ABSTRACT
Hematopoiesis is hierarchically orchestrated by a very small population of hematopoietic stem cells (HSCs) that reside in the bone-marrow niche and are tightly regulated to maintain homeostatic blood production. HSCs are predominantly quiescent, but they enter the cell cycle in response to inflammatory signals evoked by severe systemic infection or injury. Thus, hematopoietic stem and progenitor cells (HSPCs) can be activated by pathogen recognition receptors and proinflammatory cytokines to induce emergency myelopoiesis during infection. This emergency myelopoiesis counterbalances the loss of cells and generates lineage-restricted hematopoietic progenitors, eventually replenishing mature myeloid cells to control the infection. Controlled generation of such signals effectively augments host defense, but dysregulated stimulation by these signals is harmful to HSPCs. Such hematopoietic failure often results in blood disorders including chronic inflammatory diseases and hematological malignancies. Recently, we found that interleukin (IL)-27, one of the IL-6/IL-12 family cytokines, has a unique ability to directly act on HSCs and promote their expansion and differentiation into myeloid progenitors. This process resulted in enhanced production of neutrophils by emergency myelopoiesis during the blood-stage mouse malaria infection. In this review, we summarize recent advances in the regulation of myelopoiesis by proinflammatory cytokines including type I and II interferons, IL-6, IL-27, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, and IL-1 in infectious diseases.
Subject(s)
Gene Expression Regulation/immunology , Hematologic Neoplasms/immunology , Malaria/immunology , Myelopoiesis/immunology , Neutrophils/immunology , Animals , Cell Cycle/genetics , Cell Cycle/immunology , Cell Differentiation , Cell Proliferation , Granulocyte Colony-Stimulating Factor/genetics , Granulocyte Colony-Stimulating Factor/immunology , Hematologic Neoplasms/genetics , Hematologic Neoplasms/pathology , Humans , Interferons/genetics , Interferons/immunology , Interleukin-1/genetics , Interleukin-1/immunology , Interleukin-6/genetics , Interleukin-6/immunology , Interleukins/genetics , Interleukins/immunology , Macrophage Colony-Stimulating Factor/genetics , Macrophage Colony-Stimulating Factor/immunology , Malaria/genetics , Malaria/parasitology , Malaria/pathology , Mice , Myeloid Progenitor Cells/immunology , Myeloid Progenitor Cells/parasitology , Myeloid Progenitor Cells/pathology , Myelopoiesis/genetics , Neutrophils/parasitology , Neutrophils/pathology , Plasmodium berghei/growth & development , Plasmodium berghei/immunologyABSTRACT
Inflammation alters hematopoiesis, often by decreasing erythropoiesis and enhancing myeloid output. The mechanisms behind these changes and how the BM stroma contributes to this process are active areas of research. In this study, we examine these questions in the setting of murine Toxoplasma gondii infection. Our data reveal that infection alters early myeloerythroid differentiation, blocking erythroid development beyond the Pre MegE stage, while expanding the GMP population. IL-6 was found to be a critical mediator of these differences, independent of hepcidin-induced iron restriction. Comparing the BM with the spleen showed that the hematopoietic response was driven by the local microenvironment, and BM chimeras demonstrated that radioresistant cells were the relevant source of IL-6 in vivo. Finally, direct ex vivo sorting revealed that VCAM(+)CD146(lo) BM stromal fibroblasts significantly increase IL-6 secretion after infection. These data suggest that BMSCs regulate the hematopoietic changes during inflammation via IL-6.
Subject(s)
Erythroid Precursor Cells/drug effects , Interleukin-6/pharmacology , Myeloid Progenitor Cells/drug effects , Stromal Cells/drug effects , Toxoplasma/drug effects , Toxoplasmosis/drug therapy , Animals , Bone Marrow/drug effects , Bone Marrow/parasitology , Bone Marrow/pathology , Cell Differentiation/drug effects , Cells, Cultured , Colony-Forming Units Assay , Erythroid Precursor Cells/parasitology , Erythroid Precursor Cells/pathology , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/parasitology , Hematopoiesis/drug effects , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/parasitology , Hematopoietic Stem Cells/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Myeloid Progenitor Cells/parasitology , Myeloid Progenitor Cells/pathology , Stromal Cells/parasitology , Stromal Cells/pathology , Toxoplasma/pathogenicity , Toxoplasmosis/parasitology , Toxoplasmosis/pathologyABSTRACT
The mechanism of anemia in severe falciparum malaria is still not completely understood. The purpose of this study was to determine whether apoptosis in the erythroid lineage causes anemia in falciparum malaria. Bone marrow aspirated from 8 severe falciparum malaria patients, 3 normal volunteers and 5 retrospective normal bone marrow smears were investigated. By light microscopic study, 5 of 8 hyperparasitemic patients had hypocellular bone marrows and erythroid hypoplasia, whereas the other 3 patients had normal cellularity. The mean myeloid : erythroid ratio of these 5 patients was significantly (p < or = 0.05) higher than normal. Apoptosis of bone marrow nucleated cells (BMNC) could be determined from the exposure of phosphatidylserine (PS) on the cell membrane but not DNA fragmentation (180-250 bp) or ultrastructural morphology. The percentages of apoptotic BMNC and apoptotic erythroid cells in bone marrow from each patient and controls varied from low to high, and were not associated with parasitemia. This study suggests that destruction of erythroid lineage, particularly through apoptosis regulation, cannot solely account for anemia in falciparum malaria.
