Inhibition of Acute Type-2 Lung Inflammation by 2′3′-cyclic Guanosine Monophosphate-Adenosine Monophosphate (2′3′-cGAMP)

Abstract 2′3′-cGAMP is known as a novel non-classical 2nd messenger synthesized by the novel DNA sensor cyclic GMP-AMP synthase (cGAS) in response to cytosolic invasion of DNA-containing microorganisms in mammalian cells. 2′3′-cGAMP possess potent anti-tumor, antiviral and immune adjuvant effects via the STING-mediated signaling pathway. However, its function in modulating type-2 immune responses remains unclear. In this report, we investigated the role of 2′3′-cGAMP in regulating type-2 inflammatory reactions in a mouse model of allergic asthma. We demonstrate that 2′3′-cGAMP strongly inhibits both IL-33 and allergen-driven acute type-2 lung inflammation and airway hyperresponsiveness. Mechanistically, we demonstrate that 2′3′-cGAMP treatment inhibits the proliferation and function of group 2 innate lymphoid cells (ILC2) through an IFNAR1-dependent mechanism. We further show that internalization of 2′3′-cGAMP by alveolar macrophages activates STING-IRF3 signaling to induce the production of IFNα in mouse lungs. Taken together, our results present a proof-of-concept evidence to support a therapeutic value of 2′3′-cGAMP in preventing acute lung inflammation in a mouse model of allergic asthma.