Cyclic-di-GMP induces STING-dependent ILC2 to ILC1 shift during innate type 2 lung inflammation

Cavagnero, Kellen; Badrani, Jana; Naji, Luay H.; Amadeo, Michael; Leng, Anthea; Lacasa, Lee; Strohm, Allyssa; Doherty, Taylor

doi:10.1101/2020.10.19.345850

Cited by 3 publications

(2 citation statements)

References 53 publications

(54 reference statements)

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“…The relevance of innate lymphocytes such as ILC1s may be more apparent in the advent of zoonoses as has recently occurred in the SARS-CoV-2 pandemic. [100,101]. Thus, in instances where immunological memory is absent, ILC1s may serve as first-line responders to curb viral spread and alert other immune cells.…”

Section: Discussionmentioning

confidence: 99%

ILC1: Development, maturation, and transcriptional regulation

Taggenbrock

Gisbergen

2022

Eur J Immunol

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Type 1 Innate Lymphoid cells (ILC1s) are tissue-resident cells that partake in the regulation of inflammation and homeostasis. A major feature of ILC1s is their ability to rapidly respond after infections. The effector repertoire of ILC1s includes the pro-inflammatory cytokines IFN-γ and TNF-α and cytotoxic mediators such as granzymes, which enable ILC1s to establish immune responses and to directly kill target cells. Recent advances in the characterization of ILC1s have considerably furthered our understanding of ILC1 development and maintenance in tissues. In particular, it has become clear how ILC1s operate independently from conventional natural killer cells, with which they share many characteristics. In this review, we discuss recent developments with regards to the differentiation, polarization, and effector maturation of ILC1s. These processes may underlie the observed heterogeneity in ILC1 populations within and between different tissues. Next, we highlight transcriptional programs that control each of the separate steps in the differentiation of ILC1s. These transcriptional programs are shared with other tissue-resident type-1 lymphocytes, such as tissue-resident memory T cells (T RM ) and invariant natural killer T cells (iNKT), highlighting that ILC1s utilize networks of transcriptional regulation that are conserved between lymphocyte lineages to respond effectively to tissue-invading pathogens.

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Section: Discussionmentioning

confidence: 99%

ILC1: Development, maturation, and transcriptional regulation

Taggenbrock

Gisbergen

2022

Eur J Immunol

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“…We thank Dr. Hal Hoffman and Dr. Nunzio Bottini for the Il18r1-/-and Red5 mice, respectively. We would also like to thank Cody Fine and Jesus Olvera of the UCSD Human Embryonic Stem Cell Core for help with cell sorting as well as bioRxiv for hosting a preprint of this manuscript (57).…”

Section: Data Analysis and Statisticsmentioning

confidence: 99%

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

et al. 2021

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

She¹,

Barrera²,

Yan³

et al. 2021

JCI Insight

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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.

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Cyclic-di-GMP induces STING-dependent ILC2 to ILC1 shift during innate type 2 lung inflammation

Cited by 3 publications

References 53 publications

ILC1: Development, maturation, and transcriptional regulation

ILC1: Development, maturation, and transcriptional regulation

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

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

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