Toll-like receptor 9–dependent interferon production prevents group 2 innate lymphoid cell–driven airway hyperreactivity

Thio, Christina Li‐Ping; Lai, Alan Chuan‐Ying; Chi, Po‐Yu; Webster, Gill; Chang, Ya‐Jen

doi:10.1016/j.jaci.2019.03.008

Cited by 38 publications

(31 citation statements)

References 69 publications

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“…For this reason, we focused here on an HDM-dependent and TLR9-driven mechanism for suppressing the airway and lung inflammation triggered by Th2 cells. This differs from previous studies that have investigated the suppressive role of TLR9 agonists 18,19 .…”

Section: Discussioncontrasting

confidence: 71%

TLR9–IL-2 axis exacerbates allergic asthma by preventing IL-17A hyperproduction

Murakami

Ishii

Nunokawa

et al. 2020

Sci Rep

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Allergic asthma is one of most famous allergic diseases, which develops lung and airway inflammation. Recent studies have revealed the relationship between the pathology of allergic asthma and the increase of host-derived DNA in inflamed lung, but the role of the DNA-recognizing innate immune receptor for the inflammation is unknown well. Here we investigated the role of Toll-Like Receptor 9 in the pathogenesis of allergic asthma without synthesized CpG-ODNs. To examine that, we analyzed the pathology and immunology of house-dust-mite (HDM)-induced allergic asthma in Tlr9–/– mice and TLR9-inhibitory-antibody-treated mice. In Tlr9–/– mice, airway hyperresponsiveness (AHR) and the number of eosinophils decreased, and production of the Th2 cytokines IL-13, IL-5, and IL-4 was suppressed, compared with in wild-type mice. Interestingly, unlike Th2 cytokine production, IL-17A production was increased in Tlr9–/– mice. Furthermore, production of IL-2, which decreases IL-17A production, was reduced in Tlr9–/– mice. Blockade of TLR9 by treatment with TLR9-inhibitory-antibody, NaR9, effectively suppressed the development of allergic asthma pathology. IL-17A production in NaR9-treated mice was enhanced, which is comparable to Tlr9-/- mice. These results suggest that the TLR9–IL-2 axis plays an important role in Th2 inflammation by modulating IL-17A production in HDM-induced allergic asthma and that targeting of TLR9 might be a novel therapeutic method for allergic asthma.

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Section: Discussioncontrasting

confidence: 71%

TLR9–IL-2 axis exacerbates allergic asthma by preventing IL-17A hyperproduction

Murakami

Ishii

Nunokawa

et al. 2020

Sci Rep

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“…As another potentially regulatory cytokine, the suppressive function of TGF-β on the cytokine secretion of human ILC2s has been discussed, though controversially (80,83), with the implication that its described inhibitory effects on ILC2s are dependent on experimental conditions, such as cytokine concentrations and stimulation protocols. Despite IL-10, IL-27 and potentially also TGF-β, type-I interferons and IFN-γ were able to efficiently regulate ILC2 activity in the murine ILC2s in vitro and in vivo (50,84,85,131,153). Although the translation of these data into the human system still remains incomplete, the impact of the type-I interferons IFN-α and IFN-β on the activation of regulatory pathways and the downregulation of type-2 cytokine production could successfully be confirmed for human ILC2s, respectively (84,85).…”

Section: Soluble Modulators Of Human Ilc2smentioning

confidence: 99%

“…This was further expanded by the description of the neuropeptides neuromedin U and calcitonin gene-related peptide (CGRP) as efficient positive and negative regulators of murine ILC2s, respectively (162)(163)(164)(165). Furthermore, exogenous mediators, including, for example, bacterial products upon infection (153), have been suggested to alter murine ILC2 activity. To serve as potential therapeutic targets, however, translation of these results into the human system and deeper research on the behavior of human ILC2s is mandatory.…”

Section: Soluble Modulators Of Human Ilc2smentioning

confidence: 99%

Regulation of Human Innate Lymphoid Cells in the Context of Mucosal Inflammation

2020

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Since their identification as a unique cell population, innate lymphoid cells (ILCs) have revolutionized our understanding of immune responses, leaving their impact on multiple inflammatory and fibrotic pathologies without doubt. Thus, a tightly controlled regulation of local ILC numbers and their activity is of crucial importance. Even though this has been extensively studied in murine ILCs in the last few years, our knowledge of human ILCs is still lagging behind. Our review article will therefore summarize recent insights into the function of human ILCs and will particularly focus on their regulation under inflammatory conditions. The quality and intensity of ILC involvement into local immune responses at mucosal sites of the human body can potentially be modulated via three different axes: (1) activation of tissue-resident mature ILCs, (2) plasticity and local transdifferentiation of specific ILC subsets, and (3) tissue migration and accumulation of peripheral ILCs. Despite a still ongoing scientific effort in this field, already existing data on the fate of human ILCs under different pathologic conditions clearly indicate that all three of these mechanisms are of relevance for the clinical course of chronic inflammatory and autoimmune diseases and might likewise provide new target structures for future therapeutic strategies.

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“…30,31 Indeed, several studies demonstrated that pDC-derived IFN negatively regulates ILC2 cells in murine asthma models. [32][33][34] Furthermore, DCs are critical to activate Th2 responses during ongoing airway inflammation. 35 In a model of papain-induced lung inflammation, one study demonstrated that ILC2-derived IL-13 activates CD11b + CD103 À lung DCs to produce the chemokine CCL17, promoting the recruitment of CCR4 + memory Th2 cells to the lung.…”

Section: Dendritic Cellsmentioning

confidence: 99%