title: Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33.
abstract: BACKGROUND
  Asthma in a mouse model spontaneously resolves after cessation of allergen exposure. We developed a mouse model in which asthma features persisted for 6 months after cessation of allergen exposure.
  
  
  OBJECTIVE
  We sought to elucidate factors contributing to the persistence of asthma.
  
  
  METHODS
  We used a combination of immunologic, genetic, microarray, and pharmacologic approaches to dissect the mechanism of asthma persistence.
  
  
  RESULTS
  Elimination of T cells though antibody-mediated depletion or lethal irradiation and transplantation of recombination-activating gene (Rag1)(-/-) bone marrow in mice with chronic asthma resulted in resolution of airway inflammation but not airway hyperreactivity or remodeling. Elimination of T cells and type 2 innate lymphoid cells (ILC2s) through lethal irradiation and transplantation of Rag2(-/-)γc(-/-) bone marrow or blockade of IL-33 resulted in resolution of airway inflammation and hyperreactivity. Persistence of asthma required multiple interconnected feedback and feed-forward circuits between ILC2s and epithelial cells. Epithelial IL-33 induced ILC2s, a rich source of IL-13. The latter directly induced epithelial IL-33, establishing a positive feedback circuit. IL-33 autoinduced, generating another feedback circuit. IL-13 upregulated IL-33 receptors and facilitated IL-33 autoinduction, thus establishing a feed-forward circuit. Elimination of any component of these circuits resulted in resolution of chronic asthma. In agreement with the foregoing, IL-33 and ILC2 levels were increased in the airways of asthmatic patients. IL-33 levels correlated with disease severity.
  
  
  CONCLUSIONS
  We present a critical network of feedback and feed-forward interactions between epithelial cells and ILC2s involved in maintaining chronic asthma. Although T cells contributed to the severity of chronic asthma, they were redundant in maintaining airway hyperreactivity and remodeling.
authors.affiliation: Division of Allergy and Immunology, National Jewish Health, Denver, Colo.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Christianson
authors.affiliation: Division of Allergy and Immunology, National Jewish Health, Denver, Colo.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Goplen
authors.affiliation: Division of Allergy and Immunology, National Jewish Health, Denver, Colo.
authors.forename: Iram
authors.initials: I
authors.lastname: Zafar
authors.affiliation: Division of Allergy and Immunology, National Jewish Health, Denver, Colo.
authors.forename: Chaoyu
authors.initials: C
authors.lastname: Irvin
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, Colo.
authors.forename: James T
authors.initials: JT
authors.lastname: Good
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, Colo.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Rollins
authors.affiliation: Division of Allergy and Immunology, National Jewish Health, Denver, Colo.
authors.forename: Balachandra
authors.initials: B
authors.lastname: Gorentla
authors.affiliation: Division of Allergy and Immunology, National Jewish Health, Denver, Colo.
authors.forename: Weimin
authors.initials: W
authors.lastname: Liu
authors.affiliation: Division of Allergy and Immunology, National Jewish Health, Denver, Colo; University of Colorado Denver, Denver, Colo.
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Gorska
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, Colo; University of Colorado Denver, Denver, Colo.
authors.forename: HongWei
authors.initials: H
authors.lastname: Chu
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, Colo; University of Colorado Denver, Denver, Colo.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Martin
authors.affiliation: Division of Allergy and Immunology, National Jewish Health, Denver, Colo; University of Colorado Denver, Denver, Colo. Electronic address: AlamR@njhealth.org.
authors.forename: Rafeul
authors.initials: R
authors.lastname: Alam
mesh_terms: D019264:Adoptive Transfer; D056151:Airway Remodeling / Q000187:drug effects / Q000235:genetics; D000485:Allergens / Q000276:immunology; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage*; D001249:Asthma / Q000276:immunology*; D016026:Bone Marrow Transplantation; D016535:Bronchial Hyperreactivity / Q000235:genetics; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D018793:Interleukin-13 / Q000378:metabolism; D000067596:Interleukin-33; D007378:Interleukins / Q000276:immunology*; D008212:Lymphocyte Depletion; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000485:Allergens; D019138:Antibodies, Blocking; C506535:Il33 protein, mouse; D018793:Interleukin-13; D000067596:Interleukin-33; D007378:Interleukins
keywords: IL-33; T cells; Type 2 innate lymphoid cells; chronic asthma; feedback circuit