Editors' ChoiceMEDICINE

Allergic sensations fuel asthma

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Sci. Signal.  28 Jul 2015:
Vol. 8, Issue 387, pp. ec201
DOI: 10.1126/scisignal.aad0767

Allergens trigger inflammatory responses that constrict the airways, and this response is abnormally increased in asthma patients. Sensory neurons in the lung respond to chemical, mechanical, or thermal stimuli through the activation of nociceptors, including the transient receptor potential channel TRPV1, to initiate protective airway reflexes, such as coughing. Talbot et al. found that pharmacologically blocking voltage-gated sodium channels might suppress allergen-induced asthma. In naïve mice, intranasal instillation of the TRPV1 agonist capsaicin increased the abundance of neuropeptides and various immune cells in fluid isolated from the bronchoaveolae; mice challenged with the allergen ovalbumin had an even greater response to capsaicin. Blocking the voltage-gated sodium channel Nav1.8 in sensory neurons of ovalbumin-exposed mice—either through conditional knockout or inhalation of the charged sodium channel-blocking agent QX-314—increased voluntary exercise and decreased the capsaicin-induced increase in neuropeptides and immune cells in the bronchoaveolar fluid and decreased basement membrane thickening in the lung tissue. Cytokines implicated in asthma, such as interleukin-5 (IL-5), were also increased in the brochoaveolar fluid of ovalbumin-challenged mice, and QX-314 treatment decreased IL-5 abundance in the brochoaveolar fluid. Exposure to IL-5 activated Nav1.8-positive and IL-5 receptor–positive lung neurons in culture. Lung-resident ILC2 cells, a type of immune cell, are activated by allergens and produce IL-5, among other cytokines; they also contain receptors to several sensory neuron-secreted neuropeptides, including the receptor for VIP, which was released from cultured Nav1.8-positive sensory neurons stimulated with capsaicin or IL-5. Ablating Nav1.8 in sensory neurons or treating mice with QX-314 decreased the amount and activation of ILC2 cells in bronchoaveolar fluid. Ovalbumin-challenged mice had increased abundance of VIP in bronchoaveolar fluid, and this was reduced by QX-314 treatment. The findings suggest that Nav1.8-positive sensory neurons and immune cells engage in an inflammatory signaling loop involving neuron-secreted VIP and ILC2-secreted IL-5 that contributes to the airway constriction in response to allergens.

S. Talbot, R.-E. E. Abdulnour, P. R. Burkett, S. Lee, S. J. F. Cronin, M. A. Pascal, C. Laedermann, S. L. Foster, J. V. Tran, N. Lai, I. M. Chiu, N. Ghasemlou, M. DiBiase, D. Roberson, C. Von Hehn, B. Agac, O. Haworth, H. Seki, J. M. Penninger, V. K. Kuchroo, B. P. Bean, B. D. Levy, C. J. Woolf, Silencing nociceptor neurons reduces allergic airway inflammation. Neuron 87, 341–354 (2015). [Pubmed]