Toll-like receptor 9-dependent interferon production prevents group 2 innate lymphoid cell-driven airway hyperreactivity.
J Allergy Clin Immunol
; 144(3): 682-697.e9, 2019 09.
Article
em En
| MEDLINE
| ID: mdl-30914379
ABSTRACT
BACKGROUND:
Group 2 innate lymphoid cells (ILC2s) are important mediators of allergic asthma. Bacterial components, such as unmethylated CpG DNA, a Toll-like receptor (TLR) 9 agonist, are known to possess beneficial immunomodulatory effects in patients with T cell-mediated chronic asthma. However, their roles in regulating ILC2s remain unclear.OBJECTIVE:
We sought to determine the role of TLR9 activation in regulating ILC2 function and to evaluate the therapeutic utility of an immunomodulatory microparticle containing natural TLR9 ligand (MIS416).METHODS:
We evaluated the immunomodulatory effects of CpG A in IL-33-induced airway hyperreactivity (AHR) and airway inflammation. The roles of interferons were examined in vivo and in vitro by using signal transducer and activator of transcription 1 (Stat1)-/- mice and neutralizing antibodies against IFN-γ and IFN-α/ß receptor subunit 1, and their cellular sources were identified. The therapeutic utility of MIS416 was investigated in the Alternaria alternata model of allergic asthma and in humanized NSG mice.RESULTS:
We show that TLR9 activation by CpG A suppresses IL-33-mediated AHR and airway inflammation through inhibition of ILC2s. Activation of TLR9 leads to production of IFN-α, which drives IFN-γ production by natural killer cells. Importantly, IFN-γ is essential for TLR9-driven suppression, and IFN-α cannot compensate for impaired IFN-γ signaling. We further show that IFN-γ directly inhibits ILC2 function through a STAT1-dependent mechanism. Finally, we demonstrate the therapeutic potential of MIS416 in A alternata-induced airway inflammation and validated these findings in human subjects.CONCLUSION:
TLR9 activation alleviates ILC2-driven AHR and airway inflammation through direct suppression of cell function. Microparticle-based delivery of TLR9 ligands might serve as a therapeutic strategy for asthma treatment.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Asma
/
Linfócitos
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Interferons
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Receptor Toll-Like 9
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Animals
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Female
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Humans
/
Male
Idioma:
En
Revista:
J Allergy Clin Immunol
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Taiwan