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; Renusch, Samantha; Gasparian, Suzanna; Doherty, Taylor

doi:10.3389/fimmu.2021.618807

Cited by 13 publications

(8 citation statements)

References 57 publications

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“…While the role of ILC1s in asthma remains largely unknown, ILC3s are elevated in severe asthma and IL-17 producing ILC3s were required for increased airway resistance in a mouse model of obesity-induced asthma ( 60 ). A recent report demonstrated that administration of the universal bacterial second messenger, cyclic di-GMP, skewed the response to AA from ILC2s to IFNγ-producing ILC1s ( 61 ). Therefore, it is plausible that exposure to AA in the presence of CFA may cause a shift favoring ILC1 and ILC3s in the lung microenvironment along with Th1 and Th17 cells.…”

Section: Discussionmentioning

confidence: 99%

RAGE contributes to allergen driven severe neutrophilic airway inflammation via NLRP3 inflammasome activation in mice

et al. 2023

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BackgroundAsthma is a major public healthcare burden, affecting over 300 million people worldwide. While there has been great progress in the treatment of asthma, subsets of patients who present with airway neutrophilia, often have more severe disease, and tend to be resistant to conventional corticosteroid treatments. The receptor for advanced glycation endproducts (RAGE) plays a central role in the pathogenesis of eosinophilic asthma, however, it’s role in neutrophilic asthma remains largely uninvestigated.MethodsA mouse model of severe steroid resistant neutrophilic airway disease (SSRNAD) using the common fungal allergen Alternaria alternata (AA) was employed to evaluate the effects of genetic ablation of RAGE and pharmacological inhibition of the NLRP3 inflammasome on neutrophilic airway inflammation.ResultsAA exposure induced robust neutrophil-dominant airway inflammation and increased BALF levels of Th1/Th17 cytokines in wild-type mice, which was significantly reduced in RAGE-/- mice. Serum levels of IgE and IgG1 were increased similarly in both wild-type and RAGE-/- mice. Pharmacological inhibition of NLRP3 blocked the effects of AA exposure and NLRP3 inflammasome activation was RAGE-dependent. Neutrophil extracellular traps were elevated in the BALF of wild-type but not RAGE-/- mice and an atypical population of SiglecF+ neutrophils were identified in the BALF. Lastly, time-course studies found that RAGE expression promoted sustained neutrophil accumulation in the BALF of mice in response to AA.

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Section: Discussionmentioning

confidence: 99%

RAGE contributes to allergen driven severe neutrophilic airway inflammation via NLRP3 inflammasome activation in mice

et al. 2023

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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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“…However, STING represses IL-13-induced STAT6 phosphorylation in subjects with rhinosinusitis by increasing expression of the STAT6 inhibitor SOCS1 (suppressor of cytokine signaling 1) ( Figure 3 ) ( 144 ). SOS1 induction may also underlie the observation that STING signaling in ILC2s promotes a phenotypic shift to Type 1 ILC (ILC1) during lung inflammation ( 145 ). Taken together, these studies suggest that the role of STING in type 2 immunity is complex and context dependent.…”

Section: Part 2: the Role Of Autoinflammation In Type 2 Immune Responsesmentioning

confidence: 99%

The Interactions Between Autoinflammation and Type 2 Immunity: From Mechanistic Studies to Epidemiologic Associations

2022

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Autoinflammatory diseases are a group of clinical syndromes characterized by constitutive overactivation of innate immune pathways. This results in increased production of or responses to monocyte- and neutrophil-derived cytokines such as interleukin-1β (IL-1β), Tumor Necrosis Factor-α (TNF-α), and Type 1 interferon (IFN). By contrast, clinical allergy is caused by dysregulated type 2 immunity, which is characterized by expansion of T helper 2 (Th2) cells and eosinophils, as well as overproduction of the associated cytokines IL-4, IL-5, IL-9, and IL-13. Traditionally, type 2 immune cells and autoinflammatory effectors were thought to counter-regulate each other. However, an expanding body of evidence suggests that, in some contexts, autoinflammatory pathways and cytokines may potentiate type 2 immune responses. Conversely, type 2 immune cells and cytokines can regulate autoinflammatory responses in complex and context-dependent manners. Here, we introduce the concepts of autoinflammation and type 2 immunity. We proceed to review the mechanisms by which autoinflammatory and type 2 immune responses can modulate each other. Finally, we discuss the epidemiology of type 2 immunity and clinical allergy in several monogenic and complex autoinflammatory diseases. In the future, these interactions between type 2 immunity and autoinflammation may help to expand the spectrum of autoinflammation and to guide the management of patients with various autoinflammatory and allergic diseases.

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

Cited by 13 publications

References 57 publications

RAGE contributes to allergen driven severe neutrophilic airway inflammation via NLRP3 inflammasome activation in mice

RAGE contributes to allergen driven severe neutrophilic airway inflammation via NLRP3 inflammasome activation in mice

ILC1: Development, maturation, and transcriptional regulation

The Interactions Between Autoinflammation and Type 2 Immunity: From Mechanistic Studies to Epidemiologic Associations

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