MicroRNA-155 is a critical regulator of type 2 innate lymphoid cells and IL-33 signaling in experimental models of allergic airway inflammation

Johansson, Karin; Malmhäll, Carina; Ramos‐Ramírez, Patricia; Rådinger, Madeleine

doi:10.1016/j.jaci.2016.06.035

Cited by 98 publications

(120 citation statements)

References 46 publications

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“…However, others have reported that BM ILC2s are functional in disease models (37, 38). In view of their potential importance, we determined whether BM ILC2s showed sex differences in number, phenotype, or function.…”

Section: Resultsmentioning

confidence: 99%

“…A substantial pool of KLRG1 − ILC2s is present in the bone marrow (BM). Whereas one report suggested these cells are ILC2 precursors due to their differentiation to KLRG1 + ILC2s upon adoptive transfer (23), others have shown that BM ILC2s are an important source of type 2 cytokines and mobilized from BM during IL-33–induced inflammation (37, 38). The effects of sex hormones on the functional capacity of KLRG1 − ILC2s in the BM or lungs have not been described.…”

Section: Introductionmentioning

confidence: 99%

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A Major Population of Functional KLRG1– ILC2s in Female Lungs Contributes to a Sex Bias in ILC2 Numbers

et al. 2018

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Humans show significant sex differences in the incidence and severity of respiratory diseases, including asthma and virus infection. Sex hormones contribute to the female sex bias in type 2 inflammation associated with respiratory diseases, consistent with recent reports that female lungs harbor greater numbers of GATA-3–dependent group 2 innate lymphoid cells (ILC2s). In this study, we determined whether sex hormone levels govern sex differences in the numbers, phenotype, and function of ILC2s in the murine lung and bone marrow (BM). Our data show that lungs of female mice harbor significantly greater ILC2 numbers in homeostasis, in part due to a major subset of ILC2s lacking killer-cell lectin like receptor G1 (KLRG1), a population largely absent in male lungs. The KLRG1− ILC2s were capable of type 2 cytokine production and increased with age after sexual maturity, suggesting that a unique functional subset exists in females. Experiments with gonadectomized mice or mice bearing either global or lymphocyte restricted estrogen receptor α (Esr1) deficiency showed that androgens rather than estrogens regulated numbers of the KLRG1− ILC2 subset and ILC2 functional capacity in the lung and BM, as well as levels of GATA-3 expression in BM ILC2s. Furthermore, the frequency of BM PLZF+ ILC precursors was higher in males and increased by excess androgens, suggesting that androgens act to inhibit the transition of ILC precursors to ILC2s. Taken together, these data show that a functional subset of KLRG1− ILC2s in females contributes to the sex bias in lung ILC2s that is observed after reproductive age.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Major Population of Functional KLRG1– ILC2s in Female Lungs Contributes to a Sex Bias in ILC2 Numbers

et al. 2018

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“…In addition, miR-155 appears to be essential for the development of an eosinophil response, apparently via its capacity to inhibit expression of the transcription factor PU.1, which is a negative regulator of Th2 cytokine production [39]. Furthermore, miR-155 is strikingly up-regulated in type 2 innate lymphoid cells in response to IL-33 and appears to contribute to their expansion [40].…”

Section: Discussion/conclusionmentioning

confidence: 99%

Enhanced Pro-Inflammatory Response of Macrophages to Interleukin-33 in an Allergic Environment

Chia

Kumar

Foster

et al. 2018

Int Arch Allergy Immunol

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Background: Allergic asthma is common in childhood and is associated with a T-helper type 2 (Th2)-biased immunological response. Exacerbations of asthma are characterised by increased inflammation of the airways, which appears to be driven by interleukin (IL)-33 that can activate pulmonary macrophages. The Th2 cytokine environment of allergic asthma may contribute to exaggerated airway inflammation. Objectives: To test this, we assessed whether production of pro-inflammatory cytokines by IL-33-stimulated macrophages was enhanced in cells pre-treated with the key Th2 cytokines IL-4 and IL-13. We also investigated whether this was associated with altered expression of regulatory microRNAs (miRNAs). Methods: RAW264.7 cells cultured with IL-4 and IL-13 for 48 h were stimulated with IL-33 for 4 h. Pro-inflammatory mediators were assessed using quantitative real-time PCR (RT-PCR). Expression of miRNAs was assessed using microarrays and RT-PCR. In further experiments, we examined whether resolvin E1 (RvE1), which promotes the resolution of experimental asthmatic inflammation in vivo, could suppress the enhanced response by treating cells with RvE1 concurrently with IL-33 stimulation. Results: In cells pre-treated with IL-4 and IL-13, expression of mRNA for Ccl3, Ccl5, Ccl17, Ccl24, and Il1b in response to IL-33 stimulation was significantly increased. This was paralleled by up-regulated expression of miR-155-5p, a miRNA that is predicted to regulate several aspects of allergic inflammation. RvE1 suppressed the enhanced production of Ccl3, Ccl5, Ccl24, and Il1b. Conclusions: We conclude that IL-33-activated macrophages may contribute to the exaggerated airway inflammation in exacerbations of allergic asthma, and that RvE1 has potential as a therapeutic agent that targets macrophages.

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“…This alteration may be due to the damage induced by the Th2 response, as reduced Th2-dependent eosinophils in allergen-challenged miR-155 KO mice may be restored by the adoptive transfer of OVA-specific CD4+ Th2 cells from OVA-sensitized WT mice [45]. Most recently, a novel mechanism was proposed that miR-155 acts as a key positive regulator in allergen-induced inflammation via type 2 innate lymphoid cell (ILC2s, previously known as natural helper cells) and IL-33 [50]. ILC2s are a type of Th2 cytokine producing cells in airway mucosa [51].…”

Section: The Role Of Mir-155 In Asthmamentioning

confidence: 99%

miR-155: A Novel Target in Allergic Asthma

Zhou

Gao

et al. 2016

IJMS

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MicroRNAs (miRNAs), a class of small non-coding RNAs of 18–24 nucleotides in length, function to posttranscriptionally regulate protein expression. miR-155 was one of the first identified and, to date, the most studied miRNA, and has been linked to various cellular processes such as modulation of immune responses and oncogenesis. Previous studies have identified miR-155 as a crucial positive regulator of Th1 immune response in autoimmune diseases, but as a suppressor of Th2 immunity in allergic disorders. However, recent studies have found new evidence that miR-155 plays an indispensible role in allergic asthma. This review summarizes the recent findings with respect to miR-155 in immune responses and the underlying mechanisms responsible for miR-155-related allergic diseases, as well as the similarities between miR-155 and glucocorticoids in immunity.

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MicroRNA-155 is a critical regulator of type 2 innate lymphoid cells and IL-33 signaling in experimental models of allergic airway inflammation

Abstract: Our findings for the first time demonstrate that ILC2s and IL-33 signaling are regulated by miR-155 in allergic airway inflammation.

Cited by 98 publications

References 46 publications

A Major Population of Functional KLRG1– ILC2s in Female Lungs Contributes to a Sex Bias in ILC2 Numbers

A Major Population of Functional KLRG1– ILC2s in Female Lungs Contributes to a Sex Bias in ILC2 Numbers

Enhanced Pro-Inflammatory Response of Macrophages to Interleukin-33 in an Allergic Environment

miR-155: A Novel Target in Allergic Asthma

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