Steroid Resistance of Airway Type 2 Innate Lymphoid Cells (ILC2s) from Severe Asthma: The Role of Thymic Stromal cell Lymphopoietin (TSLP)

Publication date: Available online 20 April 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Sucai Liu, Mukesh Verma, Lidia Michalec, Weimin Liu, Anand Sripada, Donald Rollins, James Good, Yoko Ito, HongWei Chu, Magdalena M. Gorska, Richard J. Martin, Rafeul Alam
BackgroundILC2s represent an important type 2 immune cell. Glucocorticoid regulation of human ILC2s is largely unknown.ObjectiveTo assess steroid resistance of human blood and airway ILC2s from asthmatic patients and examine its mechanism of induction.MethodsWe studied human blood and lung ILC2s from asthmatic and control subjects by flow cytometry and ELISA.ResultsDexamethasone (Dex) inhibited (P=0.04) CRTH2 and type 2 cytokine expression by blood ILC2s stimulated with IL25 and IL33. However, it failed to do so when ILC2s were stimulated with IL7 and TSLP, two ligands of IL7Rα. Unlike blood ILC2s, BAL ILC2s from asthmatic patients were resistant to Dex. BAL from the asthmatic patients had elevated TSLP but not IL7. The BAL TSLP level correlated (r=0.74) with steroid resistance of ILC2s. TSLP was synergistically induced in epithelial cells by IL13 and human rhinovirus. Mechanistically, Dex upregulated ILC2 expression of IL7Rα , which augmented and sustained STAT5 signaling by TSLP. TSLP induced MEK, c-Fos, ID3, pSTAT3 and pSTAT5—molecules linked to steroid resistance. Dex inhibited c-Fos, ID3 and pSTAT3, but not pSTAT5 and MEK. The MEK inhibitor Trametinib, the JAK-STAT inhibitor Tofacitinib and the STAT5 inhibitor Pimozide reversed steroid resistance of BAL ILC2s.ConclusionsDex inhibited type 2 cytokine production by blood ILC2s. IL7 and TSLP abrogated this inhibition and induced steroid resistance of ILC2s in a MEK and STAT5-dependent manner. BAL ILC2s from asthmatic patients with elevated TSLP were steroid resistant, which was reversed by clinically available inhibitors of MEK and STAT5.

Teaser

Dexamethasone inhibited CRTH2 and IL5 but promoted IL7Rα expression by ILC2s, which led to the development of steroid resistance This steroid resistance was reversed by MEK and STAT5 inhibitors.


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