Th1 Cells Alter the Inflammatory Signature of IL-6 by Channeling STAT Transcription Factors to Alu-like Retroelements
Date
2023
Authors
Millrine, D.
Cardus Figueras, A.
Uceda Fernandez, J.
Andrews, R.
Szomolay, B.
Cossins, B.C.
Rice, C.M.
Li, J.
Tyrrell, V.J.
McLeod, L.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Journal of Immunology, 2023; 211(2):274-286
Statement of Responsibility
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, and Simon A. Jones
Conference Name
Abstract
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-y-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-y-secreting CD4+ T cells altered this transcriptional program and channeled STAT1 and STAT3 to a previously latent IFN-g 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.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
Copyright©2023 The Authors. This article is distributed under the terms of the CC BY4.0Unported license.