STING activation in alveolar macrophages and group 2 innate lymphoid cells suppresses IL-33–driven type 2 immunopathology
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
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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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 6

The inhibitory effect of 2′3′-cGAMP is mediated by the type I IFN signaling pathway.

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The inhibitory effect of 2′3′-cGAMP is mediated by the type I IFN signal...
(A) Induction of IFN-α protein after administration of 2′3′-cGAMP at 5, 10, and 20 μg/mouse for 24 hours. The mouse lungs from WT mice were processed for the ELISA measurement. (B) BM-DCs and alveolar macrophages derived from WT and IFNAR1–/– mice were treated with 2′3′-cGAMP. Then, the expression of a costimulatory molecule CD40 was analyzed by FACS. (C) Groups of IFNAR1–/– and WT mice were treated with PBS, 2′3′-cGAMP, IL-33, or IL-33 + 2′3′-cGAMP as indicated. BALF was collected and analyzed for differential immune cell types. In contrast to WT mice, administration of 2′3′-cGAMP into IFNAR1–/– mice did not significantly change number of airway eosinophils after exposure to IL-33. (D) Administration of 2′3′-cGAMP in IFNAR1–/– mice did not significantly decrease the percentage and number of lung eosinophils after exposure to IL-33. (E) Similar to C, the number and percentage of IL-5+IL-13+ double-positive ILC2 cells in lungs of IFNAR1–/– mice were analyzed (n = 3–7 per group as indicated with open circles, a P value of greater than or equal to 0.05 was not considered significant [NS], Student’s unpaired t test, *P < 0.05, **P < 0.01, ***P < 0.001).