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Erythroblastic islands (EBIs) are specialized structures that are formed by a central macrophage surrounded by maturating erythroblasts. The central macrophage mediates EBI formation and plays a crucial role in the proliferation, differentiation, enucleation, and maturation of erythroblasts. In stress erythropoiesis, the expression levels of several adhesion molecules mediating EBI formation become abnormal, leading to various erythroid diseases. These findings have indicated that targeting central macrophages may become a new therapeutic approach for treating erythroid diseases. This review summarizes the structure and function of EBIs, macrophage-erythroblast interactions in EBIs, and potential therapeutic direction of EBI central macrophages for erythroid diseases, providing new insights for the clinical treatment of erythroid diseases.

Macrophages play a key role in the progression of nonalcoholic fatty liver disease (NAFLD). Liver macrophages are composed of tissue resident macrophages (Kupffer cells) derived from yolk sac and fetal liver and bone-marrow monocytes-derived macrophages, which have heterogeneity of origin. In addition, the activation state of transcriptomic macrophages in vivo presents broad-spectrum changes rather than a traditional simple M1 or M2 polarization, which in turn causes different functional changes. Therefore, in this review, we assessed the evidence for macrophage involvement in NALFD progression from three aspects, macrophage heterogeneity including its origin, polarization and function, the mechanisms of macrophage activation and action, and the potential therapy strategies for NAFLD through targeting macrophages. These studies on NAFLD development will bring forth more novel treatment targets and strategies in clinic.

Macrophages play critical roles in renal fibrosis. However, macrophages exhibit ontogenic and functional heterogeneities, and which population of macrophages contributes to renal fibrosis and the underlying mechanisms remain unclear. In this study, we genetically targeted Notch signaling by disrupting the transcription factor recombination signal binding protein-Jκ (RBP-J), to reveal its role in regulation of macrophages during the unilateral ureteral obstruction (UUO)-induced murine renal fibrosis. Myeloid-specific disruption of RBP-J attenuated renal fibrosis with reduced extracellular matrix deposition and myofibroblast activation, as well as attenuated epithelial-mesenchymal transition, likely owing to the reduced expression of TGF-β. Meanwhile, RBP-J deletion significantly hampered macrophage infiltration and activation in fibrotic kidney, although their proliferation appeared unaltered. By using macrophage clearance experiment, we found that kidney resident macrophages made negligible contribution, but bone marrow (BM)-derived macrophages played a major role in renal fibrogenesis. Further mechanistic analyses showed that Notch blockade reduced monocyte emigration from BM by down-regulating CCR2 expression. Finally, we found that myeloid-specific Notch activation aggravated renal fibrosis, which was mediated by CCR2 + macrophages infiltration. In summary, our data have unveiled that myeloid-specific targeting of Notch could ameliorate renal fibrosis by regulating BM-derived macrophages recruitment and activation, providing a novel strategy for intervention of this disease.

The liver is the predominant metastatic site for several types of malignancies. Tumor-associated macrophages (TAMs) in the liver play crucial roles in the metastasis process. Shifting tumor-promoting M2-like TAMs toward the M1-like phenotype, which exerts tumor suppressor functions via phagocytosis and the secretion of inhibitory factors, may be a potential therapeutic strategy for liver cancer metastasis treatment.We first cloned NDRG2 (N-myc downstream-regulated gene 2) and verified its tumor suppressor role in multiple solid tumors, including colorectal cancer and hepatocellular carcinoma. However, its role in the tumor-associated liver microenvironment, especially in TAMs, has not been illustrated. By establishing a liver cancer metastasis model in wild-type (WT) and Ndrg2 knockout (Ndrg2-/-) mice, we found that the loss of the tumor suppressor Ndrg2 in liver microenvironment significantly suppressed the growth of liver colonies. In addition, this process was accompanied by a higher proportion of M1-like TAM infiltration in Ndrg2-/- mice. Interestingly, bone marrow (BM) transplantation revealed that BM-derived macrophages (BMDMs) rather than liver resident Kupffer cells were responsible for the inhibitory effect. We further demonstrated that loss of Ndrg2 influenced TAM polarization via the NF-κB pathway. Inhibition of IκBα phosphorylation in cancer cell-conditioned medium-stimulated BMDMs decreased M1 marker expression in Ndrg2-/- macrophages. Finally, in vitro, invasion, migration, and proliferation assays confirmed that NF-κB participated in the tumor suppressor function of Ndrg2-/- macrophages. Collectively, our findings highlight the role of NDRG2 in the regulation of TAM polarization and its function in promoting cancer liver metastasis.

Objective: To construct the eukaryotic expression vector of monocyte chemokine protein 1 (MCP-1) driven by the cytomegalovirus (CMV) promoter, transfect the vector into HEK293T cells, and detect its chemotaxis to macrophages., Methods: MCP-1 promoter was obtained from mouse genome by PCR, and inserted into the vector named pFLAG-CMV1. We validated it by double-enzymes digestion and sequencing. Then HEK293T cells were transfected with pFLAG-CMV1-MCP-1. The expression of MCP-1 was detected by Western blotting. Finally, we identified the chemotaxis of the recombinant vector to macrophage by Transwell(TM) assay., Results: The recombinant vector could generate target fragment by double enzyme digestion. HEK293T cells expressed MCP-1 after they were transfected with the recombinant vector, which increased the migration of macrophages., Conclusion: MCP-1 expressed by HEK293T cells could apparently increase the migration of macrophages.

Methods: In the present study, we investigated hepatic macrophage heterogeneity in murine liver regeneration after 2/3 PHx through immunofluorescence staining, fluorescence-activated cell sorting analysis, and quantitative reverse transcription-polymerase chain reaction.Results: Our research showed that Kupffer cells reduced rapidly in the early PHx and restored gradually depending on local proliferation and replenishment from infiltrating monocyte-derived macrophages. The ratio of ly6Chi to ly6Clo subset of macrophages in the liver changed dynamically, and hepatic macrophage function exhibits a significant difference in different stages of liver regeneration. Moreover, blocking infiltrating monocyte-derived macrophage recruitment augmented Kupffer cell proliferation but impaired the restoration of the hepatic macrophage pool, which led to delayed hepatocyte mitosis and liver regeneration.Conclusions: Our data suggest that hepatic macrophage changes dynamically in origin and function during liver regeneration following PHx and macrophage-targeted liver regeneration should consider macrophage heterogeneity. [ABSTRACT FROM AUTHOR]