A critical role for c‐Myc in group 2 innate lymphoid cell activation

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. 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.

Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc

“…It was recently verified that c-Myc expression is upregulated in group 2 innate lymphoid cells (ILC2s) in the blood of asthma patients. Using a mouse model of allergic inflammation, it was found that inhibition of c-Myc repressed ILC2 activity, causing reduction in airways inflammation and other pathogenic responses [ 54 ]. These findings suggest that targeting c-Myc may unlock novel strategies to combat asthma.…”

The Role of Type 2 Innate Lymphoid Cells in Allergic Diseases

“…In addition, c-Myc is a basic helix-loop-helix transcription factor mainly responded to IL-33, IL-25 and TSLP, which is closely related to the activation and pathogenicity of ILC2s in vivo . The activation of ILC2s results in the upregulation of c-Myc expression, which leads to proliferation and cytokine production of ILC2 ( 38 ). The AP-1 superfamily basic leucine zipper transcription factor, activating transcription factor-like (BATF) potentially regulates ILC2s.…”

Microarrays and NGS for Drug Discovery

“…Microarray and pathway enrichment analyses revealed that MYC expression could be downregulated by 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranoside (PGG) in hepatocellular carcinoma [78]. Using a genome-wide microarray analysis, it was reported that targeting c-Myc would unlock novel strategies to combat asthma [79]. β-catenin could be deemed as an anticancer therapeutic target by regulating c-Myc and CDKN1A expression in breast cancer cells [80].…”