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In mouse chronic pancreatitis CD25+FOXP3+ regulatory T cells control pancreatic fibrosis by suppression of the type 2 immune response

Author

Listed:
  • Juliane Glaubitz

    (University Medicine, University of Greifswald)

  • Anika Wilden

    (University Medicine, University of Greifswald)

  • Janine Golchert

    (University Medicine Greifswald)

  • Georg Homuth

    (University Medicine Greifswald)

  • Uwe Völker

    (University Medicine Greifswald)

  • Barbara M. Bröker

    (University Medicine)

  • Thomas Thiele

    (University Medicine)

  • Markus M. Lerch

    (University Medicine, University of Greifswald)

  • Julia Mayerle

    (University Medicine, University of Greifswald
    University Hospital, LMU Munich)

  • Ali A. Aghdassi

    (University Medicine, University of Greifswald)

  • Frank U. Weiss

    (University Medicine, University of Greifswald)

  • Matthias Sendler

    (University Medicine, University of Greifswald)

Abstract

Chronic pancreatitis (CP) is characterized by chronic inflammation and the progressive fibrotic replacement of exocrine and endocrine pancreatic tissue. We identify Treg cells as central regulators of the fibroinflammatory reaction by a selective depletion of FOXP3-positive cells in a transgenic mouse model (DEREG-mice) of experimental CP. In Treg-depleted DEREG-mice, the induction of CP results in a significantly increased stroma deposition, the development of exocrine insufficiency and significant weight loss starting from day 14 after disease onset. In CP, FOXP3+CD25+ Treg cells suppress the type-2 immune response by a repression of GATA3+ T helper cells (Th2), GATA3+ innate lymphoid cells type 2 (ILC2) and CD206+ M2-macrophages. A suspected pathomechanism behind the fibrotic tissue replacement may involve an observed dysbalance of Activin A expression in macrophages and of its counter regulator follistatin. Our study identified Treg cells as key regulators of the type-2 immune response and of organ remodeling during CP. The Treg/Th2 axis could be a therapeutic target to prevent fibrosis and preserve functional pancreatic tissue.

Suggested Citation

  • Juliane Glaubitz & Anika Wilden & Janine Golchert & Georg Homuth & Uwe Völker & Barbara M. Bröker & Thomas Thiele & Markus M. Lerch & Julia Mayerle & Ali A. Aghdassi & Frank U. Weiss & Matthias Sendle, 2022. "In mouse chronic pancreatitis CD25+FOXP3+ regulatory T cells control pancreatic fibrosis by suppression of the type 2 immune response," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32195-2
    DOI: 10.1038/s41467-022-32195-2
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    References listed on IDEAS

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    1. Tiffany Bouchery & Ryan Kyle & Mali Camberis & Amy Shepherd & Kara Filbey & Alexander Smith & Marina Harvie & Gavin Painter & Karen Johnston & Peter Ferguson & Rohit Jain & Ben Roediger & Brett Delahu, 2015. "ILC2s and T cells cooperate to ensure maintenance of M2 macrophages for lung immunity against hookworms," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    2. Daniele C. Nascimento & Paulo H. Melo & Annie R. Piñeros & Raphael G. Ferreira & David F. Colón & Paula B. Donate & Fernanda V. Castanheira & Aline Gozzi & Paula G. Czaikoski & Wanda Niedbala & Marcos, 2017. "IL-33 contributes to sepsis-induced long-term immunosuppression by expanding the regulatory T cell population," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    3. Jing Xue & Vishal Sharma & Michael H. Hsieh & Ajay Chawla & Ramachandran Murali & Stephen J. Pandol & Aida Habtezion, 2015. "Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    4. Yuzo Koda & Toshiaki Teratani & Po-Sung Chu & Yuya Hagihara & Yohei Mikami & Yosuke Harada & Hanako Tsujikawa & Kentaro Miyamoto & Takahiro Suzuki & Nobuhito Taniki & Tomohisa Sujino & Michiie Sakamot, 2021. "CD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
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