STING activation in alveolar macrophages and group 2 innate lymphoid cells suppresses IL-33–driven type 2 immunopathology
| Title: | STING activation in alveolar macrophages and group 2 innate lymphoid cells suppresses IL-33–driven type 2 immunopathology |
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| Authors: | Li She, Gema D. Barrera, Liping Yan, Hamad H. Alanazi, Edward G. Brooks, Peter H. Dube, Yilun Sun, Hong Zan, Daniel P. Chupp, Nu Zhang, Xin Zhang, Yong Liu, Xiao-Dong Li |
| Source: | JCI Insight, Vol 6, Iss 3 (2021) |
| Publisher Information: | American Society for Clinical investigation, 2021. |
| Publication Year: | 2021 |
| Collection: | LCC:Medicine |
| Subject Terms: | Immunology, Inflammation, Medicine |
| More Details: | 2′3′-cGAMP is known as a nonclassical second messenger and small immune modulator that possesses potent antitumor and antiviral activities via inducing the stimulator of IFN genes–mediated (STING-mediated) signaling pathway. However, its function in regulating type 2 immune responses remains unknown. Therefore, 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 hyperreactivity induced by IL-33 and a fungal allergen, Aspergillus flavus. Mechanistically, upon the respiratory delivery, 2′3′-cGAMP was mainly internalized by alveolar macrophages, in which it activated the STING/IFN regulatory factor 3/type I IFN signaling axis to induce the production of inhibitory factors containing IFN-α, which blocked the IL-33–mediated activation of group 2 innate lymphoid (ILC2) cells in vivo. We further demonstrated that 2′3′-cGAMP directly suppressed the proliferation and function of both human and mouse ILC2 cells 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2379-3708 |
| Relation: | https://doaj.org/toc/2379-3708 |
| DOI: | 10.1172/jci.insight.143509 |
| Access URL: | https://doaj.org/article/db14a51abcf04de99bf76b9d52c62425 |
| Accession Number: | edsdoj.b14a51abcf04de99bf76b9d52c62425 |
| Database: | Directory of Open Access Journals |
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