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EDA fibronectin–TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis

The fibronectin EDA isoform (EDA FN) is instrumental in fibrogenesis but, to date, its expression and function in bone marrow (BM) fibrosis have not been explored. We found that mice constitutively expressing the EDA domain (EIIIA(+/+)), but not EDA knockout mice, are more prone to develop BM fibros...

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Autores principales: Malara, Alessandro, Gruppi, Cristian, Abbonante, Vittorio, Cattaneo, Daniele, De Marco, Luigi, Massa, Margherita, Iurlo, Alessandra, Gianelli, Umberto, Balduini, Carlo L., Tira, Maria E., Muro, Andrès F., Chauhan, Anil K., Rosti, Vittorio, Barosi, Giovanni, Balduini, Alessandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400533/
https://www.ncbi.nlm.nih.gov/pubmed/30733282
http://dx.doi.org/10.1084/jem.20181074
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author Malara, Alessandro
Gruppi, Cristian
Abbonante, Vittorio
Cattaneo, Daniele
De Marco, Luigi
Massa, Margherita
Iurlo, Alessandra
Gianelli, Umberto
Balduini, Carlo L.
Tira, Maria E.
Muro, Andrès F.
Chauhan, Anil K.
Rosti, Vittorio
Barosi, Giovanni
Balduini, Alessandra
author_facet Malara, Alessandro
Gruppi, Cristian
Abbonante, Vittorio
Cattaneo, Daniele
De Marco, Luigi
Massa, Margherita
Iurlo, Alessandra
Gianelli, Umberto
Balduini, Carlo L.
Tira, Maria E.
Muro, Andrès F.
Chauhan, Anil K.
Rosti, Vittorio
Barosi, Giovanni
Balduini, Alessandra
author_sort Malara, Alessandro
collection PubMed
description The fibronectin EDA isoform (EDA FN) is instrumental in fibrogenesis but, to date, its expression and function in bone marrow (BM) fibrosis have not been explored. We found that mice constitutively expressing the EDA domain (EIIIA(+/+)), but not EDA knockout mice, are more prone to develop BM fibrosis upon treatment with the thrombopoietin (TPO) mimetic romiplostim (TPO(high)). Mechanistically, EDA FN binds to TLR4 and sustains progenitor cell proliferation and megakaryopoiesis in a TPO-independent fashion, inducing LPS-like responses, such as NF-κB activation and release of profibrotic IL-6. Pharmacological inhibition of TLR4 or TLR4 deletion in TPO(high) mice abrogated Mk hyperplasia, BM fibrosis, IL-6 release, extramedullary hematopoiesis, and splenomegaly. Finally, developing a novel ELISA assay, we analyzed samples from patients affected by primary myelofibrosis (PMF), a well-known pathological situation caused by altered TPO signaling, and found that the EDA FN is increased in plasma and BM biopsies of PMF patients as compared with healthy controls, correlating with fibrotic phase.
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spelling pubmed-64005332019-09-04 EDA fibronectin–TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis Malara, Alessandro Gruppi, Cristian Abbonante, Vittorio Cattaneo, Daniele De Marco, Luigi Massa, Margherita Iurlo, Alessandra Gianelli, Umberto Balduini, Carlo L. Tira, Maria E. Muro, Andrès F. Chauhan, Anil K. Rosti, Vittorio Barosi, Giovanni Balduini, Alessandra J Exp Med Research Articles The fibronectin EDA isoform (EDA FN) is instrumental in fibrogenesis but, to date, its expression and function in bone marrow (BM) fibrosis have not been explored. We found that mice constitutively expressing the EDA domain (EIIIA(+/+)), but not EDA knockout mice, are more prone to develop BM fibrosis upon treatment with the thrombopoietin (TPO) mimetic romiplostim (TPO(high)). Mechanistically, EDA FN binds to TLR4 and sustains progenitor cell proliferation and megakaryopoiesis in a TPO-independent fashion, inducing LPS-like responses, such as NF-κB activation and release of profibrotic IL-6. Pharmacological inhibition of TLR4 or TLR4 deletion in TPO(high) mice abrogated Mk hyperplasia, BM fibrosis, IL-6 release, extramedullary hematopoiesis, and splenomegaly. Finally, developing a novel ELISA assay, we analyzed samples from patients affected by primary myelofibrosis (PMF), a well-known pathological situation caused by altered TPO signaling, and found that the EDA FN is increased in plasma and BM biopsies of PMF patients as compared with healthy controls, correlating with fibrotic phase. Rockefeller University Press 2019-03-04 /pmc/articles/PMC6400533/ /pubmed/30733282 http://dx.doi.org/10.1084/jem.20181074 Text en © 2019 Malara et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Malara, Alessandro
Gruppi, Cristian
Abbonante, Vittorio
Cattaneo, Daniele
De Marco, Luigi
Massa, Margherita
Iurlo, Alessandra
Gianelli, Umberto
Balduini, Carlo L.
Tira, Maria E.
Muro, Andrès F.
Chauhan, Anil K.
Rosti, Vittorio
Barosi, Giovanni
Balduini, Alessandra
EDA fibronectin–TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis
title EDA fibronectin–TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis
title_full EDA fibronectin–TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis
title_fullStr EDA fibronectin–TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis
title_full_unstemmed EDA fibronectin–TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis
title_short EDA fibronectin–TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis
title_sort eda fibronectin–tlr4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400533/
https://www.ncbi.nlm.nih.gov/pubmed/30733282
http://dx.doi.org/10.1084/jem.20181074
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