TRPV1 Sensory Nerves – Asthma
A new study in the Proceedings of the National Academy of Sciences (PNAS) of the USA implicates the transient receptor potential vanilloid 1 (TRPV1)-expressing sensory nerves in the pathogenesis of asthma and/or asthma attacks.
Asthmatics suffer from pulmonary obstruction caused primarily by a decrease in the inner airway diameter as a result of excess mucus secretion and thickening of the walls of airways. In addition, asthmatic airways are hyperreactive to broncho-constricting stimuli. Thus, asthmatics frequently experience “asthma attacks,” acute bronchospasms that severely obstruct breathing by further decreasing airway diameter. Notably, many asthma-related fatalities occur during the acute asthma attacks.
A significant body of physiological data suggests that asthmatic symptoms may be significantly modulated by the nervous system. Indeed, basic respiratory responses, such as cough, are mediated by sensory neurons innervating the lungs. Furthermore, in addition to detecting and relaying the presence of nociceptive stimuli to brain centers, activated lung sensory neurons can themselves directly release proinflammatory peptides into surrounding tissue. Therefore, it is likely that these cells play an important modulatory role in lung inflammation.
The TRPV1 receptor, initially identified as the receptor for capsaicin, the hot component of chilli peppers, is typically expressed in sensory neurons and responds to various stimuli including noxious heat, protons and tissue acidosis.
Vagal sensory neurons innervate the entire respiratory tract and affect cellular networks through axonal and local reflexes, but also signal the brain to regulate pulmonary functions. Interestingly, recent evidence indicates that TRPV1 sensory nerves trigger IL-23 output in psoriasis, whereas the TRPV1 receptor is functionally expressed in T cells.
In the PNAS study Dimitri Tränkner and a joint research team from the Janelia Farm Research Campus, Ashburn, VA; the NationalInstitutes of Health, Bethesda, MD and the Columbia University, NY, have used the ovalbumin-sensitized murine model of asthma to investigate the role of sensory innervation in airway hyperresponsiveness.
The researchers found that in this disease modelablating or genetically silencing TRPV1 vagal sensory nerves prevented the airway hyperreactivity and bronchoconstriction, in spite of the presence of a full-fledgedlung inflammatory response. Conversely, they observed that pharmacological stimulation of the receptor forsphingosine-1-phosphate (S1PR3),which is restricted to TRPV1 neurons, resulted in a robustairway hyperreactivity in the absence of immune sensitizationwith ovalbumin.
The authors 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 “de-novo” broncho-constrictions, even in the absence of an immune response following S1PR stimulation.
The authors suggest that during allergic inflammation the release of proinflammatory mediators are able to sensitize vagal sensory nerves, which, in turn, modulate airway responses to broncho-constricting stimuli and further increase the severity of airway hyperreactivity.
These observations seem to substantiate another recent study (Kristof Raemdonck et al., Thorax 2012;67:19) indicating that during the late asthmatic response, the allergen challenge leads to sensory nerve activation, which initiates a reflex event leading toa parasympathetic cholinergic constrictor response.
In conclusion, all these data support a model in which lung inflammation leads to the release of proinflammatory mediators that “sensitize” vagal sensory neurons (and their processes). These, in turn, modulate airway responses to broncho-constricting stimuli by acting like cellular “rheostats,” thus translating the degree of inflammation into severity of airway hyperreactivity. The genetic dissociation of the airway hyperreactivity from the immunological components of inflamed lungs provides a noteworthy avenue for exploring therapies that may target TRPV1-expressing neurons as a strategy for the management of asthma attacks.
Source: Proc Natl Acad Sci U S A, 2014, 111:11515. doi: 10.1073/pnas.1411032111. Epub 2014 Jul 21
Read more: pnas.org