Journal article
EDA fibronectin-TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis
The Journal of experimental medicine, Vol.216(3), pp.587-604
03/01/2019
DOI: 10.1084/jem.20181074
PMCID: PMC6400533
PMID: 30733282
Abstract
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 (TPOhigh). 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-kappa B activation and release of profibrotic IL-6. Pharmacological inhibition of TLR4 or TLR4 deletion in TPOhigh 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.
Details
- Title: Subtitle
- EDA fibronectin-TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis
- Creators
- Alessandro Malara - University of PaviaCristian Gruppi - University of PaviaVittorio Abbonante - University of PaviaDaniele Cattaneo - Fondazione IRCCS Ca' Granda Ospedale Maggiore PoliclinicoLuigi De Marco - Scripps Research InstituteMargherita Massa - Policlinico San Matteo FondazioneAlessandra Iurlo - Fondazione IRCCS Ca' Granda Ospedale Maggiore PoliclinicoUmberto Gianelli - University of MilanCarlo L. Balduini - Policlinico San Matteo FondazioneMaria E. Tira - University of PaviaAndres F. Muro - International Centre for Genetic Engineering and BiotechnologyAnil K. Chauhan - University of IowaVittorio Rosti - Policlinico San Matteo FondazioneGiovanni Barosi - Policlinico San Matteo FondazioneAlessandra Balduini - Tufts University
- Resource Type
- Journal article
- Publication Details
- The Journal of experimental medicine, Vol.216(3), pp.587-604
- Publisher
- Rockefeller Univ Press
- DOI
- 10.1084/jem.20181074
- PMID
- 30733282
- PMCID
- PMC6400533
- ISSN
- 0022-1007
- eISSN
- 1540-9538
- Number of pages
- 18
- Grant note
- RBFR1299KO / Italian Ministry of University and Research Future in Research R35HL139926; R01 NS109910; R01-HL134829 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA GR-2016-02363136 / Ricerca Finalizzata Giovani Ricercatori 2016 by the Italian Ministry of Health R01HL134829 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) 2013-0717 / Cariplo Foundation; Fondazione Cariplo AIRC IG 2016 18700 / Associazione Italiana per la Ricerca sul Cancro; Fondazione AIRC per la ricerca sul cancro 18EIA33900009 / American Heart Association 1005 / Associazione Italiana per la Ricerca sul Cancro "Special Program Molecular Clinical Oncology 5x1000"; Fondazione AIRC per la ricerca sul cancro R01NS109910 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS)
- Language
- English
- Date published
- 03/01/2019
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359660402771
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