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

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 and Matthias Sendler ()
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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
Ali A. Aghdassi: University Medicine, University of Greifswald
Frank U. Weiss: University Medicine, University of Greifswald
Matthias Sendler: University Medicine, University of Greifswald

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32195-2

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