Diabetes‐mediated myelopoiesis and the relationship to cardiovascular risk

Abstract

Diabetes is the greatest risk factor for the development of cardiovascular disease, which, in turn, is the most prevalent cause of mortality and morbidity in diabetics. These patients have elevations in inflammatory monocytes, a factor consistently reported to drive the development of atherosclerosis. In preclinical models of both type 1 and type 2 diabetes, studies have demonstrated that the increased production and activation of monocytes is driven by enhanced myelopoiesis, promoted by factors, including hyperglycemia, impaired cholesterol efflux, and inflammasome activation, that affect the proliferation of bone marrow precursor cells. This suggests that continued mechanistic investigations of the enhanced myelopoiesis and the generation of inflammatory monocytes are timely, from the dual perspectives of understanding more deeply the underlying bases of diabetes pathophysiology and identifying therapeutic targets to reduce cardiovascular risk in these patients.

Glucose metabolism controls disease-specific signatures of macrophage effector functions

“…These data are in line with the current observation that extracellular glucose concentrations can deviate macrophage differentiation towards high production of IL-1β, IL-6, and high expression of PD-L1. In preclinical models, evidence has been provided that hyperglycemia can drive enhanced production and activation of myelopoiesis by regulating proliferative activity of bone marrow precursor cells (52,53), in line with data presented here that monocytes in CAD patients already are imprinted with a proinflammatory program. Experiments that measured the impact of changing glucose concentrations in the extracellular fluid indicated that human monocytes and macrophages can sense glucose availability and dynamically adapt their glycolytic machinery.…”

Neutrophil extracellular traps promote macrophage inflammation and impair atherosclerosis resolution in diabetic mice

“…The information presented above suggested to us that the failure of lipid-lowering therapies to fully reduce CVD risk in patients with diabetes, or to maximally resolve atherosclerosis in mice and patients with diabetes (reviewed in refs. [26][27][28], represented adverse consequences of the increased plaque level of NETs in this metabolic setting (25). This phenomenon would be similar to NETs impairing wound healing in diabetes (24).…”

HDL and Reverse Cholesterol Transport

“…In addition to being essential for the removal of cholesterol from plaque macrophages 28 , ABCA1 and ABCG1 regulate the proliferation of hematopoietic stem and progenitor cells to control the abundance of blood monocytes 27 . Given the link between myelopoiesis and CVD risk 130,171 , suppression of this process is likely to directly inhibit the progression of atherosclerotic lesions, and promote lesion regression 166 . Diabetes can suppress hematopoietic precursor cell ABCA1 and ABCG1 levels, promoting myelopoiesis and atherosclerosis 165 .…”