A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma

Abstract

Asthma is an inflammatory disorder caused by airway exposures to allergens and chemical irritants. Studies focusing on immune, smooth muscle, and airway epithelial function revealed many aspects of the disease mechanism of asthma. However, the limited efficacies of immune-directed therapies suggest the involvement of additional mechanisms in asthmatic airway inflammation. TRPA1 is an irritant-sensing ion channel expressed in airway chemosensory nerves. TRPA1-activating stimuli such as cigarette smoke, chlorine, aldehydes, and scents are among the most prevalent triggers of asthma. Endogenous TRPA1 agonists, including reactive oxygen species and lipid peroxidation products, are potent drivers of allergen-induced airway inflammation in asthma. Here, we examined the role of TRPA1 in allergic asthma in the murine ovalbumin model. Strikingly, genetic ablation of TRPA1 inhibited allergen-induced leukocyte infiltration in the airways, reduced cytokine and mucus production, and almost completely abolished airway hyperreactivity to contractile stimuli. This phenotype is recapitulated by treatment of wild-type mice with HC-030031, a TRPA1 antagonist. HC-030031, when administered during airway allergen challenge, inhibited eosinophil infiltration and prevented the development of airway hyperreactivity. Trpa1 ؊/؊ mice displayed deficiencies in chemically and allergen-induced neuropeptide release in the airways, providing a potential explanation for the impaired inflammatory response. Our data suggest that TRPA1 is a key integrator of interactions between the immune and nervous systems in the airways, driving asthmatic airway inflammation following inhaled allergen challenge. TRPA1 may represent a promising pharmacological target for the treatment of asthma and other allergic inflammatory conditions. airway hyperreactivity ͉ TRP channel ͉ TRPA1

Population of sensory neurons essential for asthmatic hyperreactivity of inflamed airways

“…Here we took a molecular genetic approach to dissect the role of lung sensory neurons in a murine model of allergic airway inflammation (asthma-like), and identified vagal TRPV1-expressing neurons as essential players in the hyperreactive airway responses (see also ref. 22). We showed that the hyperreactivity phenotype of sensitized lungs can be physiologically dissociated from the immune component, and demonstrated how TRPV1 vagal sensory neurons can dramatically affect airway hyperreactivity, covering the full spectrum of phenotypes: from a total loss of hyperreactivity in animals lacking (or with synaptically silenced) TRPV1-neurons, to greatly exacerbating asthmatic-like broncho-constrictions in sensitized lungs via their direct optogenetic control, to triggering intense "denovo" broncho-constrictions, even in the absence of an immune response following S1PR stimulation.…”

“…Interestingly, a loss-of-function mutation in TRPA1, a different member of the TRP family, reduces inflammatory airway hyperreactivity (22). However, in contrast to animals where we ablated TRPV1-expressing cells, TRPA1 knockouts also showed a profound deficit in their airway immune response (22), suggesting a different site or mode of action.…”

“…To induce an immune response in the lung and produce airway reactivity, mice were injected with ovalbumin for 3 wk, followed by 3 consecutive days of direct airway ovalbumin challenge (Fig. 1A) (22). Wild-type mice treated this way develop a robust immune reaction with increased serum levels of ovalbumin-specific IgE (Fig.…”

“…Notably, the development of airway hyperreactivity is not dependent on the ion-channel TRPV1 itself (i.e., it requires the cells marked by the TRPV1 channel rather than the TRPV1 channel) (Fig. S3) (22). Interestingly, a loss-of-function mutation in TRPA1, a different member of the TRP family, reduces inflammatory airway hyperreactivity (22).…”

Exercise-induced asthma: why is it so frequent in Olympic athletes?

“…Jordt et al recently suggested that TRPA1 may function as an integrator of chemical and immunological stimuli modulating inflammation in the airways [10]. Furthermore, chemical irritant-induced activation of TRPA1 may trigger the release of neuropeptides and chemokines in the airways, thereby exacerbating the cellular and tissue inflammatory response observed in allergic individuals [11]. The question remains of whether a similar mechanism could occur in athletes exposed to irritants, such as those resulting from disinfection products used in swimming pools and others when training outdoors, independent of their atopic and asthma status.…”