NADPH oxidase-2 is a key regulator of human dermal fibroblasts: a potential therapeutic strategy for the treatment of skin fibrosis

2014 ◽  
Vol 23 (9) ◽  
pp. 639-644 ◽  
Author(s):  
Guo-You Zhang ◽  
Liang-Cai Wu ◽  
Tao Dai ◽  
Shi-Yi Chen ◽  
An-Yuan Wang ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Therapeutic Strategy ◽  
Dermal Fibroblasts ◽  
Skin Fibrosis ◽  
Human Dermal Fibroblasts ◽  
Nadph Oxidase 2

scholarly journals cRel expression regulates distinct transcriptional and functional profiles driving fibroblast matrix production in systemic sclerosis

Rheumatology ◽  
2020 ◽  
Vol 59 (12) ◽  
pp. 3939-3951 ◽  
Author(s):  
Julie C Worrell ◽  
Jack Leslie ◽  
Graham R Smith ◽  
Marco Y W Zaki ◽  
Hannah L Paish ◽  
...  
Keyword(s):  
Normal Skin ◽  
Gene Signature ◽  
Dermal Fibroblasts ◽  
Skin Fibrosis ◽  
Human Dermal Fibroblasts ◽  
Murine Lung ◽  
Skin Physiology ◽  
Matrix Production ◽  
And Migration ◽  
Functional Profiles

Abstract Objectives NF-κB regulates genes that control inflammation, cell proliferation, differentiation and survival. Dysregulated NF-κB signalling alters normal skin physiology and deletion of cRel limits bleomycin-induced skin fibrosis. This study investigates the role of cRel in modulating fibroblast phenotype in the context of SSc. Methods Fibrosis was assessed histologically in mice challenged with bleomycin to induce lung or skin fibrosis. RNA sequencing and pathway analysis was performed on wild type and Rel−/− murine lung and dermal fibroblasts. Functional assays examined fibroblast proliferation, migration and matrix production. cRel overexpression was investigated in human dermal fibroblasts. cRel immunostaining was performed on lung and skin tissue sections from SSc patients and non-fibrotic controls. Results cRel expression was elevated in murine lung and skin fibrosis models. Rel−/− mice were protected from developing pulmonary fibrosis. Soluble collagen production was significantly decreased in fibroblasts lacking cRel while proliferation and migration of these cells was significantly increased. cRel regulates genes involved in extracellular structure and matrix organization. Positive cRel staining was observed in fibroblasts in human SSc skin and lung tissue. Overexpression of constitutively active cRel in human dermal fibroblasts increased expression of matrix genes. An NF-κB gene signature was identified in diffuse SSc skin and nuclear cRel expression was elevated in SSc skin fibroblasts. Conclusion cRel regulates a pro-fibrogenic transcriptional programme in fibroblasts that may contribute to disease pathology. Targeting cRel signalling in fibroblasts of SSc patients could provide a novel therapeutic avenue to limit scar formation in this disease.

scholarly journals NADPH oxidase is a novel target of delphinidin for the inhibition of UVB-induced MMP-1 expression in human dermal fibroblasts

2013 ◽  
Vol 22 (6) ◽  
pp. 428-430 ◽  
Author(s):  
Tae-Gyu Lim ◽  
Sung Keun Jung ◽  
Jong-eun Kim ◽  
Yoona Kim ◽  
Hyong Joo Lee ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Dermal Fibroblasts ◽  
Human Dermal Fibroblasts ◽  
Novel Target

scholarly journals Skin Aging-Dependent Activation of the PI3K Signaling Pathway via Downregulation of PTEN Increases Intracellular ROS in Human Dermal Fibroblasts

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Eun-Mi Noh ◽  
Jinny Park ◽  
Hwa-Ryung Song ◽  
Jeong-Mi Kim ◽  
Minok Lee ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Signaling Pathway ◽  
Skin Aging ◽  
Dermal Fibroblasts ◽  
Ros Generation ◽  
Human Dermal Fibroblasts ◽  
Chronological Aging ◽  
Aged Skin ◽  
Pi3k Signaling Pathway ◽  
High Level

Reactive oxygen species (ROS) play a major role in both chronological aging and photoaging. ROS induce skin aging through their damaging effect on cellular constituents. However, the origins of ROS have not been fully elucidated. We investigated that ROS generation of replicative senescent fibroblasts is generated by the modulation of phosphatidylinositol 3,4,5-triphosphate (PIP3) metabolism. Reduction of the PTEN protein, which dephosphorylates PIP3, was responsible for maintaining a high level of PIP3 in replicative cells and consequently mediated the activation of the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway. Increased ROS production was blocked by inhibition of PI3K or protein kinase C (PKC) or by NADPH oxidase activating in replicative senescent cells. These data indicate that the signal pathway to ROS generation in replicative aged skin cells can be stimulated by reduced PTEN level. Our results provide new insights into skin aging-associated modification of the PI3K/NADPH oxidase signaling pathway and its relationship with a skin aging-dependent increase of ROS in human dermal fibroblasts.

SAT0294 IL33 ACTIVATES FIBROBLASTS AND INDUCES SKIN FIBROSIS IN SYSTEMIC SCLEROSIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1091.1-1092
Author(s):  
X. Wu ◽  
B. Ming ◽  
L. Dong
Keyword(s):  
Systemic Sclerosis ◽  
Dermal Fibroblast ◽  
Human Dermal Fibroblast ◽  
Dermal Fibroblasts ◽  
Skin Fibrosis ◽  
Human Dermal Fibroblasts ◽  
Interleukin 33 ◽  
Dermal Fibrosis

Background:Systemic sclerosis (SSc) is a chronic immune-mediated autoimmune disease that is characterized by fibrotic changes of the skin and internal organs, which in turn leads to distortion of tissue structure and gradual loss of organ function. So far, there is still no treatment allows full recovery from this severe disorder. Therefore, it is of great social significance to study the pathogenesis of this disease and find new targets for treatment. Interleukin 33 (IL-33), which is a potent inducer of type 2 immune response, has been confirmed to be involved in the development and progression of multiple fibrotic diseases. However, the role and mechanism of IL-33 in SSc-related fibrosis remains unclear.Objectives:To clarify the role of interleukin 33 (IL-33) and its receptor Suppression of tumorigenicity 2 (ST2) in the skin fibrosis of SSc, so to provides a new target for the treatment of fibrosis in patients with SSc.Methods:The levels of IL-33 and ST2 was analysed in human samples, murine models of SSc and in cultured fibroblasts by immunohistochemistry and immunofluorescence. The functional role of IL-33 was evaluated by detecting changes in proliferation, migration, and activation of fibroblasts stimulated with recombinant IL-33 protein. MAPK and NF-κB signallings of fibroblasts were assessed by western blotting and analyses of target genes. The role of IL-33 in skin fibrosis was analysed in IL-33 deficient mice (il33−/−) and wild-type controls injected with bleomycin or NaCl.Results:The expression of IL-33 and its receptor ST2 were up-regulated in skin lesions of SSc patients (Fig 1 A-C) and bleomycin-treated mice(Fig1 D-F). Compared to the healthy skin, the skin from SSc patients expressed more ST2 on fibroblasts membrane(Fig 1 B-C). IL33 induces MAPK and IκBα activation in human dermal fibroblast(Fig 2 A), and promote proliferation, migration and production of collagen of human dermal fibroblasts, but not the release of inflammatory factors(IL-6, MCP-1)(Fig2 B-G). Mice deficient for IL33 are protected from bleomycin-induced dermal fibrosis (Fig3).Fig 1.Increased expression of IL33, ST2 in SSc patients and bleomycin-treated mice.Fig 2.IL33 induces MAPK and IκBα activation in human dermal fibroblast, and and promote proliferation, migration and production of collagen of human dermal fibroblasts.Fig 3.Mice deficient for IL33 are protected from bleomycin-induced dermal fibrosis.Conclusion:IL33 promotes skin fibrosis by activating fibroblasts, and IL33/ST2 may be an important target for the treatment of fibrosis in patients with SSc.References:[1]Ingegnoli F, Ughi N, Mihai C. Update on the epidemiology, risk factors, and disease outcomes of systemic sclerosis. Best practice & research. Clinical rheumatology. 2018;32(2):223-240.[2]Schmitz J, Owyang A, Oldham E, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23(5):479-490.[3]Molofsky AB, Savage AK, Locksley RM. Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation.Immunity.2015;42(6):1005-1019.Disclosure of Interests:None declared

Very long chain fatty acids activate NADPH oxidase in human dermal fibroblasts

2004 ◽  
Vol 23 (1) ◽  
pp. 65-68 ◽  
Author(s):  
Gursev S. Dhaunsi ◽  
Jaspal Kaur ◽  
Khaled Alsaeid ◽  
Ronald B. Turner ◽  
Milad S. Bitar
Keyword(s):  
Fatty Acids ◽  
Nadph Oxidase ◽  
Dermal Fibroblasts ◽  
Long Chain Fatty Acids ◽  
Human Dermal Fibroblasts ◽  
Long Chain ◽  
Chain Fatty Acids
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