Pro‐inflammatory immunity supports fibrosis advancement in epidermolysis bullosa: intervention with Ang‐(1‐7)

• Published in: EMBO molecular medicine Vol. 13; no. 10; pp. e14392 - n/a
• Main Authors: Bernasconi, Rocco, Thriene, Kerstin, Romero‐Fernández, Elena, Gretzmeier, Christine, Kühl, Tobias, Maler, Mareike, Nauroy, Pauline, Kleiser, Svenja, Rühl‐Muth, Anne‐Catherine, Stumpe, Michael, Kiritsi, Dimitra, Martin, Stefan F, Hinz, Boris, Bruckner‐Tuderman, Leena, Dengjel, Jörn, Nyström, Alexander
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-10-2021; EMBO Press; John Wiley and Sons Inc; Springer Nature
• Subjects: Angiotensin; Cell interactions; Collagen; collagen VII; Disease; Dystrophic epidermolysis bullosa; EMBO16; EMBO19; EMBO38; Epidermolysis bullosa; Extracellular matrix; Fibrosis; genetic disease; Inflammation; Peptides; Proteins; Proteomes; Proteomics; Renin; Skin; Skin diseases; Structural proteins; therapy; Wound healing; skin; collagen VII; inflammation; genetic disease; therapy
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.202114392

Recessive dystrophic epidermolysis bullosa (RDEB), a genetic skin blistering disease, is a paradigmatic condition of tissue fragility‐driven multi‐organ fibrosis. Here, longitudinal analyses of the tissue proteome through the course of naturally developing disease in RDEB mice revealed that increased pro‐inflammatory immunity associates with fibrosis evolution. Mechanistically, this fibrosis is a consequence of altered extracellular matrix organization rather than that of increased abundance of major structural proteins. In a humanized system of disease progression, we targeted inflammatory cell fibroblast communication with Ang‐(1‐7)—an anti‐inflammatory heptapeptide of the renin‐angiotensin system, which reduced the fibrosis‐evoking aptitude of RDEB cells.
In vivo,
systemic administration of Ang‐(1‐7) efficiently attenuated progression of multi‐organ fibrosis and increased survival of RDEB mice. Collectively, our study shows that selective down‐modulation of pro‐inflammatory immunity may mitigate injury‐induced fibrosis. Furthermore, together with published data, our data highlight molecular diversity among fibrotic conditions. Both findings have direct implications for the design of therapies addressing skin fragility and fibrosis.
SYNOPSIS
Injury‐evoked fibrosis in recessive dystrophic epidermolysis bullosa (RDEB) associates with inflammatory immunity. This fibrosis is a consequence of altered extracellular matrix (ECM) organization. Targeting fibro‐inflammatory communication with Ang‐(1‐7) effectively attenuates fibrosis in RDEB.
Inflammatory immunity with seemingly little involvement of tissue‐repair immunity supports fibrosis in RDEB.
Established fibrotic lesions in RDEB display modest changes of major structural proteins including fibrillar collagens, but show changed abundance of minor ECM organizer and altered ECM architecture.
Selective targeting of dysregulated fibro‐inflammatory communication in injured RDEB tissue with Ang‐(1‐7) effectively attenuates progression of multi‐organ fibrosis.
Graphical Abstract
Injury‐evoked fibrosis in recessive dystrophic epidermolysis bullosa (RDEB) associates with inflammatory immunity. This fibrosis is a consequence of altered extracellular matrix (ECM) organization. Targeting fibro‐inflammatory communication with Ang‐(1‐7) effectively attenuates fibrosis in RDEB.