Background: Over the past decade, there has been increasing interest and research into understanding the type 2 immune responses by the epithelium-derived cytokines interleukin (IL) 33, IL-25, and thymic stromal lymphopoietin. Innate lymphoid cells (ILC) are a unique family of effector immune cells that functionally resemble T cells but lack clonal distributed antigen receptors. Group 2 ILCs, ILC2s, are known for their capability to secrete proallergic cytokines, including IL-5 and IL-13. ILC2s are enriched at mucosal barriers in lung, gut, and skin, and their activation has been associated with a variety of allergic disorders. Objective: To study the role of ILC2 in different allergic disorders, including allergic rhinitis, asthma, atopic dermatitis, and food allergies. Methods: A MEDLINE search was performed for articles that reported on ILC2 in allergic disorders, including allergic rhinitis, asthma, atopic dermatitis, and food allergies. Results: A review of the literature revealed an important role of ILC2 in various allergic disorders. Conclusion: Identification of ILC2s in patients with allergic rhinitis, asthma, and atopic dermatitis indicates that these cells may represent a new therapeutic target. In this review, we discussed the current understanding of ILC2 biology and its function and regulation in various allergic diseases.
Background: Asthma is a complicated chronic inflammatory disorder characterized by airway inflammation and bronchial hyperresponsiveness. Group 2 innate lymphoid cells (ILC2) are tissue-resident innate effector cells that can mediate airway inflammation and hyperresponsiveness through production of IL-5, IL-13 and VEGFA. ILC2 in asthma patients exhibit an activated phenotype. However, molecular pathways that control ILC2 activation are not well understood.Methods: MYC expression was examined in ILC2 sorted from peripheral blood of healthy controls and asthma patients or cultured with or without activating cytokines. CRISPR knockout technique was used to delete c-Myc in primary murine lung ILC2 or an ILC2 cell line. Cell proliferation was examined, gene expression pattern was profiled by genome-wide microarray analysis, and direct gene targets were identified by Chromatin immunoprecipitation (ChIP). ILC2 responses, airway inflammation and airway hyperresponsiveness were examined in Balb/c mice challenged with Alternaria extracts, with or without treatment with JQ1. Results: ILC2 from asthma patients expressed increased amounts of MYC. Deletion of c-Myc in ILC2 results in reduced proliferation, decreased cytokine production, and reduced expression of many lymphocyte activation genes. ChIP identified Stat6 as a direct gene target of c-Myc in ILC2. In vivo inhibition of c-Myc by JQ1 treatment repressed ILC2 activity and suppressed Alternaria-induced airway inflammation and AHR. Conclusion: c-Myc expression is upregulated during ILC2 activation. c-Myc is essential for ILC2 activation and their in vivo pathogenic effects. These findings suggest that targeting c-Myc may unlock novel strategies to combat asthma or asthma exacerbation. K E Y W O R D S airway hyperresponsiveness, asthma, c-Myc, ILC2 S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Ye L, Pan J, Liang M, et al. A critical role for c-Myc in group 2 innate lymphoid cell activation. Allergy. 2020;75:841-852. https ://doi.
Asthma is a complicated chronic airway inflammatory disorder.In addition to standard steroid treatment, biologic therapies targeting specific cytokines have emerged to reduce exacerbation and improve lung function. Neutralizing antibodies against IL-5, a critical growth factor for eosinophils, reduced asthma exacerbation in patients with severe eosinophilic asthma. 1 Blockade of IL4Rα, the receptor to IL-4 and IL-13, also lowered exacerbation rates and improved lung function in moderate to severe uncontrolled asthma. 2 While these biologic therapies are now used as add-on maintenance treatment of moderate to severe asthma, the effects of these biologic therapies on human immune responses are yet to be better understood.Recent work from us and others has indicated critical roles for group-2 innate lymphoid cells (ILC2), a type of lung-resident innate effector cells, in asthma pathogenesis. 3-5 ILC2 may mediate airway inflammation and hyperresponsiveness through production of IL-5, IL-13 and VEGFA. 5,6 They may also enhance Th2 responses by expression of MHCII and co-stimulating factors. 7 How human ILC2 may respond to biologic therapies remains unclear. A recent study demonstrates that human ILC2 do not express IL-5R, indicating that human ILC2 are unlikely to directly respond to anti-IL-5 therapy. 8Nevertheless, previous work with mouse models suggest that IL-4 might promote cytokine production activity of mouse ILC2, through direct interaction with IL-4Rα 9 However, whether and how human ILC2 may respond to IL-4 remain unknown.We hypothesize that IL-4/IL-4Rα signalling may promote human ILC2 response through both autocrine and endocrine regulation and that blockade of IL-4Rα by dupilumab can repress pathogenic ILC2 responses in asthma patients.To examine human ILC2 function, we isolated human blood ILC2 by fluorescence-activated cell sorting (FACS) and cultured them in vitro in the presence of IL-2, IL-7, IL-25 and IL-33. Human ILC2 were identified as CD45 + Lin -IL7Ra + CRTH2 + cells as previously described ( Figure 1A). 5 A total of 5 Χ 10 3 sorted ILC2 were cultured in 200 µL of alpha-MEDM medium supplemented with 20% FCS and 20 ng/mL IL-2, IL-7, IL-25 and IL-33 in round bottom 96-well plates. Human ILC2 produced a large amount of IL-5 and IL-13, and also intermediate levels of IL-4 in vitro ( Figure 1B). We next sought to understand whether IL-4 and/or IL-13 may control human ILC2 activity through autocrine regulation. We used neutralizing antibodies to block IL-4 and/or IL-13 activity in human ILC2 culture. Blockade of IL-4 signalling significantly repressed proliferation of human ILC2 in vitro ( Figure 1C). ELISA revealed that the production of IL-13 by human ILC2 was also greatly reduced with IL-4 blockade ( Figure 1D). Thus, IL-4 may promote human ILC2 proliferation and activation through autocrine regulation. IL-13 also acts through IL-4Rα signalling. However, neutralization of IL-13 did not affect the proliferation or the cytokine production of cultured human ILC2 ( Figure 1C,E,F). Combined treatment w...
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