Diversity of Mechanisms Underlying Latent TGF-β Activation in Recessive Dystrophic Epidermolysis Bullosa.

Abstract

Injury- and inflammation-driven progressive dermal fibrosis is a severe manifestation of recessive dystrophic epidermolysis bullosa-a genetic skin blistering disease caused by mutations in COL7A1. TGF-β activation plays a prominent part in progressing dermal fibrosis. However, the underlying mechanisms are not fully elucidated. TGF-β is secreted in a latent form, which has to be activated for its biological functions. In this study, we determined that recessive dystrophic epidermolysis bullosa fibroblasts have an enhanced capacity to activate the latent form. Mechanistic and functional assessment demonstrated that this process depends on multiple latent TGF-β activators, including TSP-1, RGD-binding integrins, matrix metalloproteinases, and ROS, which act in concert, in a self-perpetuating feedback loop to progress fibrosis. Importantly, our study also disclosed keratinocytes as prominent facilitators of fibrosis in recessive dystrophic epidermolysis bullosa. They stimulate microenvironmental latent TGF-β activation through enhanced production of the above mediators. Collectively, our study provides data on the molecular mechanism behind dysregulated TGF-β signaling in recessive dystrophic epidermolysis bullosa, which are much needed for the development of evidence-based fibrosis-delaying treatments.

• Authors: Eijiro Akasaka, Svenja Kleiser, Gerhard Sengle, Leena Bruckner-Tuderman, Alexander Nyström
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 141 Issue 6 Pg. 1450-1460.e9 (06 2021) ISSN: 1523-1747 [Electronic] United States
• PMID: 33333127 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• COL7A1 protein, human
• Collagen Type VII
• Reactive Oxygen Species
• TGFB1 protein, human
• Thrombospondin 1
• Transforming Growth Factor beta1
• Matrix Metalloproteinases

Topics

• Adolescent
• Adult
• Aged, 80 and over
• Child
• Child, Preschool
• Collagen Type VII (genetics)
• Epidermolysis Bullosa Dystrophica (genetics, immunology, pathology)
• Female
• Fibroblasts (metabolism, pathology)
• Fibrosis
• Healthy Volunteers
• Humans
• Infant
• Infant, Newborn
• Male
• Matrix Metalloproteinases (metabolism)
• Mutation
• Reactive Oxygen Species (metabolism)
• Signal Transduction (immunology)
• Skin (cytology, immunology, pathology)
• Thrombospondin 1 (metabolism)
• Transforming Growth Factor beta1 (metabolism)