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Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):8765-70. doi: 10.1073/pnas.1601914113. Epub 2016 Jul 18.

Alternative splicing of interleukin-33 and type 2 inflammation in asthma.

Author information

1
Department of Pulmonary and Critical Care Medicine, University of California, San Francisco, CA 94143; erin.gordon@ucsf.edu john.fahy@ucsf.edu.
2
Department of Microbiology and Immunology, University of California San Francisco, CA 94143;
3
Center for Genes, Environment, and Health, National Jewish Health, Denver, CO 80206;
4
Cardiovascular Research Institute, University of California, San Francisco, CA 94143;
5
Department of Pulmonary and Critical Care Medicine, University of California, San Francisco, CA 94143;
6
Department of Pulmonary and Critical Care Medicine, University of California, San Francisco, CA 94143; Sandler Asthma Basic Research Center, University of California, San Francisco, CA 94143;
7
Department of Microbiology and Immunology, University of California San Francisco, CA 94143; Sandler Asthma Basic Research Center, University of California, San Francisco, CA 94143;
8
Immunoscience, Pfizer Worldwide Research and Development, Cambridge, MA 02139;
9
Center for Genes, Environment, and Health, National Jewish Health, Denver, CO 80206; Department of Pediatrics, National Jewish Health, Denver, CO 80206; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045.
10
Department of Pulmonary and Critical Care Medicine, University of California, San Francisco, CA 94143; Cardiovascular Research Institute, University of California, San Francisco, CA 94143; Sandler Asthma Basic Research Center, University of California, San Francisco, CA 94143; erin.gordon@ucsf.edu john.fahy@ucsf.edu.

Abstract

Type 2 inflammation occurs in a large subgroup of asthmatics, and novel cytokine-directed therapies are being developed to treat this population. In mouse models, interleukin-33 (IL-33) activates lung resident innate lymphoid type 2 cells (ILC2s) to initiate airway type 2 inflammation. In human asthma, which is chronic and difficult to model, the role of IL-33 and the target cells responsible for persistent type 2 inflammation remain undefined. Full-length IL-33 is a nuclear protein and may function as an "alarmin" during cell death, a process that is uncommon in chronic stable asthma. We demonstrate a previously unidentified mechanism of IL-33 activity that involves alternative transcript splicing, which may operate in stable asthma. In human airway epithelial cells, alternative splicing of the IL-33 transcript is consistently present, and the deletion of exons 3 and 4 (Δ exon 3,4) confers cytoplasmic localization and facilitates extracellular secretion, while retaining signaling capacity. In nonexacerbating asthmatics, the expression of Δ exon 3,4 is strongly associated with airway type 2 inflammation, whereas full-length IL-33 is not. To further define the extracellular role of IL-33 in stable asthma, we sought to determine the cellular targets of its activity. Comprehensive flow cytometry and RNA sequencing of sputum cells suggest basophils and mast cells, not ILC2s, are the cellular sources of type 2 cytokines in chronic asthma. We conclude that IL-33 isoforms activate basophils and mast cells to drive type 2 inflammation in chronic stable asthma, and novel IL-33 inhibitors will need to block all biologically active isoforms.

KEYWORDS:

alternative splicing; asthma; basophils; interleukin-33; type 2 inflammation

PMID:
27432971
PMCID:
PMC4978244
DOI:
10.1073/pnas.1601914113
[Indexed for MEDLINE]
Free PMC Article

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