Transforming growth factor β1-induced collagen production in myofibroblasts is mediated by reactive oxygen species derived from NADPH oxidase 4

Hotta, Yuma; Uchiyama, Kazuhiko; Takagi, Tomohisa; Kashiwagi, Saori; Nakano, Takahiro; Mukai, Rieko; Toyokawa, Yuki; Yasuda, Takenori; Ueda, Tomohiro; Suyama, Yosuke; Murakami, Takaaki; Tanaka, Makoto; Majima, Atsushi; Doi, Takehiko; Hirai, Yasuko; Mizushima, Katsura; Morita, Mayuko; Higashimura, Yasuki; Inoue, Ken; Fukui, Akifumi; Okayama, Tetsuya; Katada, Kazuhiro; Kamada, Kazuhiro; Handa, Osamu; Ishikawa, Takeshi; Naito, Yuji; Itoh, Yoshito

doi:10.1016/j.bbrc.2018.10.116

Cited by 13 publications

(9 citation statements)

References 22 publications

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“…Studies examining the relationship of TGF-β and NOX4 in the intestine are very limited. NOX4 expression was upregulated in intestinal myofibroblasts derived from three patients with fibrostenotic CD [ 20 ], and similar to reports on myofibroblasts derived from other tissues, TGF-β-stimulated collagen production in a murine myofibroblast cell line required the Smad-Nox4 pathway [ 21 ]. Whether Nox4 is also a critical signal conduit and amplifier in TGF-β1-mediated intestinal fibrosis has not yet been addressed in vivo.…”

Section: Introductionsupporting

confidence: 60%

NADPH oxidase 4 is protective and not fibrogenic in intestinal inflammation

et al. 2020

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Dysregulated redox signaling and oxidative injury are associated with inflammatory processes and fibrosis. H 2 O 2 generation by NOX4 has been suggested as a key driver in the development of fibrosis and a small molecule drug is under evaluation in clinical trials for idiopathic pulmonary fibrosis and primary biliary cholangitis. Fibrosis is a common complication in Crohn's disease (CD) leading to stricture formation in 35–40% of patients, who require surgical interventions in the absence of therapeutic options. Here we assess NOX4 expression in CD patients with inflammatory or stricturing disease and examine whether loss of NOX4 is beneficial in acute and fibrotic intestinal disease. NOX4 was upregulated in inflamed mucosal tissue of CD and ulcerative colitis (UC) patients, in CD ileal strictures, and in mice with intestinal inflammation. Nox4 deficiency in mice promoted pathogen colonization and exacerbated tissue injury in acute bacterial and chemical colitis. In contrast, in two chronic injury models aberrant tissue remodeling and fibrosis-related gene expression did not differ substantially between Nox4 −/− mice and wildtype mice, suggesting that Nox4 is dispensable in TGF-β1-driven intestinal fibrogenesis. While animal models do not recapitulate all the hallmarks of CD fibrosis, the tissue-protective role of Nox4 warrants a cautious approach to pharmacological inhibitors.

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Section: Introductionsupporting

confidence: 60%

NADPH oxidase 4 is protective and not fibrogenic in intestinal inflammation

et al. 2020

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“…This study provides evidence to suggest that palladin isoforms play a role in known CAF functions like d-ECM production (able to support tumor growth), and secretion of immunosuppressive cytokines 6,13,26 . Our data suggest that palladin isoform specific roles may vary; especially with regards to TGFβ1-dependent fibroblastic activation 22,[36][37][38][39][40][41][42][43][44] . Experiments using palladin KD CAFs advocate in favor of a palladin isoform interdependency.…”

Section: Discussionmentioning

confidence: 87%

Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma

Alexander

Vendramini–Costa

Francescone

et al. 2021

Sci Rep

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Pancreatic Ductal Adenocarcinoma (PDAC) has a five-year survival under 10%. Treatment is compromised due to a fibrotic-like stromal remodeling process, known as desmoplasia, which limits therapeutic perfusion, supports tumor progression, and establishes an immunosuppressive microenvironment. These processes are driven by cancer-associated fibroblasts (CAFs), functionally activated through transforming growth factor beta1 (TGFβ1). CAFs produce a topographically aligned extracellular matrix (ECM) that correlates with reduced overall survival. Paradoxically, ablation of CAF populations results in a more aggressive disease, suggesting CAFs can also restrain PDAC progression. Thus, unraveling the mechanism(s) underlying CAF functions could lead to therapies that reinstate the tumor-suppressive features of the pancreatic stroma. CAF activation involves the f-actin organizing protein palladin. CAFs express two palladin isoforms (iso3 and iso4) which are up-regulated in response to TGFβ1. However, the roles of iso3 and iso4 in CAF functions remain elusive. Using a CAF-derived ECM model, we uncovered that iso3/iso4 are required to sustain TGFβ1-dependent CAF activation, secrete immunosuppressive cytokines, and produce a pro-tumoral ECM. Findings demonstrate a novel role for CAF palladin and suggest that iso3/iso4 regulate both redundant and specific tumor-supportive desmoplastic functions. This study highlights the therapeutic potential of targeting CAFs to restore fibroblastic anti-tumor activity in the pancreatic microenvironment.

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“…This proposition is further supported by the observation that the deletion of NOX4 abrogates TGF-β1-induced fibrosis in mice [160]. Moreover, TGF-β1 has been reported to activate NOX4-mediated collagen production in myofibroblasts [161], and this signaling pathway is strongly implicated in IPF pathogenesis [162,163]. Although the role of mitochondrial mtROS in IPF onset and progression is not fully understood approaches to beneficially modulate mtROS levels with antioxidants are currently under investigation (Fig.…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 81%

Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis

Phan

Paliogiannis

Nasrallah

et al. 2020

Cell. Mol. Life Sci.

198

152

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Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonia, is a progressive, irreversible, and typically lethal disease characterized by an abnormal fibrotic response involving vast areas of the lungs. Given the poor knowledge of the mechanisms underpinning IPF onset and progression, a better understanding of the cellular processes and molecular pathways involved is essential for the development of effective therapies, currently lacking. Besides a number of established IPF-associated risk factors, such as cigarette smoking, environmental factors, comorbidities, and viral infections, several other processes have been linked with this devastating disease. Apoptosis, senescence, epithelial-mesenchymal transition, endothelial-mesenchymal transition, and epithelial cell migration have been shown to play a key role in IPF-associated tissue remodeling. Moreover, molecules, such as chemokines, cytokines, growth factors, adenosine, glycosaminoglycans, non-coding RNAs, and cellular processes including oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, hypoxia, and alternative polyadenylation have been linked with IPF development. Importantly, strategies targeting these processes have been investigated to modulate abnormal cellular phenotypes and maintain tissue homeostasis in the lung. This review provides an update regarding the emerging cellular and molecular mechanisms involved in the onset and progression of IPF.

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Transforming growth factor β1-induced collagen production in myofibroblasts is mediated by reactive oxygen species derived from NADPH oxidase 4

Cited by 13 publications

References 22 publications

NADPH oxidase 4 is protective and not fibrogenic in intestinal inflammation

NADPH oxidase 4 is protective and not fibrogenic in intestinal inflammation

Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma

Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis

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