Frontiers in Immunology (Feb 2021)

Cyclic-di-GMP Induces STING-Dependent ILC2 to ILC1 Shift During Innate Type 2 Lung Inflammation

  • Kellen J. Cavagnero,
  • Kellen J. Cavagnero,
  • Jana H. Badrani,
  • Luay H. Naji,
  • Michael B. Amadeo,
  • Anthea S. Leng,
  • Lee Diego Lacasa,
  • Allyssa N. Strohm,
  • Samantha R. Renusch,
  • Suzanna S. Gasparian,
  • Taylor A. Doherty,
  • Taylor A. Doherty

DOI
https://doi.org/10.3389/fimmu.2021.618807
Journal volume & issue
Vol. 12

Abstract

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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 intranasal CDG induced early airway type 1 interferon (IFN) production and dramatically suppressed CD127+ST2+ ILC2s and type 2 lung inflammation during Alternaria and IL-33 exposure. Further, CD127–ST2–Thy1.2+ lung ILCs, which showed a transcriptomic signature consistent with ILC1s, were expanded and activated by CDG combined with either Alternaria or IL-33. CDG-mediated suppression of type 2 inflammation occurred independent of IL-18R, IL-12, and STAT6 but required the stimulator of interferon genes (STING) and 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.

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