Decreased stability of erythroblastic islands in integrin β3-deficient mice

Abstract

Erythroblasts proliferate and differentiate in hematopoietic organs within erythroblastic islands (EI) composed of erythropoietic progenitor cells attached to a central macrophage. This cellular interaction crucially involves the erythroid intercellular adhesion molecule-4 (ICAM-4) and αv integrin. Because integrins are biologically active as α/β heterodimers, we asked whether β3 could be a heterodimerization partner of αv integrin in EIs. To this end we compared stress erythropoiesis driven by two different mechanisms, namely that of integrin β3-deficient (β3−/−) mice that exhibit impaired hemostasis due to platelet dysfunction with that of systemically erythropoietin-overexpressing (tg6) mice. While compared to the respective wild type (wt) controls β3−/− mice had much less erythropoietic stimulation than tg6 mice β3−/− blood contained more erythrocytes of a lower maturity stage. Unexpectedly, membranes of peripheral erythrocytes from β3−/− mice (but not those from either wt control or from tg6 mice) contained calnexin, a chaperone that is normally completely lost during terminal differentiation of reticulocytes prior to their release into the circulation. In contrast to erythropoietin-overexpressing mice, the erythropoietic subpopulations representing orthochromatic erythroblasts and premature reticulocytes as well as the number of cells per EI were reduced in β3−/− bone marrow. In conclusion, absence of integrin β3 impairs adhesion of the latest erythroid developmental stage to the central macrophage of EIs resulting in preterm release of abnormally immature erythrocytes into the circulation.

Evidence of hemolysis in pigs infected with highly virulent African swine fever virus

“…Its early appearance is a characteristic pathology of the central macrophage of erythroblastic island. A similar phenomenon is well described in literature [24], and we can reasonably suppose that the main reason of erythroblastosis is the direct lesion of these macrophages by the virus. The next etiological component in the pathology of red blood identified in our laboratory is intravascular hemolysis.…”

β-Thalassemia and Polycythemia vera: Targeting chronic stress erythropoiesis

“…Some adhesion molecules are under investigation, including integrin β3 (Wang et al, 2013), and integrin α4β1 which is highly expressed on developing erythroblasts and may interact with VCAM-1 present on macrophages (Ulyanova et al, 2014). In addition, focal adhesion kinase (FAK), located downstream of the integrin signaling pathway, has been associated with the stress erythroid response, possibly through mediation of the Epo/STAT5 pathway (Vemula et al, 2010).…”

Erythropoiesis, EPO, macrophages, and bone

“…Cell-cell interactions between erythroblasts and their attendant central macrophage are crucial to the maintenance of the island. These interactions have been demonstrated to depend on erythroid macrophage protein (EMP or macrophage erythroblast attacher [MAEA]), intracellular adhesion molecule 4 (ICAM4) -α v β 3 integrin, and vascular cell adhesion molecule 1 (VCAM-1) -very late activation antigen 4 (VLA4) integrin α 4 β 1 (66)(67)(68)(69)(70). During the final stages of their development, nascent reticulocytes undergo enucleation and their close association with the central macrophage allows the macrophage to efficiently clear the resultant pyrenocytes (71).…”