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

Carlos M. Minutti, Rucha V. Modak, Felicity Macdonald, Fengqi Li, Danielle J. Smyth, David A. Dorward, Natalie Blair, Connor Husovsky, Andrew Muir, Evangelos Giampazolias, Ross Dobie, Rick M. Maizels, Timothy J. Kendall, David W. Griggs, Manfred Kopf, Neil C. Henderson, Dietmar M. Zaiss

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

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-α V 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.

Original languageEnglish
Pages (from-to)645-654.e6
JournalImmunity
Volume50
Issue number3
DOIs
Publication statusPublished - 19 Mar 2019

Keywords

  • Amphiregulin
  • Macrophages
  • pericytes
  • TGFb

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