AUTHOR=Cao Meiwan , Chen Peiyu , Peng Baoling , Cheng Yang , Xie Jing , Hou Ziang , Chen Huan , Ye Liping , Li Huiwen , Wang Hongli , Ren Lu , Xiong Liya , Geng Lanlan , Gong Sitang 

TITLE=The transcription factor ELF4 alleviates inflammatory bowel disease by activating IL1RN transcription, suppressing inflammatory TH17 cell activity, and inducing macrophage M2 polarization

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1270411

DOI=10.3389/fimmu.2023.1270411

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder affecting millions worldwide. Due to the complexity of its pathogenesis, the treatment options for IBD are limited. This study focuses on ELF4, a member of the ETS transcription factor family, as a target to elucidate its role in IBD and investigate its mechanism of action in alleviating IBD symptoms by activating IL1RN transcription to suppress the activity of inflammatory TH17 cells.</p></sec><sec><title>Methods</title><p>Using the GEO database, this study examined LPS-induced intestinal inflammatory genes and their regulation mechanisms. We examined the colon length of LPS-treated mice and derived the Disease Activity Index (DAI). H&amp;E staining, ELISA, and flow cytometry were used to detect mice colon tissue damage, inflammatory factor levels in mouse serum, mouse macrophage types and inflammatory TH17 cell activity. RT-qPCR and Western blot detected ELF4, IL1RN, M1, and M2 polarization markers. <italic>In Vitro</italic>, using dual-luciferase and ChIP assays, we tested mouse bone marrow-derived macrophages (BMDMs) and mouse intestinal epithelial cells for IL1RN promoter activity and ELF4 enrichment.</p></sec><sec><title>Results</title><p>Bioinformatics showed that LPS-induced colitis animals have reduced ELF4 expression in their colon tissue. <italic>In vivo</italic> tests confirmed reduced ELF4 expression in mice with LPS-induced colitis. ELF4 overexpression reduced mouse intestinal inflammation. ELF4 activated IL1RN transcription in bioinformatics and <italic>in vitro</italic> tests. ELF4 promoted IL1RN transcription and macrophage M2 polarization to limit intestinal epithelial cell death and inflammation and reduce mouse intestinal inflammation <italic>in vitro</italic>. ELF4 also reduced the Th17/Treg ratio by increasing IL1RN transcription.</p></sec><sec><title>Conclusion</title><p>ELF4 activates IL1RN transcription, suppresses inflammatory TH17 cells, and induces macrophage M2 polarization to treat IBD.</p></sec>