Background and Purpose Asthma is characterized by airway inflammation, mucus hypersecretion and airway hyperresponsiveness (AHR). The activation of cholinergic anti‐inflammatory pathway (CAP) through nicotinic agents has been shown to control experimental asthma. Yet, the effects of vagus nerve stimulation (VNS)-induced CAP on allergic inflammation remain unknown. Experimental Approach BALB/c mice were sensitized and challenged with house dust mite (HDM) extract, and treated with active VNS (5Hz, 0.5 ms, 0.1 mA). Bronchoalveolar lavage (BAL) fluid was assessed for total and differential cell counts and cytokine levels. Lungs were examined by histopathology and electron microscopy. AHR in response to methacholine was also measured. Key Results In the HDM mouse asthma model, active but not sham VNS reduced BAL fluid total and differential cell counts, blocked mucus hypersecretion and suppressed choline acetyltransferase (ChAT) expression in bronchial epithelial cells. Besides, active VNS also abated HDM-induced elevation of type 2 cytokines IL-4 and IL-5. Furthermore, goblet cell hyperplasia and collagen deposition were diminished in VNS-treated mice. Mechanistically, VNS was found to block the phosphorylation of transcription factor STAT6 and the level of IRF4 in total lung lysates. Finally, VNS abrogated methacholine-induced AHR in asthma mice. Therapeutic effects of VNS were abolished by prior administration with α-bungarotoxin, a specific inhibitor of α7 nicotinic receptors (α7nAChR). Conclusion Our data revealed the protective effects of VNS on various clinical features in allergic airway inflammation model. VNS, a clinically approved therapy for depression and epilepsy, appears to be a promising new strategy for controlling allergic asthma through α7nAChR.

Background and Purpose: The activation of the defense reaction inhibits the baroreflex response through the B3 and nucleus tractus solitarius (NTS) regions. Our aim was to determine whether and how baroreflex inhibition induced by the disinhibition of the rostral cuneiform nucleus, part of the defense pathway, involves serotonin cells in B3 and 5-HT3 receptors in the NTS. Experimental Approach: We performed immunohistochemistry and anatomical experiments to determine whether raphe serotonin cells expressing Fos were directly targeted by the rostral cuneiform nucleus. The effect of blocking raphe serotonin transmission and NTS 5-HT3 receptors, on cuneiform-induced inhibition of the baroreflex cardiac response, were also analyzed. Key Results: Bicuculline microinjected into the rostral cuneiform nucleus induced an increase of double labeled Fos-5-HT IR cells in both the LPGi and Raphe Magnus. The anterograde tracer Phaseolus vulgaris leucoaggutinin into the rostral cuneiform nucleus revealed a dense projection to the LPGi but not Raphe Magnus. Cuneiform-induced baroreflex inhibition was prevented by B3 injection of 8-OH-DPAT, a specific agonist for 5-HT1A receptors. Cuneiform disinhibition also failed to inhibit the baroreflex bradycardia after microinjection of a 5-HT3 receptor antagonist (granisetron) into the NTS or in 5-HT3 receptor knock-out mice. Conclusion and Implications: In conclusion, the rostral cuneiform nucleus participates in the defense inhibition of the baroreflex bradycardia via direct activation of the LPGi and a relay to the Raphe Magnus, to activate NTS 5-HT3 receptors and inhibit second-order baroreflex neurons. These data bring new insights in primary and secondary mechanisms involved in vital baroreflex prevention during stress.