Loss of regulator of G protein signaling 5 promotes airway hyperresponsiveness in the absence of allergic inflammation

Background Although eosinophilic inflammation typifies allergic asthma, it is not a prerequisite for airway hyperresponsiveness (AHR), suggesting that underlying abnormalities in structural cells, such as airway smooth muscle (ASM), contribute to the asthmatic diathesis. Dysregulation of procontractile G protein-coupled receptor (GPCR) signaling in ASM could mediate enhanced contractility. Objective We explored the role of a regulator of procontractile GPCR signaling, regulator of G protein signaling 5 (RGS5), in unprovoked and allergen-induced AHR. Methods We evaluated GPCR-evoked Ca²⁺ signaling, precision-cut lung slice (PCLS) contraction, and lung inflammation in naive and Aspergillus fumigatus-challenged wild-type and Rgs5^-/- mice. We analyzed lung resistance and dynamic compliance in live anesthetized mice using invasive plethysmography. Results Loss of RGS5 promoted constitutive AHR because of enhanced GPCR-induced Ca²⁺ mobilization in ASM. PCLSs from naive Rgs5^-/- mice contracted maximally at baseline independently of allergen challenge. RGS5 deficiency had little effect on the parameters of allergic inflammation, including cell counts in bronchoalveolar lavage fluid, mucin production, ASM mass, and subepithelial collagen deposition. Unexpectedly, induced IL-13 and IL-33 levels were much lower in challenged lungs from Rgs5^-/- mice relative to those seen in wild-type mice. Conclusion Loss of RGS5 confers spontaneous AHR in mice in the absence of allergic inflammation. Because it is selectively expressed in ASM within the lung and does not promote inflammation, RGS5 might be a therapeutic target for asthma.