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

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.