OASL1-Mediated Inhibition of Type I IFN Reduces Influenza A Infection-Induced Airway Inflammation by Regulating ILC2s

Yuna Chang, Ji Seon Kang, Keehoon Jung, Doo Hyun Chung, Sang Jun Ha, Young Joon Kim, Hye Young Kim

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Three observations drove this study. First, 2'-5'-oligoadenylate synthetase-like protein (OASL) is a negative regulator of type I interferon (IFN). Second, type I IFN plays a central role during virus infections and the pathogenesis of various diseases, including asthma. Third, influenza A virus (IAV) causes non-eosinophilic asthma. To evaluate the potential relationships between OASL, type I IFN, and pulmonary innate immune cells in IAV-induced acute airway inflammation by using Oasl1-/- mice. Methods: Asthma was induced in wild-type (WT) and Oasl1-/- mice with IAV or ovalbumin (OVA). Airway hyperreactivity (AHR) and immune cell infiltration in the bronchoalveolar lavage (BAL) fluids were measured. The immune cells in the lungs were analyzed by flow cytometry. To investigate the ability of type I IFN to shape the response of lung type 2 innate lymphoid cells (ILC2s), IFN-α was treated intratracheally. Plasmacytoid dendritic cells (pDCs) sorted from bone marrow and ILC2s sorted from lungs of naive mice were co-cultured with/without interferon-alpha receptor subunit 1 (IFNAR-1)-blocking antibodies. Results: In the IAV-induced asthma model, Oasl1-/- mice developed greater AHR and immune cell infiltration in the BAL fluids than WT mice. This was not observed in OVA-induced asthma, a standard model of allergen-induced asthma. The lungs of infected Oasl1-/- mice also had elevated DC numbers and Ifna expression and depressed IAV-induced ILC2 responses, namely, proliferation and type 2 cytokine and amphiregulin production. Intratracheal administration of type I IFN in naïve mice suppressed lung ILC2 production of type 2 cytokines and amphiregulin. Co-culture of ILC2s with pDCs showed that pDCs inhibit the function of ILC2s by secreting type I IFN. Conclusions: OASL1 may impede the IAV-induced acute airway inflammation that drives AHR by inhibiting IAV-induced type I IFN production from lung DCs, thereby preserving the functions of lung ILC2s, including their amphiregulin production.

Original languageEnglish
Pages (from-to)99-116
Number of pages18
JournalAllergy, Asthma and Immunology Research
Volume14
Issue number1
DOIs
Publication statusPublished - 2022 Jan

Bibliographical note

Funding Information:
This study was supported by grants from the National Research Foundation of Korea (SRC 2017R1A5A1014560 and NRF-2019R1A2C2087574). Y.C. and J.S.K. designed, and performed the experiments. K.J, D.H.C, S.J.H, Y.J.K contributed to the interpretation of the results. Y.C, and H.Y.K. wrote the manuscript. Y.J.K and H.Y.K. supervised the project. The authors declare that they have no competing interests.

Publisher Copyright:
© 2022 The Korean Academy of Asthma.

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Pulmonary and Respiratory Medicine

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