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

H Kabata, K Moro, K Fukunaga, Y Suzuki… - Nature …, 2013 - nature.com
H Kabata, K Moro, K Fukunaga, Y Suzuki, J Miyata, K Masaki, T Betsuyaku, S Koyasu
Nature communications, 2013nature.com
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 …
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.
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