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

Millrine, David, Cardus Figueras, Ana, Uceda Fernandez, Javier, Andrews, Robert, Szomolay, Barbara ORCID:, Cossins, Benjamin, Rice, Christopher M., Li, Jasmine, Tyrrell, Victoria, McLeod, Louise, Holmans, Peter ORCID:, O'Donnell, Valerie ORCID:, Taylor, Philip ORCID:, Turner, Stephen J., Jenkins, Brendan J., Jones, Gareth, Topley, Nicholas, Williams, Nigel ORCID: and Jones, Simon ORCID: 2023. Th1 cells alter the inflammatory signature of IL-6 by channeling STAT transcription factors to Alu-like retroelements. The Journal of Immunology 211 (2) , pp. 274-286. 10.4049/jimmunol.2300114

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Cytokines that signal via STAT1 and STAT3 transcription factors instruct decisions affecting tissue homeostasis, anti-microbial host defense, and inflammation-induced tissue injury. To understand the coordination of these activities, we applied RNA-seq, ChIP-seq, and ATAC-seq to identify the transcriptional output of STAT1 and STAT3 in peritoneal tissues during acute resolving inflammation and inflammation primed to drive fibrosis. Bioinformatics focussed on the transcriptional signature of the immuno-modulatory cytokine IL-6 in both settings and examined how pro-fibrotic IFNg- 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 anti-microbial immunity and tissue homeostasis. The introduction of IFNg-secreting CD4+ T-cells altered this transcriptional program and channeled STAT1 and STAT3 to a previously latent GAS 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 re-tune the transcriptional output of IL-6 by shaping a regulatory interplay between STAT1 and STAT3 in inflammation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RB Pathology
Additional Information: This article is distributed under the terms of the CC BY 4.0 Unported license.
Publisher: American Association of Immunologists
ISSN: 0022-1767
Funders: Kidney Research UK, Versus Arthritis, UKRI MRC, Wellcome Trust, NHMRC (Australia), La Caixa, UK Dementia Research Institute
Date of First Compliant Deposit: 6 June 2023
Date of Acceptance: 2 May 2023
Last Modified: 11 Oct 2023 21:34

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