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 () and Koichiro Asano ()
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Hiroki Kabata: Keio University School of Medicine
Kazuyo Moro: Laboratory for Immune Cell System, RCAI, RIKEN Research Center for Integrative Medical Sciences (IMS-RCAI)
Koichi Fukunaga: Keio University School of Medicine
Yusuke Suzuki: Keio University School of Medicine
Jun Miyata: Keio University School of Medicine
Katsunori Masaki: Keio University School of Medicine
Tomoko Betsuyaku: Keio University School of Medicine
Shigeo Koyasu: Keio University School of Medicine
Koichiro Asano: Keio University School of Medicine

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3675

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