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

Alessandro Malara, Cristian Gruppi, Vittorio Abbonante, Daniele Cattaneo, Luigi De Marco, Margherita Massa, Alessandra Iurlo, Umberto Gianelli, Carlo L. Balduini, Maria E. Tira, Andrès F. Muro, Anil K. Chauhan, Vittorio Rosti, Giovanni Barosi, Alessandra Balduini

Research output: Contribution to journalArticle

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-κB 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.

Original languageEnglish
Pages (from-to)587-604
Number of pages18
JournalThe Journal of experimental medicine
Volume216
Issue number3
DOIs
Publication statusPublished - Mar 4 2019

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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