title: RORα-dependent type 2 innate lymphoid cells are required and sufficient for mucous metaplasia in immature mice.
abstract: Early-life wheezing-associated respiratory tract infection by rhinovirus (RV) is considered a risk factor for asthma development. We have shown that RV infection of 6-day-old BALB/c mice, but not mature mice, induces an asthmalike phenotype that is associated with an increase in the population of type 2 innate lymphoid cells (ILC2s) and dependent on IL-13 and IL-25. We hypothesize that ILC2s are required and sufficient for development of the asthmalike phenotype in immature mice. Mice were infected with RV1B onday 6of life and treated with vehicle or a chemical inhibitor of retinoic acid receptor-related orphan receptor-α (RORα), SR3335 (15 mg·kg-1·day-1ip for 7 days). We also infectedRorasg/sgmice without functional ILC2s. ILC2s were identified as negative for lineage markers and positive for cluster of differentiation 25 (CD25)/IL-2Rα and CD127/IL-7Rα. Effects of SR3335 on proliferation and function of cultured ILC2s were determined. Finally, sorted ILC2s were transferred into naïve mice, and lungs were harvested 14 days later for assessment of gene expression and histology. SR3335 decreased the number of RV-induced lung lineage-negative, CD25+, CD127+ILC2s in immature mice. SR3335 also attenuated lung mRNA expression of IL-13, Muc5ac, and Gob5 as well as mucous metaplasia. We also found reduced expansion of ILC2s in RV-infectedRorasg/sgmice. SR3335 also blocked IL-25 and IL-33-induced ILC2 proliferation and IL-13 production ex vivo. Finally, adoptive transfer of ILC2s led to development of asthmalike phenotype in immature and adult mice. RORα-dependent ILC2s are required and sufficient for type 2 cytokine expression and mucous metaplasia in immature mice.
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan; and.
authors.forename: Charu
authors.initials: C
authors.lastname: Rajput
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan; and.
authors.forename: Tracy
authors.initials: T
authors.lastname: Cui
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan; and.
authors.forename: Mingyuan
authors.initials: M
authors.lastname: Han
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan; and.
authors.forename: Jing
authors.initials: J
authors.lastname: Lei
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan; and.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Hinde
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan; and.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan; and.
authors.forename: J Kelley
authors.initials: JK
authors.lastname: Bentley
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan; and mhershen@umich.edu.|Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Marc B
authors.initials: MB
authors.lastname: Hershenson
mesh_terms: D019264:Adoptive Transfer; D000375:Aging / Q000276:immunology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D008679:Metaplasia; D008807:Mice, Inbred BALB C; D009093:Mucus / Q000276:immunology*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000378:metabolism*; D012229:Rhinovirus / Q000187:drug effects; D013449:Sulfonamides; D013876:Thiophenes
chemical_list: D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C561766:SR 3335; D013449:Sulfonamides; D013876:Thiophenes
keywords: asthma; newborn; retinoic acid receptor-related orphan receptor-α; rhinovirus; type 2 innate lymphoid cells