Inhibition of CXCR1/2 reduces the emperipolesis between neutrophils and megakaryocytes in the Gata1 low model of myelofibrosis.

Autor: Arciprete F; Unit of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico, Rome, Italy., Verachi P; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy., Martelli F; National Center for Preclinical and Clinical Research and Evaluation of Pharmaceutical Drugs, Istituto Superiore di Sanità, Rome, Italy., Valeri M; Center for Animal Experimentation and Well-Being, Istituto Superiore di Sanità, Rome, Italy., Balliu M; Center Research and Innovation of Myeloproliferative Neoplasm, University Hospital Careggi, University of Florence, Florence, Italy., Guglielmelli P; Center Research and Innovation of Myeloproliferative Neoplasm, University Hospital Careggi, University of Florence, Florence, Italy., Vannucchi AM; Center Research and Innovation of Myeloproliferative Neoplasm, University Hospital Careggi, University of Florence, Florence, Italy., Migliaccio AR; Unit of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico, Rome, Italy; Altius Institute for Biomedical Sciences, Seattle, WA., Zingariello M; Unit of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico, Rome, Italy. Electronic address: m.zingariello@unicampus.it.
Jazyk: angličtina
Zdroj: Experimental hematology [Exp Hematol] 2023 May; Vol. 121, pp. 30-37. Date of Electronic Publication: 2023 Mar 01.
DOI: 10.1016/j.exphem.2023.02.003
Abstrakt: Emperipolesis between neutrophils and megakaryocytes was first identified by transmission electron microscopy. Although rare under steady-state conditions, its frequency greatly increases in myelofibrosis, the most severe of myeloproliferative neoplasms, in which it is believed to contribute to increasing the transforming growth factor (TGF)-β microenvironmental bioavailability responsible for fibrosis. To date, the challenge of performing studies by transmission electron microscopy has hampered the study of factors that drive the pathological emperipolesis observed in myelofibrosis. We established a user-friendly confocal microscopy method that detects emperipolesis by staining with CD42b, specifically expressed on megakaryocytes, coupled with antibodies that recognize the neutrophils (Ly6b or neutrophil elastase antibody). With such an approach, we first confirmed that the bone marrow from patients with myelofibrosis and from Gata1 low mice, a model of myelofibrosis, contains great numbers of neutrophils and megakaryocytes in emperipolesis. Both in patients and Gata1 low mice, the emperipolesed megakaryocytes were surrounded by high numbers of neutrophils, suggesting that neutrophil chemotaxis precedes the actual emperipolesis event. Because neutrophil chemotaxis is driven by CXCL1, the murine equivalent of human interleukin 8 that is expressed at high levels by malignant megakaryocytes, we tested the hypothesis that neutrophil/megakaryocyte emperipolesis could be reduced by reparixin, an inhibitor of CXCR1/CXCR2. Indeed, the treatment greatly reduced both neutrophil chemotaxis and their emperipolesis with the megakaryocytes in treated mice. Because treatment with reparixin was previously reported to reduce both TGF-β content and marrow fibrosis, these results identify neutrophil/megakaryocyte emperipolesis as the cellular interaction that links interleukin 8 to TGF-β abnormalities in the pathobiology of marrow fibrosis.
Competing Interests: Conflict of Interest Disclosure Dr. AR Migliaccio received research funds from Dompé Farmaceutici SPA.
(Copyright © 2023 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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