Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation

Hiroki Kabata, Kazuyo Moro, Koichi Fukunaga, Yusuke Suzuki, Jun Miyata, Katsunori Masaki, Tomoko Betsuyaku, Shigeo Koyasu, Koichiro Asano

Research output: Contribution to journalArticle

151 Citations (Scopus)

Abstract

Type-2 innate immune responses that occur in airways and are accompanied by goblet-cell hyperplasia and mucus production are largely driven by interleukin-33 (IL-33) and natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2s) and the major target of IL-33. Here we report that the corticosteroid resistance observed as a result of airway inflammation triggered by sensitization and exposure to allergen is induced via the IL-33/NH-cell axis. Thymic stromal lymphopoietin (TSLP) synthesized during airway inflammation plays a pivotal role in the induction of NH-cell corticosteroid resistance in vitro and in vivo, by controlling phosphorylation of STAT5 and expression of Bcl-xL in NH cells. Blockade of TSLP with a neutralizing antibody or blocking the TSLP/STAT5 signalling pathway with low molecular-weight STAT5 inhibitors such as pimozide restores corticosteroid sensitivity. Thus, the TSLP-STAT5 pathway could be a new therapeutic target in severe, corticosteroid-resistant asthma.

Original languageEnglish
Article number2675
JournalNature communications
Volume4
DOIs
Publication statusPublished - 2013 Oct 25

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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