Clinical Implications of Novel Regulatory Mechanisms for Production of Platelets, Neutrophils, and Erythrocytes

Several 2015 publications involving mouse models that examined blood counts and underlying hematopoietic events have advanced our understanding of both steady-state and emergency production rates for platelets, neutrophils, and erythrocytes. These studies provided insights that were specific to each of the three bone marrow lineages. These newly identified regulatory mechanisms suggest potential new approaches for treating diseases that result in abnormal numbers of platelets, neutrophils, or erythrocytes.

A newly described mechanism for rapid platelet production, which occurs in emergency situations such as low circulating platelet levels due to enhanced destruction or increased platelet numbers from intense inflammation or infection, is megakaryocytic rupture induced by interleukin-1α (IL-1α).¹  Sudden IL-1α–mediated release of larger-than-normal platelets increases production rates by more than an order of magnitude over the pro-platelet shearing mechanism of steady-state platelet production.¹  Both of these release mechanisms require development of mature megakaryocytes located adjacent to the vascular sinuses of the marrow, a process regulated by thrombopoietin (TPO), the principal growth factor for megakaryocytes that is produced mainly by the liver. Aging of circulating platelets has been associated with desialylation of surface glycoproteins, which in turn leads to platelet removal from the circulation after binding by asialoglycoprotein receptors on hepatocytes.²  The bound asialoglycoprotein receptors in turn signal through the JAK2-STAT3 pathway inducing TPO transcription, thereby completing a feedback loop that maintains steady-state platelet numbers.²  Megakaryocyte rupture provides explanations for increased platelet size and rapid recovery, with potential overshoot thrombocytosis following correction of platelet destruction processes. The asialoglycoprotein-mediated removal of aged platelets and JAK2-STAT3-linked production of TPO help explain thrombocytopenia associated with JAK inhibitor therapy and rapid normalization of platelet numbers after overshoot thrombocytosis. Both of these newly described mechanisms may allow for future approaches to treating thrombocytopenia with sequential TPO mimetics and inducers of megakaryocytic rupture.

Despite brief intravascular life spans, neutrophils were found to age in the circulation in response to products of the gut microbiota that signal through Toll-like receptors and myeloid differentiation factor-88.³  The more aged neutrophils had increased tissue adhesiveness and pro-inflammatory activity, and their expanded population in the chronic inflammation of a murine model of sickle cell disease was reversed by antibiotic treatment of microbiome organisms.³  During acute inflammation or infection, the myeloid progenitor cell pool was shown to expand in response to interstitial reactive oxygen species (ROS) generated by phagocytic NADPH oxidase activity emanating from adjacent mature myeloid cells in the marrow.⁴  This ROS-mediated emergency granulopoiesis is related to PTEN oxidation/inactivation and does not involve granulocyte colony-stimulating factor (G-CSF).⁴  Therefore, it has therapeutic potential beyond that provided by G-CSF and granulocyte macrophage colony-stimulating factor (GM-CSF) to raise neutrophil counts in acute situations of increased demand such as sepsis. These new insights provide an opportunity to test two hypotheses: 1) whether antibiotic-mediated suppression of gut microbiota can improve chronic inflammatory states, and 2) whether pharmacologic manipulation of the ROS-PTEN pathway can improve emergency granulopoiesis in chronic granulomatous disease, in which defective myeloid NADPH oxidase activity increases susceptibility to bacterial infections.

Transferrin receptor-2 (TFR2) plays a role in hepcidin transcription in liver when iron saturation of transferrin is increased. TFR2’s function in erythroid cells, where it had been shown to associate with erythropoietin (EPO) receptors, was not known. However, CBCs of mice with TFR2-deficient erythroid cells showed increased hemoglobin owing to increased numbers of RBCs that had decreased MCHs and MCVs, indicating that TFR2 restricts steady-state erythropoiesis and maintains normal RBC size during iron sufficiency, presumably by decreasing EPO responsiveness.⁵  In iron sufficiency therefore, TFR2 restricts both erythropoietic iron supply via hepcidin-mediated control of iron flux and erythropoietic use of iron. Conversely, in iron deficiency, instability of unbound TFR2 leads to increased iron absorption and flux via decreased hepcidin and increased EPO responsiveness of erythroid cells. The method by which increased EPO responsiveness coordinates with other regulators of erythropoiesis in iron deficiency (such as iron regulatory protein-1 (IRP-1) limiting EPO production and heme-regulated inhibitor (HRI) limiting hemoglobin synthesis) is unknown, but multiple levels of control are present in the erythropoietic response to this common cause of anemia.

The emergency situation in anemia is tissue hypoxia, and the erythropoietic response to anemia is termed “stress erythropoiesis.” Renal EPO production has been extensively studied in stress erythropoiesis. However, beginning at the burst-forming unit-erythroid (BFU-E) stage and extending to the proerythroblast stage of differentiation, non-EPO mediators such as glucocorticoid hormones, stem cell factor, and bone morphogenetic protein-4, can expand erythroid progenitor cell populations without inducing differentiation. Glucocorticoid-induced expansion of BFU-Es was shown to involve a direct synergistic interaction between dexamethasone and peroxisome proliferator-activated receptor-α (PPAR-α),⁶  whereas expansion of EPO-dependent erythroid progenitors, colony-forming units-erythroid (CFU-Es) and proerythroblasts, did not involve PPAR-α, suggesting that other mechanisms are involved in glucocorticoid-mediated expansion of these later differentiation stages. From the clinical standpoint, enhancement of glucocorticoid-mediated erythropoietic activity by PPAR-α agonists⁶  indicates that, when steroidal side effects become problematic, PPAR-α agonists may allow reduced doses of glucocorticoids. Such agonists could be particularly useful in bone marrow failure syndromes such as Diamond-Blackfan anemia, in which glucocorticoids are the mainstay of treatment.