Department of Medicine, University of California, San Diego, La Jolla, CA, United States.
Department of Dermatology, University of California, San Diego, La Jolla, CA, United States.
Front Immunol. 2021 Feb 18;12:618807. doi: 10.3389/fimmu.2021.618807. eCollection 2021.
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 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 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.
2 型炎症存在于大多数哮喘形式中，可能与反复的病毒感染、细菌定植和宿主细胞死亡共存。这些过程会导致细胞内环二核苷酸（如环二鸟苷酸（CDG））的积累。在小鼠真菌过敏原暴露期间，2 型先天淋巴细胞（ILC2）是 2 型肺部炎症的关键驱动因素；然而，CDG 如何在肺部炎症期间调节肺 ILC 反应尚不清楚。在这里，我们表明，鼻内 CDG 诱导早期气道 1 型干扰素（IFN）产生，并在 和 IL-33 暴露期间显著抑制 CD127+ST2+ILC2 和 2 型肺部炎症。此外，CD127-ST2-Thy1.2+肺 ILCs 表现出与 ILC1 一致的转录组特征，通过 CDG 与 或 IL-33 联合扩增和激活。CDG 介导的 2 型炎症抑制与 IL-18R、IL-12 和 STAT6 无关，但需要干扰素基因刺激物（STING）和 1 型 IFN 信号。因此，CDG 强烈抑制 ILC2 驱动的肺部炎症并促进 ILC1 反应。这些结果表明，STING 的潜在治疗调节可能抑制呼吸道感染期间的 2 型炎症和/或增加抗病毒反应。
