Identification of extracellular matrix-derived biomarkers and targets in dystrophic epidermolysis bullosa
Final Report Abstract
The aim of this project was to, using the genetic disease recessive dystrophic epidermolysis bullosa (RDEB) as a paradigm of injury- and inflammation-evoked fibrosis, understand how fibrosis occurs in such a context and its wider consequences. Our strategy was to take a retrospective approach by focusing analyses on the extracellular matrix after development of fibrosis and from these conclude how the fibrosis developed. Our project revealed many important insights. We found that fibrosis in RDEB is not the consequence of changes in the abundance of major structural extracellular matrix proteins frequently associated with fibrosis, such as collagen I. In RDEB fibrosis is to a large extent the consequence of altered collagen matrix arrangement, which likely occurs through increased abundance of regulators of extracellular matrix deposition including periostin and tenascin-C. We revealed that fibrosis progression in RDEB is associated with active pro-inflammatory immunity and heightened exchange with fibroblasts. Targeting this exchange by reducing cellular activities attenuated progression of RDEB fibrosis in in vitro models and in RDEB model mice. Furthermore, using the concepts developed from understanding of fibrosis in RDEB, we could disclose mechanistically how DPP4 promotes formation of a pro-fibrotic extracellular matrix. This occurs thorough proteolysis of fibronectin molecules which alters fibronectin-guided extracellular matrix deposition. Again these findings support the idea that fibrosis is in large a consequence of altered extracellular matrix arrangement with changes in abundance of e.g. fibrillar collagens being of lesser importance for RDEB and fibroses arising in a similar context. We addressed the consequences of sensing of increasing stiffness by basal epidermal keratinocytes which occurs during fibrotic-like remodeling of the dermis. Intriguingly, our investigations revealed a link of response to increasing stiffness and altered epidermal barrier formation. Our data indicated that this is applicable to many skin inflammatory conditions and we also conceptually showed that targeting signaling pathways in keratinocytes evoked by mechanosignaling restores the appearance of the epidermal barriers. To conclude our project has provided advances in the understanding of fibrosis and its consequences, which are predicted to not be limited to RDEB but also applicable to more common skin diseases.
Publications
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Generation of rabbit polyclonal human and murine collagen VII monospecific antibodies: A useful tool for dystrophic epidermolysis bullosa therapy studies. Matrix Biology Plus, 4, 100017.
Bornert, Olivier; Kocher, Thomas; Gretzmeier, Christine; Liemberger, Bernadette; Hainzl, Stefan; Koller, Ulrich & Nyström, Alexander
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Pseudomonas aeruginosalectin LecB impairs keratinocyte fitness by abrogating growth factor signalling. Life Science Alliance, 2(6), e201900422.
Landi, Alessia; Mari, Muriel; Kleiser, Svenja; Wolf, Tobias; Gretzmeier, Christine; Wilhelm, Isabel; Kiritsi, Dimitra; Thünauer, Roland; Geiger, Roger; Nyström, Alexander; Reggiori, Fulvio; Claudinon, Julie & Römer, Winfried
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STAT3 targeting in dystrophic epidermolysis bullosa. British Journal of Dermatology, 182(5), 1279-1281.
Mittapalli, V.R.; Kühl, T.; Kuzet, S.E.; Gretzmeier, C.; Kiritsi, D.; Gaggioli, C.; Bruckner‐Tuderman, L. & Nyström, A.
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Proteomic Profiling of Fibroblasts Isolated from Chronic Wounds Identifies Disease-Relevant Signaling Pathways. Journal of Investigative Dermatology, 140(11), 2280-2290.e4.
Berberich, Bettina; Thriene, Kerstin; Gretzmeier, Christine; Kühl, Tobias; Bayer, Hans; Athanasiou, Ioannis; Rafei-Shamsabadi, David Ali; Bruckner-Tuderman, Leena; Nyström, Alexander; Kiritsi, Dimitra & Dengjel, Jörn
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Diversity of Mechanisms Underlying Latent TGF-β Activation in Recessive Dystrophic Epidermolysis Bullosa. Journal of Investigative Dermatology, 141(6), 1450-1460.e9.
Akasaka, Eijiro; Kleiser, Svenja; Sengle, Gerhard; Bruckner-Tuderman, Leena & Nyström, Alexander
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Pro‐inflammatory immunity supports fibrosis advancement in epidermolysis bullosa: intervention with Ang‐(1‐7). EMBO Molecular Medicine, 13(10).
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
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QR-313, an Antisense Oligonucleotide, Shows Therapeutic Efficacy for Treatment of Dominant and Recessive Dystrophic Epidermolysis Bullosa: A Preclinical Study. Journal of Investigative Dermatology, 141(4), 883-893.e6.
Bornert, Olivier; Hogervorst, Marieke; Nauroy, Pauline; Bischof, Johannes; Swildens, Jim; Athanasiou, Ioannis; Tufa, Sara F.; Keene, Douglas R.; Kiritsi, Dimitra; Hainzl, Stefan; Murauer, Eva M.; Marinkovich, M. Peter; Platenburg, Gerard; Hausser, Ingrid; Wally, Verena; Ritsema, Tita; Koller, Ulrich; Haisma, Elisabeth M. & Nyström, Alexander
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Case Report: Diagnostic and Therapeutic Challenges in Severe Mechanobullous Epidermolysis Bullosa Acquisita. Frontiers in Immunology, 13.
Schauer, Franziska; Nyström, Alexander; Kunz, Manfred; Hübner, Stefanie; Scholl, Sarah; Athanasiou, Ioannis; Alter, Svenja; Fischer, Judith; Has, Cristina & Kiritsi, Dimitra
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Comparison of extracellular matrix enrichment protocols for the improved characterization of the skin matrisome by mass spectrometry. Journal of Proteomics, 251, 104397.
Dussoyer, Mélissa; Page, Adeline; Delolme, Frédéric; Rousselle, Patricia; Nyström, Alexander & Moali, Catherine
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Occurrence of autoantibodies against skin proteins in patients with hereditary epidermolysis bullosa predisposes to development of autoimmune blistering disease. Frontiers in Immunology, 13.
Lehr, Saskia; Felber, Felicitas; Tantcheva-Poór, Iliana; Keßler, Christina; Eming, Rüdiger; Nyström, Alexander; Rizzi, Marta & Kiritsi, Dimitra
