Cyclic-Di-GMP promotes STING-dependent ILC2 to ILC1 shift and abrogates eosinophilia in ILC2-driven lung inflammation

Abstract

Asthma has been associated with viral infection, bacterial colonization, and host cell death. These processes drive the accumulation of intracellular cyclic-di-nucleotides such as cyclic-di-GMP (CDG). Group 2 innate lymphoid cells (ILC2s) are critical drivers of experimental models of asthma; however, it is unclear how CDG regulates innate type 2 inflammation. In this study, we sought to determine whether CDG modulates ILC2-driven allergic responses. WT and genetically modified mice were challenged intranasally with the clinically relevant fungal allergen Alternaria alternata, with and without CDG, daily for 3 days. One day following the final challenge, lungs and brochoalveolar lavage fluid were harvested for flow cytometric analysis and ELISA. ILCs were identified by flow cytometry as CD45+Lineage−Thy1.2+ lymphocyte-sized cells and were further separated into ST2+CD127+ ILC2s and ST2−CD127− ILC1s. Finally, intracellular staining for ILC cytokine and transcription factors was performed. CDG induced STING-dependent early type 1 and 3 interferon (IFN) production and significantly suppressed lung ILC2s and airway eosinophilia. Further, CDG administration led to the expansion of Tbet+IFNγ+ ILC1s and airway neutrophil accumulation, through IL-18-, IL-12-, and STAT6-independent mechanisms. CDG is a strong immunomodulator of innate type 2 airway inflammation and activity through STING could potentially be used as a strategy to reduce ILC2-driven inflammation.