STING activation in alveolar macrophages and group 2 innate lymphoid cells suppresses IL-33–driven type 2 immunopathology
Li She, … , Yong Liu, Xiao-Dong Li
Li She, … , Yong Liu, Xiao-Dong Li
Published January 5, 2021
Citation Information: JCI Insight. 2021;6(3):e143509. https://doi.org/10.1172/jci.insight.143509.
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Research Article Immunology Inflammation

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

Abstract

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.

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

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Figure 3

2′3′-cGAMP inhibits ILC2 cell activation and proliferation induced by IL-33 and A. flavus in WT or IL-13 reporter mice.

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2′3′-cGAMP inhibits ILC2 cell activation and proliferation induced by IL...
(A) Experimental protocol showing the animal groups (IL-13-eGFP+ and WT), the corresponding treatment regimen and timeline. (B) The heterozygous IL-13-eGFP+ mice were treated with PBS, 2′3′-cGAMP, IL-33, or IL-33 + 2′3′-cGAMP. Lung single cell suspensions were prepared and the number of ILC2 cells in lungs were analyzed. In addition, lung cells were stimulated with phorbol 12-myristate 13-acetate in cultures as described in the Methods. The percentage of IL-5+IL-13+ double-positive ILC2 cells in lungs was analyzed (n = 2–6 per group as indicated with open circles). (C) Similar to B, instead, WT mice were used (n = 3–4 per group as indicated with open circles). (D) Similar to C, instead of IL-33, WT mice were treated with A. flavus (n = 3–8 per group as indicated with open circles). For A–D, a P value of less than 0.05 was considered significant using unpaired Student’s t test. **P < 0.01, ***P < 0.001, ****P < 0.0001. (E) WT mice were treated with PBS, 2′3′-cGAMP, IL-33, or IL-33 + 2′3′-cGAMP. The lung ILC2 cells were analyzed with Ki-67 staining and isotype antibody. The result is representative of 2 independent experiments.