Disordered haematopoiesis and athero-thrombosis

Abstract

Atherosclerosis, the major underlying cause of cardiovascular disease, is characterized by a lipid-driven infiltration of inflammatory cells in large and medium arteries. Increased production and activation of monocytes, neutrophils, and platelets, driven by hypercholesterolaemia and defective high-density lipoproteins-mediated cholesterol efflux, tissue necrosis and cytokine production after myocardial infarction, or metabolic abnormalities associated with diabetes, contribute to atherogenesis and athero-thrombosis. This suggests that in addition to traditional approaches of low-density lipoproteins lowering and anti-platelet drugs, therapies directed at abnormal haematopoiesis, including anti-inflammatory agents, drugs that suppress myelopoiesis, and excessive platelet production, rHDL infusions and anti-obesity and anti-diabetic agents, may help to prevent athero-thrombosis.

Keywords: Athero-thrombosis; Atherosclerosis; Haematopoiesis; Monocytes; Neutrophils; Platelets.

Figure 1

Cardiovascular risk factors promote myelopoiesis and contribute to athero-thrombosis. (A) Increased plasma low-density lipoproteins and decreased high-density lipoproteins levels, (B) hyperglycaemia, and (C) obesity are major cardiovascular risk factors. Through various mechanisms, these risk factors directly or indirectly stimulate the production of myeloid cells (monocytes, neutrophils, and reticulated platelets) increasing the abundance in circulation. Hypercholesterolaemia also promotes the mobilization of haematopoietic stem cells (HSCs) to the spleen resulting in extramedullary haematopoiesis further contributing to the circulating pool of myeloid cells. (1) The increased abundance in circulating myeloid cells enhances the progression and impairs the regression of the atheroma. (2) There is also increased platelet–leucocyte interactions that enhance the recruitment of the leucocytes to the atherosclerotic lesion. (3) Neutrophils activation can also result in the formation of neutrophil extracellular traps (NETs), which contribute to enhanced atherogenesis and athero-thrombosis by binding platelets.

Figure 2

Defects in cellular cholesterol efflux pathways trigger myelopoiesis, extramedullary haematopoiesis, and enhanced atherosclerosis. In the bone marrow, defects in intrinsic cellular efflux pathways in haematopoietic stem (HSC) and myeloid progenitor cells result in increased membrane cholesterol levels and increased sensitivity to growth factor and cytokines. Deletion of ABCG4 in megakaryocyte progenitors (MkPs) results in increased c-MPL expression and enhanced thrombopoietin (TPO) signalling. This stimulates the production of immature reticulated platelets that can enhance atherogenesis via a number of mechanisms including deposition of cytokines (CCL5) and binding and activating leucocytes. Defective cholesterol efflux in haematopoietic stem cell and myeloid progenitors increased the cell surface abundance of the common β-subunit (CBS) of the IL-3, IL-5, and GM-CSF receptors resulting in enhanced proliferation. Inflammatory stimuli from a myocardial infarction including damage-associated molecular pattern molecules and IL-1β can influence haematopoietic stem cell proliferation and lineage fate. HSCs can also mobilize and migrate to the spleen when efferocytosis fails in macrophages with defective cholesterol efflux as there is a failure to shut down the expression of IL-23; thus, IL-17 and in turn G-CSF levels remain increased. In the spleen, there is an increased abundance of the innate response activator B cells (IRA B-cells) in the setting of hypercholesterolaemia, which produce GM-CSF driving the haematopoietic stem cells to produce monocytes and neutrophils. Defective cholesterol efflux in splenic macrophages also promotes M-CSF production to enhance myelopoiesis and CCL2 to promote monocyte migration. Together, the increased abundance of platelets, monocytes, and neutrophils all contribute to promoting the accumulation of macrophages in the atherosclerotic lesion.

Figure 3

Mechanisms contributing to myeloid production in metabolic disorders. Hyperglycaemia: In the setting of elevated blood glucose, neutrophils are stimulated to produce S100A8/A9, which travels to the bone marrow to interact with RAGE on the surface of macrophages and common myeloid progenitors (CMPs) triggering the production of M-CSF and GM-CSF. These cytokines increase the abundance of common myeloid progenitors and granulocyte–macrophage progenitors (GMPs) promoting the production of monocytes and neutrophils. Obesity: In the context of obesity, local inflammation in the adipose tissue occurs which appears to be initiated by S100A8/A9 interacting with TLR4 on adipose tissue macrophages (ATMs). This induces IL-1β, which is processed by the NLRP3 inflammasome to its mature form. IL-1β then travels to the bone marrow and binds the IL-1 receptor, which is up-regulated on common myeloid progenitors and granulocyte–macrophage progenitors in the obese state. This interaction drives myelopoiesis. As people with diabetes and obesity have increased diabetes and common myeloid progenitor cells are precursors of megakaryocytes, this may be a mechanism contributing to increased platelets. The enhanced production of myeloid cells in diabetes impairs the regression of atherosclerotic lesions due to persistent entry of monocytes.