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

Nat Commun. 2013;4:2675. doi: 10.1038/ncomms3675.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Hormones / pharmacology
  • Animals
  • Antibodies, Neutralizing / pharmacology
  • Asthma / drug therapy
  • Asthma / immunology*
  • Asthma / pathology
  • Cytokines / antagonists & inhibitors
  • Cytokines / genetics
  • Cytokines / immunology*
  • Dopamine Antagonists / pharmacology
  • Drug Tolerance*
  • Gene Expression Regulation
  • Immunity, Innate / drug effects
  • Inflammation / drug therapy
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-33
  • Interleukins / genetics
  • Interleukins / immunology
  • Lung / drug effects
  • Lung / immunology*
  • Lung / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Pimozide / pharmacology
  • STAT5 Transcription Factor / antagonists & inhibitors
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / immunology*
  • Signal Transduction
  • T-Lymphocytes, Helper-Inducer / drug effects*
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / pathology
  • bcl-X Protein / genetics
  • bcl-X Protein / immunology

Substances

  • Adrenal Cortex Hormones
  • Antibodies, Neutralizing
  • Bcl2l1 protein, mouse
  • Cytokines
  • Dopamine Antagonists
  • Il33 protein, mouse
  • Interleukin-33
  • Interleukins
  • STAT5 Transcription Factor
  • bcl-X Protein
  • Pimozide
  • thymic stromal lymphopoietin