The macrophage contribution to stress erythropoiesis: when less is enough

Abstract

• Significant expansion only of native splenic macrophages that are F4/80 1 /Cd11b lo occurs in both post-Epo and post-hemolysis-induced stress.• VCAM-1 2/2 mice, like Spi-C 2/2 , mice have significantly decreased macrophages but did not have a compromised E-stress response.Although the importance of native bone marrow and spleen macrophages in enhancing baseline and stress erythropoiesis has been emphasized over several decades, their kinetic and phenotypic changes during a variety of stress responses have been unclear. Furthermore, whether monocyte-derived recruited macrophages can functionally substitute for inadequate or functionally impaired native macrophages has been controversial and seem to be not only tissue-but also stress-type dependent. To provide further insight into these issues, we made detailed observations at baseline and post-erythroid stress (E-stress) in 2 mouse models with genetically depressed macrophage numbers and compared them to their controls. We documented that, irrespective of the stressinduced (hemolytic or post-erythropoietin [Epo]) treatment, only native CD11b lo splenic macrophages expand dramatically post-stress in normal mice without significant changes in the monocyte-derived CD11b hi subset. The latter remained a minority and did not change post-stress in 2 genetic models lacking either Spi-C or VCAM-1 with impaired native macrophage proliferative expansion. Although CD11b lo macrophages in these mice were one-fifth of normal at their peak response, surprisingly, their erythroid response was not compromised and was similar to controls. Thus, despite the prior emphasis on numerical macrophage reliance to provide functional rescue from E-stress, our data highlight the importance of previously described non-macrophage-dependent pathways activated under certain stress conditions to compensate for low macrophage numbers. (Blood. 2016;128(13):1756-1765

Glucocorticoids induce differentiation of monocytes towards macrophages that share functional and phenotypical aspects with erythroblastic island macrophages

“…reported that Vcam1 −/− mice do not display a compromised erythroid stress response in spleen and BM. 17 Whether another interaction substitutes for VCAM1 would need to be determined. The presented monocyte differentiation methodology has potential to be exploited as an imaging platform to delineate the hierarchy of contributions of various receptors within the macrophage-erythroblasts in BM and GC-macrophages in future studies.…”

“…have shown that Vcam −/− mice do not display an erythroid phenotype during homeostasis or phenylhydrazide-induced stress. 17 During terminal differentiation erythroblasts enucleate, resulting in reticulocytes and pyrenocytes. The latter are also still encapsulated by plasma membrane.…”

Reappraising the role of α5 integrin and the microenvironmental support in stress erythropoiesis

“…Our recently published data on VCAM-1 ko mice reveal that reduction in the number of MFs or their failure to appropriately expand post stress (decreased response or survival disadvantage?) do not diminish the response of normal erythroid cells [2,35]. All these data provided divergent and incongruous twists as to the importance or strength of the contribution of these interactions to the overall response Therefore, considering the prior data and those presented here, we can suggest that, at least in the context of a4 and a5 integrin expression by erythroid cells, it is primarily the functional status of erythroid cells with their inability to counteract the increased ROS consequences that sets the amplitude of the stress response and not the extrinsic influence of MFs.…”

The Shape Shifting Story of Reticulocyte Maturation

“…Blocking of α4β1integrin with antibodies decreased cell proliferation and increased apoptosis in vitro and arrests erythropoiesis at E12 in α4 deficient mice ( Sadahira et al, 1995 ; Lee et al, 2006 ). Interestingly though VCAM knockout mice do not display any phenotype regarding erythropoiesis, shedding doubt on whether VCAM is the interaction partner of α4β1 integrin ( Ulyanova et al, 2016 ). Erythroblasts themselves can modulate inhibitory signaling from macrophages.…”