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

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

Abstract / Description of output

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
Number of pages	16
Journal	Immunity
Volume	50
Issue number	3
Early online date	12 Feb 2019
DOIs	https://doi.org/10.1016/j.immuni.2019.01.008
Publication status	Published - 19 Mar 2019

Keywords / Materials (for Non-textual outputs)

macrophages
TGFb
amphiregulin
pericytes

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10.1016/j.immuni.2019.01.008Licence: Creative Commons: Attribution (CC-BY)

ZaissEtalI2019AMacrophagePericyteAxisDirectsTissueRestorationViaAmphiregulinFinal published version, 7.45 MBLicence: Creative Commons: Attribution (CC-BY)

Use of EGF-R antagonists for the treatment of infections and tumour growth
Zaiss, D.
MRC
1/04/15 → 31/03/18
Project: Research
An intravital imaging approach to elucidate novel mechanisms of organ fibrosis and repair
Henderson, N.
UK-based charities
1/08/14 → 31/01/20
Project: Research
EGF-R: Use of EGF-R antagonists for the treatment of chronic infections and tumor growth
Zaiss, D.
EU government bodies
1/03/14 → 28/02/18
Project: Research

Timothy Kendall
- Tim.Kendalled.acuk
- Deanery of Clinical Sciences - Personal Chair of Liver Pathology
- Centre for Inflammation Research
- Edinburgh Pathology
Person: Academic: Research Active

Cite this

M. Minutti, C., 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

@article{9a952bf74266494a839ded7ea049cd11,

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-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 = "macrophages, TGFb, amphiregulin, pericytes",

author = "{M. Minutti}, Carlos 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.}",

note = "This will be Gold (confirmed by Fiona). The AAM attached will possibly have changes as it was 'conditionally accepted', hence the DoA may vary too 9/01/2019 EN - Pub but not yet in PubMed 15/02/2019 EN",

year = "2019",

month = mar,

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doi = "10.1016/j.immuni.2019.01.008",

language = "English",

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pages = "645--654.e6",

journal = "Immunity",

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M. Minutti, C, 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

TY - JOUR

T1 - A macrophage-pericyte axis directs tissue restoration via amphiregulin-induced transforming growth factor beta activation

AU - M. Minutti, Carlos

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.

N1 - This will be Gold (confirmed by Fiona). The AAM attached will possibly have changes as it was 'conditionally accepted', hence the DoA may vary too 9/01/2019 EN - Pub but not yet in PubMed 15/02/2019 EN

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-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.

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-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.

KW - macrophages

KW - TGFb

KW - amphiregulin

KW - pericytes

U2 - 10.1016/j.immuni.2019.01.008

DO - 10.1016/j.immuni.2019.01.008

M3 - Article

C2 - 30770250

SN - 1074-7613

VL - 50

SP - 645-654.e6

JO - Immunity

JF - Immunity

IS - 3

ER -

A macrophage-pericyte axis directs tissue restoration via amphiregulin-induced transforming growth factor beta activation

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

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Projects

Use of EGF-R antagonists for the treatment of infections and tumour growth

An intravital imaging approach to elucidate novel mechanisms of organ fibrosis and repair

EGF-R: Use of EGF-R antagonists for the treatment of chronic infections and tumor growth

Profiles

Timothy Kendall

Cite this