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

Autor: Malara A; Department of Molecular Medicine, University of Pavia, Pavia, Italy.; Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientific San Matteo Foundation, Pavia, Italy., Gruppi C; Department of Molecular Medicine, University of Pavia, Pavia, Italy., Abbonante V; Department of Molecular Medicine, University of Pavia, Pavia, Italy.; Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientific San Matteo Foundation, Pavia, Italy., Cattaneo D; Hematology Division, Istituto di Ricovero e Cura a Carattere Scientific Ca' Granda-Maggiore Policlinico Hospital Foundation, Milan, Italy., De Marco L; Department of Translational Research, National Cancer Center (Istituto di Ricovero e Cura a Carattere Scientific Centro di Riferimento Oncologico), Aviano, Italy.; Department of Molecular and Experimental Research, The Scripps Research Institute, La Jolla, CA., Massa M; Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientific San Matteo Foundation, Pavia, Italy., Iurlo A; Hematology Division, Istituto di Ricovero e Cura a Carattere Scientific Ca' Granda-Maggiore Policlinico Hospital Foundation, Milan, Italy., Gianelli U; Division of Pathology, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy., Balduini CL; Department of Internal Medicine, Istituto di Ricovero e Cura a Carattere Scientific San Matteo Foundation, Pavia, Italy., Tira ME; Department of Biology and Biotechnology 'Lazzaro Spallanzani,' University of Pavia, Pavia, Italy., Muro AF; The International Center for Genetic Engineering and Biotechnology, Trieste, Italy., Chauhan AK; Department of Internal Medicine, University of Iowa, Iowa City, IA., Rosti V; Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientific Policlinico S. Matteo Foundation, Pavia, Italy., Barosi G; Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientific Policlinico S. Matteo Foundation, Pavia, Italy., Balduini A; Department of Molecular Medicine, University of Pavia, Pavia, Italy alessandra.balduini@tufts.edu.; Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientific San Matteo Foundation, Pavia, Italy.; Department of Biomedical Engineering, Tufts University, Medford, MA.
Jazyk: angličtina
Zdroj: The Journal of experimental medicine [J Exp Med] 2019 Mar 04; Vol. 216 (3), pp. 587-604. Date of Electronic Publication: 2019 Feb 07.
DOI: 10.1084/jem.20181074
Abstrakt: 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.
(© 2019 Malara et al.)
Databáze: MEDLINE
Externí odkaz: