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 language | English |
|---|---|
| Pages (from-to) | 587-604 |
| Number of pages | 18 |
| Journal | The Journal of experimental medicine |
| Volume | 216 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 4 2019 |
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ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
Cite this
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.
In: The Journal of experimental medicine, Vol. 216, No. 3, 04.03.2019, p. 587-604.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - EDA fibronectin-TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis
AU - Malara, Alessandro
AU - Gruppi, Cristian
AU - Abbonante, Vittorio
AU - Cattaneo, Daniele
AU - De Marco, Luigi
AU - Massa, Margherita
AU - Iurlo, Alessandra
AU - Gianelli, Umberto
AU - Balduini, Carlo L.
AU - Tira, Maria E.
AU - Muro, Andrès F.
AU - Chauhan, Anil K.
AU - Rosti, Vittorio
AU - Barosi, Giovanni
AU - Balduini, Alessandra
PY - 2019/3/4
Y1 - 2019/3/4
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20181074
DO - 10.1084/jem.20181074
M3 - Article
C2 - 30733282
AN - SCOPUS:85062410600
VL - 216
SP - 587
EP - 604
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 3
ER -