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

  • Immunity. 2019 Mar 19;50(3):645-654.e6. doi: 10.1016/j.immuni.2019.01.008.
Carlos M Minutti  1 ,  Rucha V Modak  2 ,  Felicity Macdonald  2 ,  Fengqi Li  3 ,  Danielle J Smyth  4 ,  David A Dorward  5 ,  Natalie Blair  2 ,  Connor Husovsky  2 ,  Andrew Muir  2 ,  Evangelos Giampazolias  6 ,  Ross Dobie  7 ,  Rick M Maizels  4 ,  Timothy J Kendall  5 ,  David W Griggs  8 ,  Manfred Kopf  3 ,  Neil C Henderson  7 ,  Dietmar M Zaiss  9
Affiliations
  • 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: [email protected].
  • 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: [email protected].
PMID: 30770250 DOI: 10.1016/j.immuni.2019.01.008
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.