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Immunity. 2019 Mar 19;50(3):645-654.e6. doi: 10.1016/j.immuni.2019.01.008. Epub 2019 Feb 12.

A Macrophage-Pericyte Axis Directs Tissue Restoration via Amphiregulin-Induced Transforming Growth Factor Beta Activation.

Author information

1
Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK; Immunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address: carlos.minutti@crick.ac.uk.
2
Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK.
3
Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich, Zürich 8093, Switzerland.
4
Wellcome Centre for Molecular Parasitology, Institute for Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK.
5
Centre for Inflammation Research, University of Edinburgh, Edinburgh EH16 4TJ, UK; Division of Pathology, University of Edinburgh, Edinburgh EH4 2XU, UK.
6
Immunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
7
Centre for Inflammation Research, University of Edinburgh, Edinburgh EH16 4TJ, UK.
8
Department of Molecular Microbiology and Immunology, Saint Louis University, Edward A. Doisy Research Center, St. Louis, MO 63104, USA.
9
Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK. Electronic address: dietmar.zaiss@ed.ac.uk.

Abstract

The epidermal growth factor receptor ligand Amphiregulin has a well-documented role in the restoration of tissue homeostasis after injury; however, the mechanism by which Amphiregulin contributes to wound repair remains unknown. Here we show that Amphiregulin functioned by releasing bioactive transforming growth factor beta (TGF-β) from latent complexes via integrin-αV activation. Using acute injury models in two different tissues, we found that by inducing TGF-β activation on mesenchymal stromal cells (pericytes), Amphiregulin induced their differentiation into myofibroblasts, thereby selectively contributing to the restoration of vascular barrier function within injured tissue. Furthermore, we identified macrophages as a critical source of Amphiregulin, revealing a direct effector mechanism by which these cells contribute to tissue restoration after acute injury. Combined, these observations expose a so far under-appreciated mechanism of how cells of the immune system selectively control the differentiation of tissue progenitor cells during tissue repair and inflammation.

KEYWORDS:

Amphiregulin; Macrophages; TGFb; pericytes

PMID:
30770250
PMCID:
PMC6436929
DOI:
10.1016/j.immuni.2019.01.008
[Indexed for MEDLINE]
Free PMC Article

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