Th1 cells alter the inflammatory signature of IL-6 by channeling STAT transcription factors to alu-like retroelements

David Millrine, Ana Cardus Figueras, Javier Uceda Fernandez, Robert Andrews, Barbara Szomolay, Benjamin C. Cossins, Christopher M. Rice, Jasmine Li, Victoria J. Tyrrell, Louise McLeod, Peter Holmans, Valerie B. O'Donnell, Philip R. Taylor, Stephen J. Turner, Brendan J. Jenkins, Gareth W. Jones, Nicholas Topley, Nigel M. Williams, Simon A. Jones (Lead / Corresponding author)

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Cytokines that signal via STAT1 and STAT3 transcription factors instruct decisions affecting tissue homeostasis, antimicrobial host defense, and inflammation-induced tissue injury. To understand the coordination of these activities, we applied RNA sequencing, chromatin immunoprecipitation sequencing, and assay for transposase-accessible chromatin with high-throughput sequencing to identify the transcriptional output of STAT1 and STAT3 in peritoneal tissues from mice during acute resolving inflammation and inflammation primed to drive fibrosis. Bioinformatics focused on the transcriptional signature of the immunomodulatory cytokine IL-6 in both settings and examined how profibrotic IFN-γ-secreting CD4+ T cells altered the interpretation of STAT1 and STAT3 cytokine cues. In resolving inflammation, STAT1 and STAT3 cooperated to drive stromal gene expression affecting antimicrobial immunity and tissue homeostasis. The introduction of IFN-γ-secreting CD4+ T cells altered this transcriptional program and channeled STAT1 and STAT3 to a previously latent IFN-γ activation site motif in Alu-like elements. STAT1 and STAT3 binding to this conserved sequence revealed evidence of reciprocal cross-regulation and gene signatures relevant to pathophysiology. Thus, we propose that effector T cells retune the transcriptional output of IL-6 by shaping a regulatory interplay between STAT1 and STAT3 in inflammation.

Original languageEnglish
Pages (from-to)274-286
Number of pages13
JournalJournal of Immunology
Issue number2
Early online date5 Jun 2023
Publication statusPublished - 15 Jul 2023


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