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

doi:10.1038/ncomms3675

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

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

Authors

Hiroki Kabata¹, Kazuyo Moro, Koichi Fukunaga, Yusuke Suzuki, Jun Miyata, Katsunori Masaki, Tomoko Betsuyaku, Shigeo Koyasu, Koichiro Asano

Affiliation

¹ 1] Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Tokyo 160-8582, Japan [2] Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Tokyo 160-8582, Japan [3] Laboratory for Immune Cell System, RCAI, RIKEN Research Center for Integrative Medical Sciences (IMS-RCAI), 1-7-22 Suehiro-cho, Yokohama 230-0045, Japan [4].

PMID: 24157859
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
Thymic Stromal Lymphopoietin
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
TSLP protein, mouse