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Mucosal Immunol. 2019 May 15. doi: 10.1038/s41385-019-0172-2. [Epub ahead of print]

Inflammasome activation is required for human rhinovirus-induced airway inflammation in naive and allergen-sensitized mice.

Author information

1
Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
2
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
3
Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
4
Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. mhershen@umich.edu.
5
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. mhershen@umich.edu.

Abstract

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.

PMID:
31089187
DOI:
10.1038/s41385-019-0172-2

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