Such factors provide useful information with regard to DNM and the prognosis. We concluded that patients with early SCC whose tumors are > 4 mm in thickness and immunopositive for Flt-4 are particularly at risk of developing DNM.
The forkhead box O (FOXO) family has been extensively investigated in aging and metabolism, but its role in tissue-repair processes remains largely unknown. Herein, we clarify the molecular aspect of the FOXO family in skin wound healing. We demonstrated that Foxo1 and Foxo3a were both up-regulated during murine skin wound healing. Partial knockout of Foxo1 in Foxo1(+/-) mice throughout the body led to accelerated skin wound healing with enhanced keratinocyte migration, reduced granulation tissue formation, and decreased collagen density, accompanied by an attenuated inflammatory response, but we observed no wound phenotype in Foxo3a(-/-) mice. Fibroblast growth factor 2, adiponectin, and notch1 genes were significantly increased at wound sites in Foxo1(+/-) mice, along with markedly altered extracellular signal-regulated kinase 1/2 and AKT phosphorylation. Similarly, transient knockdown of Foxo1 at the wound site by local delivery of antisense oligodeoxynucleotides enhanced skin wound healing. The link between FOXO1 and scarring extends to patients, in particular keloid scars, where we see FOXO1 expression markedly increased in fibroblasts and inflammatory cells within the otherwise normal dermis. This occurs in the immediate vicinity of the keloid by comparison to the center of the mature keloid, indicating that FOXO1 is associated with the overgrowth of this fibrotic response into adjacent normal skin. Overall, our data indicate that molecular targeting of FOXO1 may improve the quality of healing and reduce pathological scarring.
Activated macrophages at wound sites release many cytokines which positively affect skin wound healing. However, the molecular mechanisms controlling cytokine secretion from macrophages have not been elucidated. In the present study, we performed an RT-PCR analysis and found that 19 small GTPase Rab isoforms were expressed at skin wound sites, with six of them (i.e. Rab3B, Rab27B, Rab30, Rab33A, Rab37, and Rab40C) being upregulated during the inflammation and proliferation/migration phase of skin repair. We also found that gene expression of Rab37 in murine primary and RAW264.7 macrophages was significantly induced after stimulation with LPS. Overexpression of wild type and constitutively active Rab37 in RAW264.7 cells significantly increased TNF-a secretion, whereas knockdown of Rab37 by siRNA significantly decreased it. We also identified 29 putative Rab37-interacting proteins, including the membrane fusion regulating Munc13-1, using liquid chromatography/ linear ion trap mass spectrometry (LC-MS/MS). Immunocytochemical analysis further revealed that TNF-a-containing vesicles were colocalized with both Rab37 and Munc13-1 in activated macrophages. Knockdown of Munc13-1 by siRNA significantly decreased TNF-a secretion. Taken together, these findings demonstrate that Rab37 interacts with Munc13-1 to control TNF-a secretion from activated macrophages.Key words: Macrophage . Munc13-1 . Rab37 . Skin wound healing . TNF-a Supporting Information available online IntroductionIn response to skin tissue damage, inflammatory cells rapidly infiltrate the wound site to protect against infection. In the acute phase of inflammation, neutrophils, the first responder inflammatory cells, migrate toward wound sites to internalize and eliminate pathogens. Subsequently, macrophages preferentially infiltrate to wound sites after neutrophil recruitment, where they release cytokines, chemokines, and growth factors to control skin wound healing by stimulating the activation and proliferation of fibroblasts and keratinocytes, and by promoting wound contraction and angiogenesis [1]. Although this inflammatory response 3230is part of the wound-healing process, wound models in several organisms have shown that the inflammatory response can cause fibrotic diseases (i.e. scarring) in the skin and other organs [2]. Recently, we have shown that osteopontin is secreted by activated fibroblasts in response to platelet-derived growth factor secreted from macrophages, and that silencing of osteopontin at skin wound sites reduces scarring and improves the quality of healing in vivo [3]. Therefore, the pathways controlling inflammatory mediator secretion could provide novel molecular therapeutic targets [4].One such inflammatory mediator, TNF-a, is a pleiotropic proinflammatory cytokine expressed by macrophages and neutrophils at skin wound sites [5,6]. It has been reported that signaling via TNF-a negatively regulates skin wound healing, because TNF-a receptor p55 KO mice showed rapid skin wound healing coincident with reduced inflammatory respons...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.