STING activation in alveolar macrophages and group 2 innate lymphoid cells suppresses IL-33–driven type 2 immunopathology
| Autor: | Liping Yan, Gema D. Barrera, Peter H. Dube, Daniel P. Chupp, Hamad H. Alanazi, Xiao Dong Li, Nu Zhang, Xin Zhang, Edward G. Brooks, Yilun Sun, Yong Liu, Hong Zan, Li She |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Allergy Immunology Inflammation Mice Transgenic Biology In Vitro Techniques 03 medical and health sciences Mice 0302 clinical medicine Immune system Immunopathology Eosinophilia Macrophages Alveolar medicine Animals Humans Lymphocytes Mice Knockout Innate immunity Innate immune system Innate lymphoid cell Membrane Proteins General Medicine Allergens Interleukin-33 Asthma Guanine Nucleotides Immunity Innate Interleukin 33 Mice Inbred C57BL Sting Disease Models Animal 030104 developmental biology 030220 oncology & carcinogenesis Medicine Female medicine.symptom Signal transduction Aspergillus flavus Signal Transduction Research Article |
| Zdroj: | JCI Insight, Vol 6, Iss 3 (2021) JCI Insight |
| ISSN: | 2379-3708 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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