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bioRxiv · 10.1101/367474

A macrophage-pericyte axis directs tissue restoration via Amphiregulin-induced TGFβ activation

Modak, R.·Minutti, C.·Macdonald, F.·Li, F.·Smyth, D.·Dorward, D.·Blair, N.·Husovsky, C.·Muir, A.·Dobie, R.·Maizels, R.·Kendall, T.·Griggs, D.·Kopf, M.·Henderson, N.·Zaiss, D.
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Abstract

The Epidermal Growth Factor Receptor ligand Amphiregulin has a well-documented role in the restoration of tissue homeostasis following injury; however, the mechanism by which Amphiregulin contributes to wound repair remains unknown. Here we show that Amphiregulin functions by releasing bio-active TGFb from latent complexes via integrin-v activation. Using acute injury models in two different tissues, we found that by inducing TGFb activation on mesenchymal stromal cells (aka pericytes), Amphiregulin induced their differentiation into myo-fibroblasts, 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 following 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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Modak, R., Minutti, C., Macdonald, F., Li, F., Smyth, D., Dorward, D., Blair, N., Husovsky, C., Muir, A., Dobie, R., Maizels, R., Kendall, T., Griggs, D., Kopf, M., Henderson, N., Zaiss, D.. 2018-07-12. A macrophage-pericyte axis directs tissue restoration via Amphiregulin-induced TGFβ activation. https://doi.org/10.1101/367474

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