NADPH oxidase 4 is dispensable for skin myofibroblast differentiation and wound healing

Article Article scientifique Article NADPH oxidase 4 is dispensable for skin myofibroblast differentiation and wound healing eng 2023-01-13 2023-01-13 author Siedlar Aleksandra Malgorzata 885651 author Seredenina Tamara author Faivre Anna 0000-0002-1752-7533 801532 author Cambet Yves Alexandre 33476 author Stasia Marie-José 894356 author André-Lévigne Dominik 748833 author Bochaton-Piallat Marie-Luce 0000-0001-8408-8932 23951 Marie-Luce Piallat author Pittet Cuenod Brigitte Maud 114581 author De Seigneux Matthey Sophie 105798 author Krause Karl-Heinz 23022 author Modarressi Ghavami Seyed Ali 105647 author Jaquet Vincent 639300 102609 10.1016/j.redox.2023.102609 36708644 2213-2317 Differentiation of fibroblasts to myofibroblasts is governed by the transforming growth factor beta (TGF-β) through a mechanism involving redox signaling and generation of reactive oxygen species (ROS). Myofibroblasts synthesize proteins of the extracellular matrix (ECM) and display a contractile phenotype. Myofibroblasts are predominant contributors of wound healing and several pathological states, including fibrotic diseases and cancer. Inhibition of the ROS-generating enzyme NADPH oxidase 4 (NOX4) has been proposed to mitigate fibroblast to myofibroblast differentiation and to offer a therapeutic option for the treatment of fibrotic diseases. In this study, we addressed the role of NOX4 in physiological wound healing and in TGF-β-induced myofibroblast differentiation. We explored the phenotypic changes induced by TGF-β in primary skin fibroblasts isolated from Nox4-deficient mice by immunofluorescence, Western blotting and RNA sequencing. Mice deficient for Cyba, the gene coding for p22phox, a key subunit of NOX4 were used for confirmatory experiments as well as human primary skin fibroblasts. In vivo, the wound healing was similar in wild-type and Nox4-deficient mice. In vitro, despite a strong upregulation following TGF-β treatment, Nox4 did not influence skin myofibroblast differentiation although a putative NOX4 inhibitor GKT137831 and a flavoprotein inhibitor diphenylene iodonium mitigated this mechanism. Transcriptomic analysis revealed upregulation of the mitochondrial protein Ucp2 and the stress-response protein Hddc3 in Nox4-deficient fibroblasts, which had however no impact on fibroblast bioenergetics. Altogether, we provide extensive evidence that NOX4 is dispensable for wound healing and skin fibroblast to myofibroblast differentiation, and suggest that another H2O2-generating flavoprotein drives this mechanism. Cellular bioenergetics Mitochondrial uncoupling protein 2 Myofibroblast differentiation NADPH oxidase NOX4 Transforming growth factor β Wound healing Dewey 612 Dewey 616 Dewey 616.07 Dewey 617 Swiss National Science Foundation Novel strategies to improve wound repair: from wound oxygenation to stem cell therapy 170132 CH Projects Swiss National Science Foundation NADPH oxidases as mediators in physiology and pathology 179478 CH Projects 56 Département de médecine 221 134 Département de physiologie cellulaire et métabolisme 21C 137 Département de pathologie et immunologie 21F 57 Département de chirurgie 222 false 561 RECH.EN NEPHROLOGIE 904 38 Radicaux libres et cellules souches embryonnaires 60 897 Insuffisance rénale chronique 941 380 Bochaton-Piallat Marie-Luce (pathologie et immunologie) 646 Redox biology 60 046c6669-494a-4602-acb9-9808f89407e5 Article (Published version) Public Article pour archive ouverte.pdf 5625649 application/pdf CC BY-4.0 openAccess Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine clinique / Département de chirurgie

Title	Published in	Year	Views	Downloads

NADPH oxidase 4 is dispensable for skin myofibroblast differentiation and wound healing	Redox biology	2023	197	346
The role of NOX4 in skin fibroblasts		2021	1,100	840

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