PKCε stimulation of TRPV1 orchestrates carotid body responses to asthmakines

Abstract

We have previously shown that carotid body stimulation by lysophosphatidic acid elicits a reflex stimulation of vagal efferent activity sufficient to cause bronchoconstriction in asthmatic rats. r Here, we show that pathophysiological concentrations of asthma-associated prototypical Th2 cytokines also stimulate the carotid bodies. r Stimulation of the carotid bodies by these asthmakines involves a PKCε-transient receptor potential vanilloid 1 (TRPV1) signalling mechanism likely dependent on TRPV1 S502 and T704 phosphorylation sites. r As the carotid bodies' oxygen sensitivity is independent of PKCε-TRPV1 signalling, systemic blockade of PKCε may provide a novel therapeutic target to reduce allergen-induced asthmatic bronchoconstriction. r Consistent with the therapeutic potential of blocking the PKCε-TRPV1 pathway, systemic delivery of a PKCε-blocking peptide suppresses asthmatic respiratory distress in response to allergen and reduces airway hyperresponsiveness to bradykinin.

Asthmatic allergen inhalation sensitises carotid bodies to lysophosphatidic acid

“…We previously demonstrated an important role of the carotid bodies in regulating asthmatic bronchoconstriction, involving an LPAr-PKCε-TRPV1 pathway [ 7 , 8 ]. Here, we show that repeated allergen challenges sensitise the carotid bodies to LPA, likely due to increased LPAr expression in the carotid bodies and petrosal ganglion.…”

“…BN rats were sensitised to ovalbumin (0.1 mg, Sigma) with pertussis toxin (0.5 ng, Sigma) and aluminium hydroxide as adjuvant (0.15 g, Sigma) dissolved in saline (1 mL); days 1, 2 and 3 ( ip ) and challenged with 5% aerosolised ovalbumin (Fig. 1 a), giving an asthmatic phenotype resembling human asthma [ 13 , 14 ] as established [ 7 , 8 ]. Naïve BN rats were treated with saline.…”

“…Three hours after final aerosolisation, rats were placed in a bell jar with gauze soaked in isoflurane. Once deeply anesthetised, each animal was euthanised by decapitation and exsanguination; then, the carotid body and carotid sinus nerve were quickly removed, mounted onto a custom stage, perfused and prepared for extracellular recording as established [ 7 , 8 , 15 , 16 ]. All preparations were exposed to a brief hypoxic challenge (60 Torr O 2 ); preparations that failed to increase nerve activity by 50% during this challenge were discarded.…”

“…This bronchoconstriction was instigated, in part, by increased plasma lysophosphatidic acid (LPA) which activates LPA receptors (LPAr) and transient receptor potential vanilloid one (TRPV1) channels in the carotid body-petrosal ganglion complex [ 7 ]. We further showed that this pathway likely involved protein kinase C epsilon (PKCε) which served as an intracellular link between LPAr subtype 1 and TRPV1 [ 8 ]. The carotid bodies are sensitised by acute intermittent hypoxia after chronic intermittent hypoxia [ 9 ] and by acute intermittent hypoxia-hypercapnia without chronic intermittent hypoxia [ 10 ].…”

PKCε sensing in the carotid body – a new target for asthma?

“…In a recent issue of the Journal of Physiology , Jendzjowsky and colleagues expanded upon this initial finding to provide new evidence highlighting both a mechanism and pathway that spares the carotid body oxygen‐sensing function (Jendzjowsky et al . 2021). Specifically, the authors discovered that several key Th2 cytokines integral to asthma pathogenesis, including IL‐13, IL‐5 and IL‐4, stimulated the carotid body.…”