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

doi:10.4049/jimmunol.2300114

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

4 Citations (Scopus)

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-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 language	English
Pages (from-to)	274-286
Number of pages	13
Journal	Journal of Immunology
Volume	211
Issue number	2
Early online date	5 Jun 2023
DOIs	https://doi.org/10.4049/jimmunol.2300114
Publication status	Published - 15 Jul 2023

Bibliographical note

Funding Information:
This work was supported by the Kidney Research UK Grant RP-024-20160304, Versus Arthritis Grants 20770, 19796, and 20305, UK Research and Innovation, Medical Research Council Project Grant MR/X00077X/1, Wellcome Trust Grant 107964/Z/15/Z, the UK Dementia Research Institute, and the National Health and Medical Research Council of Australia. B.J.J. holds a Senior Research Fellowship from the National Health and Medical Research Council of Australia. J.U.F. was the recipient of a “la Caixa”

Funding Information:
Foundation Ph.D. studentship administered through the British Council. B.C.C. was supported by a Ph.D. studentship from the Systems Immunity University Research Institute at Cardiff. J.L. was awarded a Rutherford Fund Strategic Partner Grant supported by Universities UK.

Publisher Copyright:
Copyright © 2023 The Authors.

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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., Holmans, P., O'Donnell, V. B., Taylor, P. R., Turner, S. J., Jenkins, B. J., Jones, G. W., Topley, N., Williams, N. M., & Jones, S. A. (2023). Th1 Cells Alter the Inflammatory Signature of IL-6 by Channeling STAT Transcription Factors to Alu-like Retroelements. Journal of Immunology, 211(2), 274-286. https://doi.org/10.4049/jimmunol.2300114

@article{9029a6c599df488189f3c7aecd1852ec,

title = "Th1 Cells Alter the Inflammatory Signature of IL-6 by Channeling STAT Transcription Factors to Alu-like Retroelements",

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-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.",

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

note = "Funding Information: This work was supported by the Kidney Research UK Grant RP-024-20160304, Versus Arthritis Grants 20770, 19796, and 20305, UK Research and Innovation, Medical Research Council Project Grant MR/X00077X/1, Wellcome Trust Grant 107964/Z/15/Z, the UK Dementia Research Institute, and the National Health and Medical Research Council of Australia. B.J.J. holds a Senior Research Fellowship from the National Health and Medical Research Council of Australia. J.U.F. was the recipient of a “la Caixa” Funding Information: Foundation Ph.D. studentship administered through the British Council. B.C.C. was supported by a Ph.D. studentship from the Systems Immunity University Research Institute at Cardiff. J.L. was awarded a Rutherford Fund Strategic Partner Grant supported by Universities UK. Publisher Copyright: Copyright {\textcopyright} 2023 The Authors.",

year = "2023",

month = jul,

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doi = "10.4049/jimmunol.2300114",

language = "English",

volume = "211",

pages = "274--286",

journal = "Journal of Immunology",

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Millrine, D, Cardus Figueras, A, Uceda Fernandez, J, Andrews, R, Szomolay, B, Cossins, BC, Rice, CM, Li, J, Tyrrell, VJ, McLeod, L, Holmans, P, O'Donnell, VB, Taylor, PR, Turner, SJ, Jenkins, BJ, Jones, GW, Topley, N, Williams, NM & Jones, SA 2023, 'Th1 Cells Alter the Inflammatory Signature of IL-6 by Channeling STAT Transcription Factors to Alu-like Retroelements', Journal of Immunology, vol. 211, no. 2, pp. 274-286. https://doi.org/10.4049/jimmunol.2300114

TY - JOUR

T1 - Th1 Cells Alter the Inflammatory Signature of IL-6 by Channeling STAT Transcription Factors to Alu-like Retroelements

AU - Millrine, David

AU - Cardus Figueras, Ana

AU - Uceda Fernandez, Javier

AU - Andrews, Robert

AU - Szomolay, Barbara

AU - Cossins, Benjamin C

AU - Rice, Christopher M

AU - Li, Jasmine

AU - Tyrrell, Victoria J

AU - McLeod, Louise

AU - Holmans, Peter

AU - O'Donnell, Valerie B

AU - Taylor, Philip R

AU - Turner, Stephen J

AU - Jenkins, Brendan J

AU - Jones, Gareth W

AU - Topley, Nicholas

AU - Williams, Nigel M

AU - Jones, Simon A

N1 - Funding Information: This work was supported by the Kidney Research UK Grant RP-024-20160304, Versus Arthritis Grants 20770, 19796, and 20305, UK Research and Innovation, Medical Research Council Project Grant MR/X00077X/1, Wellcome Trust Grant 107964/Z/15/Z, the UK Dementia Research Institute, and the National Health and Medical Research Council of Australia. B.J.J. holds a Senior Research Fellowship from the National Health and Medical Research Council of Australia. J.U.F. was the recipient of a “la Caixa” Funding Information: Foundation Ph.D. studentship administered through the British Council. B.C.C. was supported by a Ph.D. studentship from the Systems Immunity University Research Institute at Cardiff. J.L. was awarded a Rutherford Fund Strategic Partner Grant supported by Universities UK. Publisher Copyright: Copyright © 2023 The Authors.

PY - 2023/7/15

Y1 - 2023/7/15

N2 - 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.

AB - 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.

U2 - 10.4049/jimmunol.2300114

DO - 10.4049/jimmunol.2300114

M3 - Article (Academic Journal)

C2 - 37272871

SN - 0022-1767

VL - 211

SP - 274

EP - 286

JO - Journal of Immunology

JF - Journal of Immunology

IS - 2

ER -

Th1 Cells Alter the Inflammatory Signature of IL-6 by Channeling STAT Transcription Factors to Alu-like Retroelements

Abstract

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