Patrolling the endothelium in sickle cell disease

In this issue of Blood, Liu et al provide evidence that a subset of circulating monocytes known as endothelial patrolling monocytes have increased heme oxygenase 1 (HO-1) levels and may help to protect from vaso-occlusive crisis in sickle cell disease.¹ 

Vaso-occlusive pain crises are the scourge of patients with sickle cell disease. What initiates and perpetuates these episodes has been challenging to understand for hematologists. It has long been clear that vaso-occlusive episodes are typically associated with an increase in the hemolytic rate.²  The work of Liu et al suggests that the ability to respond appropriately to an increase in hemolysis is a factor in whether a vaso-occlusive crisis develops.

Hemolysis in sickle cell disease is predominantly extravascular (ie, removal of deformed red blood cells by reticuloendothelial macrophages that are geared to safely process the hemoglobin derived from catabolized erythrocytes). About one-third of the hemolysis is intravascular, and this presents a problem because cell-free hemoglobin and heme are potentially toxic to the vascular endothelium and the organs the vessels perfuse. Circulating haptoglobin is the body’s defense that rapidly binds any cell-free hemoglobin appearing in the plasma. Hemopexin is the back-up guardian to rapidly bind any heme that dissociates from globin before binding to haptoglobin can occur.³  These molecules are already depleted in sickle cell patients at steady-state.⁴  An increase in hemolysis can lead to excessive free heme, which can interact with vascular endothelial cell membrane molecules and/or be taken up by endothelial cells. Downstream consequences include increased expression of endothelial adhesion molecules and apoptotic markers, attachment of activated leukocytes and red blood cells to endothelial cells, and microvascular occlusion.^5,6 

Endothelial patrolling monocytes are a subset of circulating monocytes, known as nonclassical CD14^lowCD16⁺ monocytes, which express a higher level of HO-1 than other monocytes. They have the duties of scavenging particles that attach to the endothelium and of phagocytosing cellular debris derived from damaged endothelial cells.⁷  Patrolling monocytes play important roles in diseases such as atherosclerosis⁸  and Alzheimer disease,⁹  in which absence of endothelial protection by these cells renders the endothelium more susceptible to atherosclerotic plaque growth and Alzheimer-related amyloid β deposition. Liu et al present a fascinating sequence of experiments that provide findings consistent with a role for patrolling monocytes to protect from vaso-occlusive crisis in sickle cell disease.

According to the present report, HO-1 expression is induced when patrolling monocytes engulf heme-damaged endothelial cells. Patrolling monocytes with an unusually high expression of heme oxygenase 1 (HO-1^hi) reflect this scavenging function and have reduced reactivity to inflammatory stimuli. The investigators found that the frequency and numbers of HO-1^hi patrolling monocytes correlated with hemolytic markers in sickle cell patients. On average, 37% of sickle cell patrolling monocytes were HO-1^hi compared with only 6% of healthy controls. However, the investigators found that sickle patients with a recent vaso-occlusive crisis episode had lower frequencies and numbers of patrolling monocytes and HO-1^hi patrolling monocytes, suggesting that decreased patrolling monocyte activity may be associated with the development and propagation of a crisis. In a subset of patients, observations were available both before and after a vaso-occlusive crisis, and the numbers of HO-1^hi patrolling monocytes were lower than patients without a crisis throughout. Extending their experiments to sickle cell mice, the authors found that heme-driven vaso-occlusion was exacerbated in mice lacking patrolling monocytes and reversed following patrolling monocyte transfer.

The investigators postulate that increased scavenging activity of sickle cell endothelial patrolling monocytes is necessary to decrease danger signals resulting from hemolysis-associated cellular damage, thereby reducing leukocyte recruitment to the vessel wall. It follows that if the numbers and/or scavenging activity of sickle cell patrolling monocytes are compromised, the vasculature will not be effectively cleared of danger signals, resulting in endothelial activation and inflammation in the vessel wall. A key implication of the study is a potential role for patrolling monocytes in protecting against vaso-occlusive crisis. Patients harboring genetic defects in patrolling monocyte development and/or in the HO-1 signaling pathway might be at an increased risk for the development or propagation of a crisis.

Returning to haptoglobin and hemopexin, the stalwart guardians against the toxicity of cell-free heme in the vasculature, perhaps they have a third ally (see figure). Patrolling monocytes appear to represent a strategy to deal with cell-free heme that has escaped the depleted reserves of haptoglobin and hemopexin and made its way to “attack” the unsuspecting endothelial cells of the sickle cell microvasculature.