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ResearchIn-Press PreviewImmunologyInflammation Open Access | 10.1172/jci.insight.143509

STING activation in alveolar macrophages and group 2 innate lymphoid cells suppresses IL-33-driven type 2 immunopathology

Li She,1 Gema D. Barrera,1 Liping Yan,1 Hamad Hazzaa Alanazi,1 Edward G. Brooks,2 Peter H. Dube,1 Yilun Sun,1 Hong Zan,1 Daniel P. Chupp,1 Nu Zhang,1 Xin Zhang,3 Yong Liu,3 and Xiao-Dong Li1

1Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health San Antonio, San Antonio, United States of America

2Division of Immunology and Infectious Disease, University of Texas Health San Antonio, San Antonio, United States of America

3Department of Otolaryngology - Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China

Find articles by She, L. in: JCI | PubMed | Google Scholar

1Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health San Antonio, San Antonio, United States of America

2Division of Immunology and Infectious Disease, University of Texas Health San Antonio, San Antonio, United States of America

3Department of Otolaryngology - Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China

Find articles by Barrera, G. in: JCI | PubMed | Google Scholar

1Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health San Antonio, San Antonio, United States of America

2Division of Immunology and Infectious Disease, University of Texas Health San Antonio, San Antonio, United States of America

3Department of Otolaryngology - Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China

Find articles by Yan, L. in: JCI | PubMed | Google Scholar |

1Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health San Antonio, San Antonio, United States of America

2Division of Immunology and Infectious Disease, University of Texas Health San Antonio, San Antonio, United States of America

3Department of Otolaryngology - Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China

Find articles by Alanazi, H. in: JCI | PubMed | Google Scholar |

1Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health San Antonio, San Antonio, United States of America

2Division of Immunology and Infectious Disease, University of Texas Health San Antonio, San Antonio, United States of America

3Department of Otolaryngology - Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China

Find articles by Brooks, E. in: JCI | PubMed | Google Scholar |

1Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health San Antonio, San Antonio, United States of America

2Division of Immunology and Infectious Disease, University of Texas Health San Antonio, San Antonio, United States of America

3Department of Otolaryngology - Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China

Find articles by Dube, P. in: JCI | PubMed | Google Scholar

1Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health San Antonio, San Antonio, United States of America

2Division of Immunology and Infectious Disease, University of Texas Health San Antonio, San Antonio, United States of America

3Department of Otolaryngology - Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China

Find articles by Sun, Y. in: JCI | PubMed | Google Scholar

1Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health San Antonio, San Antonio, United States of America

2Division of Immunology and Infectious Disease, University of Texas Health San Antonio, San Antonio, United States of America

3Department of Otolaryngology - Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China

Find articles by Zan, H. in: JCI | PubMed | Google Scholar |

1Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health San Antonio, San Antonio, United States of America

2Division of Immunology and Infectious Disease, University of Texas Health San Antonio, San Antonio, United States of America

3Department of Otolaryngology - Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China

Find articles by Chupp, D. in: JCI | PubMed | Google Scholar

1Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health San Antonio, San Antonio, United States of America

2Division of Immunology and Infectious Disease, University of Texas Health San Antonio, San Antonio, United States of America

3Department of Otolaryngology - Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China

Find articles by Zhang, N. in: JCI | PubMed | Google Scholar

1Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health San Antonio, San Antonio, United States of America

2Division of Immunology and Infectious Disease, University of Texas Health San Antonio, San Antonio, United States of America

3Department of Otolaryngology - Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China

Find articles by Zhang, X. in: JCI | PubMed | Google Scholar

1Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health San Antonio, San Antonio, United States of America

2Division of Immunology and Infectious Disease, University of Texas Health San Antonio, San Antonio, United States of America

3Department of Otolaryngology - Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China

Find articles by Liu, Y. in: JCI | PubMed | Google Scholar |

1Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health San Antonio, San Antonio, United States of America

2Division of Immunology and Infectious Disease, University of Texas Health San Antonio, San Antonio, United States of America

3Department of Otolaryngology - Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China

Find articles by Li, X. in: JCI | PubMed | Google Scholar |

Published January 5, 2021 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.143509.
Copyright © 2021, She et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 5, 2021 - Version history
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Abstract

2'3'-cGAMP is known as a non-classical 2nd messenger and small immune modulator that possesses potent anti-tumor and antiviral activities through stimulating STING-mediated signaling pathway. However, its function in regulating type 2 immune responses remains unknown. We sought to determine a role of STING activation by 2'3'-cGAMP in type 2 inflammatory reactions in multiple mouse models of eosinophilic asthma. We discovered that 2'3'-cGAMP administration strongly attenuated type 2 lung immunopathology and airway hyperresponsiveness (AHR) induced by IL-33 and a fungal allergen, A. flavus. Mechanistically, upon the respiratory delivery, 2'3'-cGAMP was mainly internalized by alveolar macrophages, in which it activated the STING-IRF3-IFN-I signaling axis to induce the production of inhibitory factors containing IFNα, which blocked the IL-33-mediated activation of group 2 innate lymphoid cells (ILC2) in vivo. We further demonstrated that 2'3'-cGAMP directly suppressed the proliferation and function of both human and mouse ILC2 in vitro. Taken together, our findings suggest that STING activation by 2'3'-cGAMP in alveolar macrophages and ILC2 cells can negatively regulate type 2 immune responses, implying that the respiratory delivery of 2'3'-cGAMP might be further developed as an alternative strategy for treating type 2 immunopathologic diseases such as eosinophilic asthma.

Supplemental material

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Version history
  • Version 1 (January 5, 2021): In-Press Preview
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