A critical role for c‐Myc in group 2 innate lymphoid cell activation. Issue 4 (29th January 2020) - Ye, Longyun
Abstract: 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. Abstract : c‐Myc expression is upregulated in peripheral blood group 2 innate lymphoid cells (ILC2) of asthma patients. c‐Myc promotes ILC2 activation in response to epithelial‐derived cytokines Thymic stromal lymphopoietin (TSLP), IL‐33, and IL‐25. Inhibition of c‐Myc expression and function by JQ1 (a c‐Myc antagonist) treatment represses allergic airway inflammation. Abbreviations: ILC2, group 2 innate lymphoid cell; JQ1, (6S)‐4‐(4‐Chlorophenyl)‐2, 3, 9‐trimethyl‐6H‐thieno[3, 2‐f][1, 2, 4]triazolo[4, 3‐a][1, 4]diazepine‐6‐acetic acid 1, 1‐dimethylethyl ester; TSLP, thymic stromal lymphopoietin