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

doi:10.1016/j.immuni.2019.01.008

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

Cell Signalling and Immunology

Research output: Contribution to journal › Article › peer-review

144 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 language	English
Pages (from-to)	645-654.e6
Journal	Immunity
Volume	50
Issue number	3
DOIs	https://doi.org/10.1016/j.immuni.2019.01.008
Publication status	Published - 19 Mar 2019

Keywords

Amphiregulin
Macrophages
pericytes
TGFb

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2019.01.008

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Minutti, C. M., Modak, R. V., Macdonald, F., Li, F., Smyth, D. J., Dorward, D. A., Blair, N., Husovsky, C., Muir, A., Giampazolias, E., Dobie, R., Maizels, R. M., Kendall, T. J., Griggs, D. W., Kopf, M., Henderson, N. C., & Zaiss, D. M. (2019). A Macrophage-Pericyte Axis Directs Tissue Restoration via Amphiregulin-Induced Transforming Growth Factor Beta Activation. Immunity, 50(3), 645-654.e6. https://doi.org/10.1016/j.immuni.2019.01.008

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

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. ",

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

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Minutti, CM, Modak, RV, Macdonald, F, Li, F, Smyth, DJ, Dorward, DA, Blair, N, Husovsky, C, Muir, A, Giampazolias, E, Dobie, R, Maizels, RM, Kendall, TJ, Griggs, DW, Kopf, M, Henderson, NC & Zaiss, DM 2019, 'A Macrophage-Pericyte Axis Directs Tissue Restoration via Amphiregulin-Induced Transforming Growth Factor Beta Activation', Immunity, vol. 50, no. 3, pp. 645-654.e6. https://doi.org/10.1016/j.immuni.2019.01.008

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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.

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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