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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alternative Splicing*
  • Asthma / genetics*
  • Asthma / metabolism
  • Basophils / metabolism
  • Cell Line
  • Epithelial Cells / metabolism
  • Female
  • Gene Expression Profiling / methods
  • Humans
  • Inflammation / genetics*
  • Inflammation / metabolism
  • Interleukin-1 Receptor-Like 1 Protein / genetics
  • Interleukin-1 Receptor-Like 1 Protein / metabolism
  • Interleukin-33 / genetics*
  • Interleukin-33 / metabolism
  • Male
  • Mast Cells / metabolism
  • Middle Aged
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / pathology
  • Sputum / cytology
  • Sputum / metabolism
  • Young Adult


  • IL1RL1 protein, human
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33

Associated data

  • GENBANK/KX463463
  • GENBANK/KX463464