Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: The role of thymic stromal lymphopoietin.
J Allergy Clin Immunol
; 141(1): 257-268.e6, 2018 01.
Article
em En
| MEDLINE
| ID: mdl-28433687
ABSTRACT
BACKGROUND:
Type 2 innate lymphoid cells (ILC2s) represent an important type 2 immune cell. Glucocorticoid regulation of human ILC2s is largely unknown.OBJECTIVE:
We sought to assess steroid resistance of human blood and airway ILC2s from asthmatic patients and to examine its mechanism of induction.METHODS:
We studied human blood and lung ILC2s from asthmatic patients and control subjects using flow cytometry and ELISA.RESULTS:
Dexamethasone inhibited (P = .04) chemoattractant receptor-homologous molecule expressed on TH2 lymphocytes and type 2 cytokine expression by blood ILC2s stimulated with IL-25 and IL-33. However, it did not do so when ILC2s were stimulated with IL-7 and thymic stromal lymphopoietin (TSLP), 2 ligands of IL-7 receptor α. Unlike blood ILC2s, bronchoalveolar lavage (BAL) fluid ILC2s from asthmatic patients were resistant to dexamethasone. BAL fluid from asthmatic patients had increased TSLP but not IL-7 levels. BAL fluid TSLP levels correlated (r = 0.74) with steroid resistance of ILC2s. TSLP was synergistically induced in epithelial cells by IL-13 and human rhinovirus. Mechanistically, dexamethasone upregulated ILC2 expression of IL-7 receptor α, which augmented and sustained signal transducer and activator of transcription (STAT) 5 signaling by TSLP. TSLP induced mitogen-activated protein kinase kinase (MEK), c-Fos, inhibitor of DNA binding 3, phosphorylated signal transducer and activator of transcription (pSTAT) 3, and pSTAT5, molecules linked to steroid resistance. Dexamethasone inhibited c-Fos, inhibitor of DNA binding 3, and pSTAT3 but not pSTAT5 and MEK. The MEK inhibitor trametinib, the Janus kinase-STAT inhibitor tofacitinib, and the STAT5 inhibitor pimozide reversed steroid resistance of BAL ILC2s.CONCLUSIONS:
Dexamethasone inhibited type 2 cytokine production by blood ILC2s. IL-7 and TSLP abrogated this inhibition and induced steroid resistance of ILC2s in a MEK- and STAT5-dependent manner. BAL fluid ILC2s from asthmatic patients with increased TSLP levels were steroid resistant, which was reversed by clinically available inhibitors of MEK and STAT5.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Asma
/
Resistência a Medicamentos
/
Citocinas
/
Subpopulações de Linfócitos
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Imunidade Inata
Tipo de estudo:
Diagnostic_studies
/
Observational_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article