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

Abstract

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.

Fibrosis as a Risk Factor for Cutaneous Squamous Cell Carcinoma in Recessive Dystrophic Epidermolysis Bullosa: A Systematic Review

“…27 Although the role of several proinflammatory cytokines, chemokines, cell types, and fibrosis in the phenotypic severity of EB has been widely described in the literature, few intervention case studies were conducted to interrupt the fibrotic process as a therapeutic method. 37 In this context, Bernasconi et al 38 Another study demonstrated that the suppression of TGF-β signaling, the expression of proinflammatory cytokines, and MMPs-9 and -13 in the RDEB skin microenvironment were able to prevent fibrosis and potentially modulate the malignant transformation of keratinocytes. 21 Although preclinical studies are still ongoing, we believe that the modulation of the main molecules involved in the fibrosis process in RDEB patients would be an important therapeutic alternative to minimize the effects that occur in the microenvironment in the face of recurrent blistering and healing events.…”

“…Although the role of several proinflammatory cytokines, chemokines, cell types, and fibrosis in the phenotypic severity of EB has been widely described in the literature, few intervention case studies were conducted to interrupt the fibrotic process as a therapeutic method. 37 In this context, Bernasconi et al 38 targeted inflammatory cell fibroblast communication with Ang-(1-7) an anti-inflammatory heptapeptide of the renin-angiotensin system. The authors demonstrated that the administration of Ang-(1-7) attenuated the progression of fibrosis in different organs and increased the survival of RDEB mice by selective modulation of proinflammatory immunity, reducing lesion-induced fibrosis.…”

Inborn errors of immunity and immunodeficiencies: Antibody‐mediated pathology and autoimmunity as a consequence of impaired immune reactions

“…However, disease evolution in DEB also correlates with increased activity of T and B cells [93]. Pharmacological down‐modulation of this inflammatory immunity in mice effectively delayed disease progression [93]. Combined with clinical trials showing benefit of immune modulation [98, 99], these data provide strong support for DEB as a partly immune‐driven disease.…”

“…1). DEB is a progressive disease, driven by injury and tissue inflammation [92,93]. In severely affected individuals, a fibrotic, multi-organ, highly debilitating disease develops with time [91].…”

“…Genetically evoked, as exemplified above, or virally induced destruction of the ECM and cell-ECM-associated structures of lymphoid organs such as conduits has, in the few instances this has been examined, been associated with some degree of immunodeficiency [89,[95][96][97]. However, disease evolution in DEB also correlates with increased activity of T and B cells [93]. Pharmacological down-modulation of this inflammatory immunity in mice effectively delayed disease progression [93].…”