Abstract
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.
Highlights
Group 2 innate lymphoid cells (ILC2s) were identified in 2010 and have since been recognized for their essential role in orchestrating innate type 2 immune responses in murine asthma models [1,2,3]
In light of the CDG-induced shift from an group 2 innate lymphoid cell (ILC2) to group 1 innate lymphoid cell (ILC1) response and recent reports of Innate lymphoid cell (ILC) plasticity [27, 30], we further investigated the impact of CDG on ILC identity, activation, FIGURE 2 | CDG induces ILC2 to ILC1 compartmental changes
Given the robust airway IFN accumulation induced by CDG, we investigated whether stimulator of interferon genes (STING) was required for suppression of type 2 lung inflammation and ILC2 responses
Summary
Group 2 innate lymphoid cells (ILC2s) were identified in 2010 and have since been recognized for their essential role in orchestrating innate type 2 immune responses in murine asthma models [1,2,3]. Insights into asthma pathogenesis have revealed associations with bacterial colonization [5], viral infections [6], as well as inappropriate cell death and mitochondrial stress [7]. These processes drive accumulation of cyclic-di-nucleotide danger signals inside of host cells [8]. CDG has been shown to induce robust type 1 and type 3 interferons (IFN) that are critical for anti-viral responses [16,17,18]
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