TGF‐β1 mediates pathologic changes of secondary lymphedema by promoting fibrosis and inflammation

Baik, Jung Eun; Park, Hyeung Ju; Kataru, Raghu P.; Savetsky, Ira L.; Ly, Catherine; Shin, Jinyeon; Encarnacion, Elizabeth; Cavali, Michele R.; Klang, Mark; Riedel, Elyn; Coriddi, Michelle; Dayan, Joseph H.; Mehrara, Babak J.

doi:10.1002/ctm2.758

Cited by 26 publications

(25 citation statements)

References 141 publications

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“…In this model, histological signs of lymphedema, such as inflammation and fibroadipose deposition, develop 4-6 weeks after skin and lymphatic excision. ( 16, 40 ) We therefore harvested tail skin specimens 2 and 6 weeks after surgery to analyze epidermal changes before and after the onset of lymphedema. ( 40 ) We found that hyperkeratosis occurred rapidly after lymphatic injury and was evident even at the 2-week time point in skin sections harvested 2-3 cm from the excision site ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…( 16, 40 ) We therefore harvested tail skin specimens 2 and 6 weeks after surgery to analyze epidermal changes before and after the onset of lymphedema. ( 40 ) We found that hyperkeratosis occurred rapidly after lymphatic injury and was evident even at the 2-week time point in skin sections harvested 2-3 cm from the excision site ( Fig. 2A and B ).…”

Section: Resultsmentioning

confidence: 99%

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Keratinocytes coordinate inflammatory responses and regulate development of secondary lymphedema

Park

Kataru

Shin

et al. 2023

Preprint

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Epidermal changes are histological hallmarks of secondary lymphedema, but it is unknown if keratinocytes contribute to its pathophysiology. Using clinical lymphedema specimens and mouse models, we show that keratinocytes play a primary role in lymphedema development by producing T-helper 2 (Th2) -inducing cytokines. Specifically, we find that keratinocyte proliferation and expression of protease-activated receptor 2 (PAR2) are early responses following lymphatic injury and regulate the expression of Th2-inducing cytokines, migration of Langerhans cells, and skin infiltration of Th2-differentiated T cells. Furthermore, inhibition of PAR2 activation with a small molecule inhibitor or the proliferation inhibitor teriflunomide (TF) prevents activation of keratinocytes stimulated with lymphedema fluid. Finally, topical TF is highly effective for decreasing swelling, fibrosis, and inflammation in a preclinical mouse model. Our findings suggest that lymphedema is a chronic inflammatory skin disease, and topically targeting keratinocyte activation may be a clinically effective therapy for this condition.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Keratinocytes coordinate inflammatory responses and regulate development of secondary lymphedema

Park

Kataru

Shin

et al. 2023

Preprint

Self Cite

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“…Noticeably, FN-1 was verified as a crucial gene closely associated with the growth of SFs and has huge potential for regulation of RA initiation. FN-1, an ECM protein produced by fibroblasts, was previously found to be involved in the pathological changes in many tissues ( Liu et al, 2019 ; Baik et al, 2022 ). Furthermore, emerging evidence has revealed that FN-1 is closely related to RA initiation and development ( Przybysz et al, 2007 ; van Beers et al, 2012 ; Xu et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Fibronectin-1 is a dominant mechanism for rheumatoid arthritis via the mediation of synovial fibroblasts activity

Yang

Zhang

Liang

et al. 2022

Front. Cell Dev. Biol.

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Rheumatoid arthritis (RA) has a high incidence and adverse effects on patients, thus posing a serious threat to people’s life and health. However, the underlying mechanisms regarding the development of RA are still elusive. Herein, we aimed to evaluate the RA-associated molecular mechanisms using the scRNA-seq technique. We used the GEO database to obtain scRNA-seq datasets for synovial fibroblasts (SFs) from RA cases, and the genes were then analyzed using principal component analysis (PCA) and T-Stochastic Neighbor Embedding (TSNE) analyses. Bioinformatics evaluations were carried out for asserting the highly enriched signaling pathways linked to the marker genes, and the key genes related to RA initiation were further identified. According to the obtained results, 3 cell types (0, 1, and 2) were identified by TSNE and some marker genes were statistically upregulated in cell type 1 than the other cell types. These marker genes predominantly contributed to extracellular matrix (ECM) architecture, collagen-harboring ECM, and ECM structural components, and identified as enriched with PI3K/AKT signaling cascade. Notably, fibronectin-1 (FN-1) has been identified as a critical gene that is strongly linked to the development of SFs and has enormous promise for regulating the onset of RA. Moreover, such an investigation offers novel perspectives within onset/progression of RA, suggesting that FN-1 may be a key therapeutic target for RA therapies.

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“…Radiotherapy together with BMI, age, tumor stages, lymph node dissection and the number of lymph nodes removed are the main risk factors for lymphedema after cancer treatment ( Tsai et al, 2009 ; DiSipio et al, 2013 ; Warren et al, 2014 ; Hu et al, 2022 ). Radiotherapy is well known to cause tissue fibrosis, as a result of transforming growth factor TGF-β1 production ( Martin et al, 2000 ; Baik et al, 2022 ). It also affects lymphatic function by inducing lymphatic endothelial cell apoptosis and decreasing the number of cutaneous lymphatic vessels ( Avraham et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Single and combined impacts of irradiation and surgery on lymphatic vasculature and fibrosis associated to secondary lymphedema

Buntinx

Lebeau²,

Gillot³

et al. 2022

Front. Pharmacol.

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Lymphedema (LD) refers to a condition of lymphatic dysfunction associated with excessive fluid accumulation, fibroadipose tissue deposition and swelling. In industrialized countries, LD development mainly results from a local disruption of the lymphatic network by an infection or cancer-related surgery (secondary LD). In the absence of efficient therapy, animal models are needed to decipher the cellular and molecular mechanisms underlying LD and test putative drugs. In this study, we optimized and characterized a murine model of LD that combines an irradiation of the mice hind limb and a radical surgery (lymph node resection associated to lymphatic vessel ligation). We investigated the respective roles of irradiation and surgery in LD formation by comparing their impacts, alone or in combination (with different intervention sequences), on eight different features of the pathology: swelling (paw thickness), indocyanine green (ICG) clearance, lymphatic vasculature remodeling, epidermal and dermal thickening, adipocyte accumulation, inflammatory cell infiltration and collagen deposition. This study supports the importance of radiation prior to surgery to experimentally induce a rapid, severe and sustained tissue remodeling harboring the different hallmarks of LD. We provide the first experimental evidence for an excessive deposition of periostin (POSTN) and tenascin-C (TNC) in LD. Through a computerized method of digital image quantification, we established the spatial map of lymphatic expansion, as well as collagen, POSTN and TNC deposition in papillary and reticular dermis of lymphedematous skins. This mouse model is available to study the patho-physiology of LD and test potential therapeutic targets.

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TGF‐β1 mediates pathologic changes of secondary lymphedema by promoting fibrosis and inflammation

Cited by 26 publications

References 141 publications

Keratinocytes coordinate inflammatory responses and regulate development of secondary lymphedema

Keratinocytes coordinate inflammatory responses and regulate development of secondary lymphedema

Fibronectin-1 is a dominant mechanism for rheumatoid arthritis via the mediation of synovial fibroblasts activity

Single and combined impacts of irradiation and surgery on lymphatic vasculature and fibrosis associated to secondary lymphedema

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