TGFBIp mediates lymphatic sprouting in corneal lymphangiogenesis

Lin, Tong; Zhang, Xiaozhao; Yang, Lu; Gong, Lan

doi:10.1111/jcmm.14633

Cited by 8 publications

(6 citation statements)

References 58 publications

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“…53 Furthermore, a recent study showed that phosphorylation of FAK was enhanced by TGFBIp and was suppressed significantly by an integrin α5β1 inhibitor. 54 Considering that TGFBIp interacts with several integrins 55 including α5β1, 56 these data indicate that TGFBIp is an upstream regulator of the integrin/FAK/PGC-1α signalling pathway. Accordingly, TFEB in GCD2 corneal fibroblasts can be reduced by reduced integrin/FAK/PGC-1α signalling.…”

Section: Discussionmentioning

confidence: 92%

“…Although it remains unclear whether the pathogenic mutation causes a loss‐of‐function or gain‐of‐function of TGFBIp, Maeng et al showed that TGFBIp activates focal adhesion kinase (FAK) signalling 53 . Furthermore, a recent study showed that phosphorylation of FAK was enhanced by TGFBIp and was suppressed significantly by an integrin α5β1 inhibitor 54 . Considering that TGFBIp interacts with several integrins 55 including α5β1, 56 these data indicate that TGFBIp is an upstream regulator of the integrin/FAK/PGC‐1α signalling pathway.…”

Section: Discussionmentioning

confidence: 99%

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Lysosomal dysfunction of corneal fibroblasts underlies the pathogenesis of Granular Corneal Dystrophy Type 2 and can be rescued by TFEB

Choi

Woo

Kim

2020

J Cellular Molecular Medi

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Granular corneal dystrophy type 2 (GCD2) is the most common form of transforming growth factor β‐induced (TGFBI) gene‐linked corneal dystrophy and is pathologically characterized by the corneal deposition of mutant‐TGFBIp. The defective autophagic degradation of pathogenic mutant‐TGFBIp has been shown in GCD2; however, its exact mechanisms are unknown. To address this, we investigated lysosomal functions using corneal fibroblasts. Levels of cathepsins K and L (CTSK and CTSL) were significantly decreased in GCD2 cells, but of cathepsins B and D (CTSB and CTSD) did not change. The maturation of the pro‐enzymes to their active forms (CTSB, CTSK and CTSL) was inhibited in GCD2 cells. CTSL enzymes directly degraded both LC3 (autophagosomes marker) and mutant‐TGFBIp. Exogenous CTSL expression dramatically reduced mutant‐TGFBIp in GCD2 cells, but not TGFBIp in WT cells. An increased lysosomal pH and clustered lysosomal perinuclear position were found in GCD2 cells. Transcription factor EB (TFEB) levels were significantly reduced in GCD2 cells, compared to WT. Notably, exogenous TFEB expression improved mutant‐TGFBIp clearance and lysosomal abnormalities in GCD2 cells. Taken together, lysosomal dysfunction in the corneal fibroblasts underlies the pathogenesis of GCD2, and TFEB has a therapeutic potential in the treatment of GCD2.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Lysosomal dysfunction of corneal fibroblasts underlies the pathogenesis of Granular Corneal Dystrophy Type 2 and can be rescued by TFEB

Choi

Woo

Kim

2020

J Cellular Molecular Medi

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“…TGF-β has also reportedly regulated lymphatic vessel sprouting during development [ 44 , 45 ]. In the cornea, TGF-β-induced protein (TGFBIp), which is abundant in the cornea, enhances lymphangiogenesis; however, the underlying mechanisms remain unknown [ 46 ].…”

Section: Cytokines and Molecular Markers For Lymphangiogenesismentioning

confidence: 99%

“…However, specific cytokine-induced lymphangiogenesis is context-dependent. For example, TGF-β can induce or inhibit lymphangiogenesis [ 44 , 46 ].…”

Section: Cytokines Promote or Inhibit Lymphangiogenesis In Various Disease Modelsmentioning

confidence: 99%

Corneal Lymphangiogenesis: Current Pathophysiological Understandings and Its Functional Role in Ocular Surface Disease

Lee

2021

IJMS

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The cornea is a transparent and avascular tissue that plays a central role in light refraction and provides a physical barrier to the external environment. Corneal avascularity is a unique histological feature that distinguishes it from the other parts of the body. Functionally, corneal immune privilege critically relies on corneal avascularity. Corneal lymphangiogenesis is now recognized as a general pathological feature in many pathologies, including dry eye disease (DED), corneal allograft rejection, ocular allergy, bacterial and viral keratitis, and transient corneal edema. Currently, sizable data from clinical and basic research have accumulated on the pathogenesis and functional role of ocular lymphangiogenesis. However, because of the invisibility of lymphatic vessels, ocular lymphangiogenesis has not been studied as much as hemangiogenesis. We reviewed the basic mechanisms of lymphangiogenesis and summarized recent advances in the pathogenesis of ocular lymphangiogenesis, focusing on corneal allograft rejection and DED. In addition, we discuss future directions for lymphangiogenesis research.

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“…In vitro, the TGFBIp’s effect is mediated by the pathway of integrin α 5 β 1 -FAK. Integrin α 5 β 1 blockade can significantly inhibit lymphatic sprouting induced by TGFBIp [ 43 ].…”

Section: Integrins and The Eyementioning

confidence: 99%

Integrins: An Important Link between Angiogenesis, Inflammation and Eye Diseases

Mrugacz

Bryl

Falkowski

et al. 2021

Cells

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Integrins belong to a group of cell adhesion molecules (CAMs) which is a large group of membrane-bound proteins. They are responsible for cell attachment to the extracellular matrix (ECM) and signal transduction from the ECM to the cells. Integrins take part in many other biological activities, such as extravasation, cell-to-cell adhesion, migration, cytokine activation and release, and act as receptors for some viruses, including severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). They play a pivotal role in cell proliferation, migration, apoptosis, tissue repair and are involved in the processes that are crucial to infection, inflammation and angiogenesis. Integrins have an important part in normal development and tissue homeostasis, and also in the development of pathological processes in the eye. This review presents the available evidence from human and animal research into integrin structure, classification, function and their role in inflammation, infection and angiogenesis in ocular diseases. Integrin receptors and ligands are clinically interesting and may be promising as new therapeutic targets in the treatment of some eye disorders.

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TGFBIp mediates lymphatic sprouting in corneal lymphangiogenesis

Cited by 8 publications

References 58 publications

Lysosomal dysfunction of corneal fibroblasts underlies the pathogenesis of Granular Corneal Dystrophy Type 2 and can be rescued by TFEB

Lysosomal dysfunction of corneal fibroblasts underlies the pathogenesis of Granular Corneal Dystrophy Type 2 and can be rescued by TFEB

Corneal Lymphangiogenesis: Current Pathophysiological Understandings and Its Functional Role in Ocular Surface Disease

Integrins: An Important Link between Angiogenesis, Inflammation and Eye Diseases

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