Deficient inflammasome activation permits an exaggerated asthma phenotype in response to early-life RV-C15 infection

Mingyuan Han1, Claudia Stroupe1, Tomoko Ishikawa1, J. Kelley Bentley1 and Marc B. Hershenson1,2

Departments of 1Pediatrics and 2Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109

Background: Early-life wheezing-associated respiratory infection with human rhinovirus (RV) is associated with asthma development. RV-A1B infection of six day-old immature mice causes an asthma-like phenotype dependent on IL-13-producing type 2 innate lymphoid cells (ILC2s) (Hong J et al. J Allergy Clin Immunol 2014). RV species C (RV-C) has been associated with severe respiratory illnesses in children and adults and is more likely to occur in children with a history of asthma or who develop asthma. We therefore examined the effect of RV-C15 infection in immature mice.

Methods: Six day-old wild type and TLR2-/- mice were inoculated with sham, RV-A1B, or RV-C15. Selected mice were treated recombinant IL-1β. Cultured macrophages derived from human peripheral blood monocytes, human THP-1 cells and mouse bone marrow were also infected with sham, RV-A1B or RV-C15.

Results: As shown previously, RV-A1B infection of six day-old mice induced type 2 cytokine expression, ILC2 expansion and mucous metaplasia. However, compared to RV-A1B infection, RV-C15 infection induced an exaggerated asthma phenotype, with significantly increased mRNA expression of Il5, Il13, Il25, Il33, Muc5ac, Muc5b and Gob5, increased lung lineage-negative CD25+CD127+ST2+ ILC2s, and increased PAS and Muc5ac immunostaining. Viral load and induction of pro-inflammatory type 1 cytokines were not different between the two viruses.

We have shown that IL-1β, a product of inflammasome activation, attenuates airway type 2 cytokine responses (Han M et al. Allergy. 2020). We therefore examined the effects of RV-C15 and RV-A1B on inflammasome priming and activation. Infection of six day-old mice with RV-C15 and RV-A1B induced an equal amount of inflammasome priming (pro-IL-1β and NLRP3), but RV-C15-induced inflammasome activation (IL-1β and caspase-1 p12) was reduced compared to RV-A1B. A similar deficiency of inflammasome activation was found in cultured macrophages. Both viruses induced TLR2-dependent inflammasome priming, but less viral genomic RNA was detected in RV-C15 infected cells. Finally, treatment with IL-1β decreased RV-C-induced type 2 cytokine and mucus-related gene expression but not viral load or expression of pro-inflammatory type 1 cytokines, consistent with the notion that inflammasome activation has a suppressive effect on the asthma phenotype.

Conclusions: Infection of immature mice with RV-C induces an enhanced asthma phenotype compared to RV-A. Interaction of RV-C with airway macrophages triggers inflammasome priming, but inflammasome activation and IL-1β are deficient, thereby permitting exaggerated type 2 inflammation and mucous metaplasia following early-life RV-C infection.

Mingyuan Han PhD

University of Michigan

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