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

TY - JOUR

T1 - A Macrophage-Pericyte Axis Directs Tissue Restoration via Amphiregulin-Induced Transforming Growth Factor Beta Activation

AU - Minutti, Carlos M.

AU - Modak, Rucha V.

AU - Macdonald, Felicity

AU - Li, Fengqi

AU - Smyth, Danielle J.

AU - Dorward, David A.

AU - Blair, Natalie

AU - Husovsky, Connor

AU - Muir, Andrew

AU - Giampazolias, Evangelos

AU - Dobie, Ross

AU - Maizels, Rick M.

AU - Kendall, Timothy J.

AU - Griggs, David W.

AU - Kopf, Manfred

AU - Henderson, Neil C.

AU - Zaiss, Dietmar M.

PY - 2019/3/19

Y1 - 2019/3/19

N2 - 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.

AB - 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.

KW - Amphiregulin

KW - Macrophages

KW - pericytes

KW - TGFb

UR - https://www.scopus.com/pages/publications/85062803127

U2 - 10.1016/j.immuni.2019.01.008

DO - 10.1016/j.immuni.2019.01.008

M3 - Article

C2 - 30770250

AN - SCOPUS:85062803127

SN - 1074-7613

VL - 50

SP - 645-654.e6

JO - Immunity

JF - Immunity

IS - 3

ER -