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

Li She,Edward G Brooks,Liping Yan,Daniel P Chupp,Yilun Sun,Hong Zan,Nu Zhang,Yong Liu,Peter H Dube,Hamad H Alanazi,Xiao-Dong Li,Xin Zhang,Gema D Barrera

doi:10.1172/jci.insight.143509

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.

Highlights

Asthma is a chronic condition of airway inflammation characterized by the recurrent episodes of airway obstruction and wheezing
It is unclear whether other innate immune stimuli such as 2′3′-cGAMP can regulate type 2 immunity through targeting ILC2 cells. 2′3′-cGAMP was discovered as a nonclassical second messenger synthesized by the novel DNA sensor cyclic GMP-AMP synthase in response to invasion of cytosolic DNA when mammalian cells are infected by DNA viruses and intracellular bacteria [18,19,20]. 2′3′-cGAMP exclusively binds and robustly activates stimulator of IFN genes (STING), which subsequently recruits the kinase TBK1 to trigger a signaling cascade leading to the production of type I IFN (IFN-I)
We reveal an important role for 2′3′-cGAMP in negatively regulating type 2 inflammation induced by IL-33, a fungal allergen, and house dust mite extract (HDM)

Summary

Introduction

Asthma is a chronic condition of airway inflammation characterized by the recurrent episodes of airway obstruction and wheezing. Recent studies have shown that microbial ligands, including unmethylated CpG-DNA, can activate the corresponding innate immune responses to attenuate eosinophilic inflammation via inhibiting ILC2 cell function in mouse models of asthma [15,16,17]. It is unclear whether other innate immune stimuli such as 2′3′-cGAMP can regulate type 2 immunity through targeting ILC2 cells. Our results identify an innate immune-driven mechanism for the 2′3′-cGAMP/STING/IFN-I signaling in regulating ILC2 cell function and show the potential development of this new mammalian cyclic dinucleotide for the prevention and treatment of eosinophilic asthma

Results

Discussion

Findings

Methods