PT  - JOURNAL ARTICLE
AU  - Kellen J. Cavagnero
AU  - Jana H. Badrani
AU  - Luay H. Naji
AU  - Michael B. Amadeo
AU  - Anthea S. Leng
AU  - Lee Diego Lacasa
AU  - Allyssa N. Strohm
AU  - Taylor A. Doherty
TI  - Cyclic-di-GMP induces STING-dependent ILC2 to ILC1 shift during innate type 2 lung inflammation
AID  - 10.1101/2020.10.19.345850
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.10.19.345850
4099  - http://biorxiv.org/content/early/2020/10/19/2020.10.19.345850.short
4100  - http://biorxiv.org/content/early/2020/10/19/2020.10.19.345850.full
AB  - Type 2 inflammation is found in most forms of asthma, which may co-exist with recurrent viral infections, 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 type 2 lung inflammation during fungal allergen exposure in mice; however, it is unclear how CDG regulates lung ILC responses during lung inflammation. Here, we show that CDG induced early airway type 1 interferon (IFN) production and dramatically suppressed both lung proliferating CD127+ST2+ ILC2s and Alternaria- and IL-33-induced lung inflammation. Further, transcriptomic analysis of CD127−ST2− Thy1.2+ ILCs, which were expanded and activated by CDG, revealed an ILC1 signature. CDG administration led to accumulation of IFNγ+ and T-bet+ ILC1s, as well as neutrophilia, independent of IL-18R, IL-12, and STAT6 but dependent on stimulator of interferon genes (STING) and partially dependent on type 1 IFN signaling. Thus, CDG potently suppresses ILC2-driven lung inflammation and promotes ILC1 responses. These results suggest potential therapeutic modulation of STING to suppress type 2 inflammation and/or increase anti-viral responses during respiratory infections.Competing Interest StatementThe authors have declared no competing interest.(ILC)Innate lymphoid cell(ILC2)group 2 innate lymphoid cell(ILC1)group 1 innate lymphoid cell(Alternaria alternata)Alt(CDN)cyclic-di-nucleotide(CDG)cyclic-di-GMP(STING)stimulator of interferon genes(IFN)interferon(BAL)bronchoalveolar lavage