stimulation of TRPV1 orchestrates carotid body responses to asthmakines"],"prefix":"10.1113","volume":"599","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4342-1839","authenticated-orcid":false,"given":"Nicholas G.","family":"Jendzjowsky","sequence":"first","affiliation":[{"name":"The Lundquist Institute for Biomedical Innovation at Harbor\u2010UCLA Medical Center  Torrance California 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