Activation of the inflammasome is a key function of the innate immune response that regulates inflammation in response to microbial substances. Inflammasome activation by human rhinovirus (RV)， a major cause of asthma exacerbations， has not been well studied. We examined whether RV induces inflammasome activation in vivo， molecular mechanisms underlying RV-stimulated inflammasome priming and activation， and the contribution of inflammasome activation to RV-induced airway inflammation and exacerbation. RV infection triggered lung mRNA and protein expression of pro-IL-1β and NLRP3， indicative of inflammasome priming， as well as cleavage of caspase-1 and pro-IL-1β， completing inflammasome activatio... More
Activation of the inflammasome is a key function of the innate immune response that regulates inflammation in response to microbial substances. Inflammasome activation by human rhinovirus (RV)， a major cause of asthma exacerbations， has not been well studied. We examined whether RV induces inflammasome activation in vivo， molecular mechanisms underlying RV-stimulated inflammasome priming and activation， and the contribution of inflammasome activation to RV-induced airway inflammation and exacerbation. RV infection triggered lung mRNA and protein expression of pro-IL-1β and NLRP3， indicative of inflammasome priming， as well as cleavage of caspase-1 and pro-IL-1β， completing inflammasome activation. Immunofluorescence staining showed IL-1β in lung macrophages. Depletion with clodronate liposomes and adoptive transfer experiments showed macrophages to be required and sufficient for RV-induced inflammasome activation. TLR2 was required for RV-induced inflammasome priming in vivo. UV irradiation blocked inflammasome activation and RV genome was sufficient for inflammasome activation in primed cells. Naive and house dust mite-treated NLRP3-/- and IL-1β-/- mice， as well as IL-1 receptor antagonist-treated mice， showed attenuated airway inflammation and responsiveness following RV infection. We conclude that RV-induced inflammasome activation is required for maximal airway inflammation and hyperresponsiveness in naive and allergic mice. The inflammasome represents a molecular target for RV-induced asthma exacerbations.
