Epidermal growth factor dampens pro-inflammatory gene expression induced by interferon-gamma in global transcriptome analysis of keratinocytes

• Type of Material: Article
• Authors: David C. Gibbs, Emory University; Myles R. McCrary, Emory University; Carlos S. Moreno, University of South Florida; Lindsey Seldin, University of South Florida; Chaoran Li, Emory University; Nourine A.H. Kamili, Emory University; Brian P. Pollack, Emory University
• Language: English
• Date: 2025-02-10
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2025, corrected publication 2025; © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2025
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1186/s12864-025-11237-1; https://doi.org/10.1186/s12864-025-11457-5
• Title of Journal or Parent Work: BMC Genetics
• Volume: 26
• Start Page: 122
• Grant/Funding Agency: United States (U.S.) Department of Veterans Affairs; Joseph Maxwell Cleland Atlanta VA Medical Center
• Grant/Funding Information: This work was supported by Merit Review Award # 5I01BX001922 from the United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research and Development Service. BPP is currently employed by the Joseph Maxwell Cleland Atlanta VA Medical Center as the Dermatology Section Chief in the Medical Specialty Care Service line.
• Keywords: Cancer; Epidermal growth factor receptor (EGFR); Skin; Keratinocyte; Transcriptomics; Interferon; Immunomodulation; RNA-seq; Epidermal growth factor
• Research Categories: Immunology; Oncology

Abstract

Background Epidermal growth factor receptor inhibitors (EGFRIs) are used to treat certain cancers but frequently cause cutaneous inflammation that can hinder treatment. This is due in part to the effects of EGFRIs on pro-inflammatory signaling by interferon-γ (IFN-γ). However, the impact of EGFR ligands (i.e. EGF) on interferon signaling is unclear. The purpose of this study was to investigate the impact of EGF on IFN-γ transcriptional responses on a genome-wide scale in keratinocytes. Methods RNA-seq was performed in human keratinocyte (HaCaT) cells treated with IFN-γ, EGF, both, or neither (control). Differentially expressed genes in each treatment group, relative to control, were identified using DESeq2 with a false discovery rate (FDR) threshold of 0.01. Associated biologic processes and gene pathways were examined in gene-set enrichment analyses. Correlations between gene expression were investigated in vivo using RNA-seq data from biopsies of psoriatic and matched normal skin, which were collected from 116 individuals with psoriasis enrolled in the AMAGINE randomized clinical trials. Results Of the 2,792 differentially expressed genes following IFN-γ treatment, 2,083 (75%) were no longer differentially expressed when EGF was added. IFN-γ-induced genes with significantly lower expression in the presence of EGF included CXCL10, IL-6, IL-1 A, HLA-DMA, and GBP5 (activator of the NLRP3 inflammasome); the top enriched biologic processes and pathways were related to MHC-class II antigen presentation (GO:0019886) and cytokine signaling (KEGG:04060). Consistent with our in vitro findings, the expression of CXCL10 and GBP5, as well as the combined expression z-scores of genes in the enriched MHC-class II and cytokine signaling pathways, were significantly lower in skin biopsies with higher EGF expression compared to those with lower EGF expression among individuals with psoriasis. Conclusions Our findings suggest that the pro-inflammatory IFN-γ-induced transcriptome may be globally attenuated by EGF in keratinocytes, supporting an immunomodulatory role of EGF in the skin. These studies provide insights for the non-canonical immunomodulatory role of EGF signaling and why blocking EGFR signaling (e.g., with EGFRIs) can cause cutaneous inflammation.