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S. Allali et al.
from SCD patients also show increased production of superoxide anions, which may be explained by the upreg- ulation of NADPH oxidase components in SCD mono- cytes.10,11 Another sign of SCD monocyte activation is increased numbers of circulating tissue factor-positive monocytes, which contribute to the coagulation abnor- malities observed in SCD patients.12 Tissue factor expres- sion on monocytes from SCD children was found to be positively correlated with pain rate, C-reactive protein level and reticulocyte percentage and negatively with hemoglobin concentration, suggesting a role for hemolysis and inflammation in SCD monocyte activation.13
In turn, as compared with normal monocytes, activated monocytes from SCD patients can activate endothelial cells via the nuclear factor (NF)-κB pathway, resulting in enhanced expression of E-selectin, intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1).6 Endothelial activation is mediated by IL-1β and TNF-α, produced by SCD monocytes, as demonstrat- ed by its abrogation with antibodies targeting these two pro-inflammatory cytokines.6 Recently, a prominent role for the monocyte–TNF-α–endothelial activation axis was reported in transgenic sickle mice, with more global bene- fits from the TNF-α blockers etanercept and infliximab than from the IL-1β blocker anakinra.14
Regarding the suspected mechanisms of monocyte acti- vation, a role for hypoxemia was first suggested by a neg- ative correlation between nocturnal oxygen saturation and CD11b expression in monocytes from children with SCD.8 The amount of circulating platelet-monocyte aggre- gates has been reported to be increased in SCD patients as compared with that in healthy controls, suggesting a pos- sible activation of monocytes by platelets, which are known to be activated in SCD.7 In whole blood from SCD patients, the formation of platelet-monocyte aggregates is mediated by a P-selectin/P-selectin glycoprotein ligand 1 (PSGL-1) interaction, which may activate monocytes.15 Other interesting results came from the demonstration that placental growth factor (PlGF) released by RBC can activate monocytes from SCD patients, resulting in increased production of several pro-inflammatory cytokines and chemokines, including IL-1β, TNF-α, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein-1β (MIP-1β), IL-8 and vascular endothelial growth factor (VEGF), via the activa- tion of Flt-1 and the PI3K/AKT and ERK-1/2 pathways.16,17 Placental growth factor plasma levels are higher in SCD patients than in healthy controls and positively correlated with anemia, pulmonary hypertension and the incidence of vaso-occlusive crises (VOC).17,18 Monocyte activation may also be mediated by interactions with sickle RBC since epinephrine-activated sickle RBC can promote monocyte adhesion to human umbilical vein endothelial cells.19 As demonstrated in vitro and in whole blood from SCD patients, plasma fibronectin creates a bridge between two integrin α4β1 molecules on monocytes and on SS reticulocytes, mediating the formation of monocyte-retic- ulocyte aggregates.15 The interaction between α4β1 on monocytes and Lutheran/basal cell adhesion molecule (Lu/BCAM) on RBC may contribute to the formation of monocyte-RBC aggregates.20 A role for heme, released by intravascular hemolysis, in inducing monocyte activation could be suspected, but contrary to lipopolysaccharide, heme was recently found to be insufficient to induce IL-6 production by monocytes from SCD patients, although it
may potentiate the effects of lipopolysaccharide.21
New insights into the role of monocytes in SCD patho- physiology have recently been provided by the descrip- tion of a patrolling monocyte subset expressing a very high level of heme oxygenase-1 (HO-1hi) in SCD patients.22 Patrolling monocytes are CD14lowCD16+ mono- cytes able to scavenge cellular debris derived from the damaged vascular endothelium. In vitro, HO-1hi expres- sion was induced in patrolling monocytes on co-culture with hemin-treated endothelial cells, and HO-1hi cells had higher levels of endothelial cell-derived material than HO-1low cells, which suggests that patrolling monocytes take up debris from heme-exposed endothelial cells, resulting in HO-1hi expression.22 Importantly, mice lacking patrolling monocytes displayed more vascular stasis in the presence of sickle RBC than did control mice and this effect was attenuated by the transfer of patrolling mono- cytes, which supports a role for these cells in preventing VOC. Among patients on chronic transfusion exchange therapy, those with recent VOC or a history of recurrent VOC showed the lowest number of HO-1hi patrolling monocytes.22 Hence, SCD patrolling monocytes may play an important role in scavenging cellular debris derived from heme-exposed endothelial cells, thus reducing the risk of VOC. Patrolling monocytes can also take up endothelial-adherent sickle RBC, especially during VOC, and HO-1 upregulation increases the survival of the patrolling monocytes by counteracting the cytotoxic effects of RBC-engulfed material.23 Further investigations are required to determine whether patrolling monocytes in SCD can remove other blood cells attached to the
endothelium, such as neutrophils.
The main findings on the involvement of monocytes in
SCD pathophysiology are summarized in Figure 1.
Dendritic cells
Alloimmunization is a major complication of RBC trans- fusion both in adults and children with SCD, but its pathogenesis remains poorly understood.24 A role for den- dritic cells in the mechanisms underlying alloimmuniza- tion was recently demonstrated in heme-exposed mono- cyte-derived dendritic cells from alloimmunized SCD patients as compared with non-alloimmunized patients and healthy controls.25 In vitro, heme downregulated mat- uration of monocyte-derived dendritic cells from non- alloimmunized patients and healthy controls, which resulted in inhibited priming of pro-inflammatory CD4+ type 1 T cells by the dendritic cells. By contrast, in alloim- munized patients, heme did not affect the maturation of dendritic cells or their ability to prime Th1 cells. Hence, the defective anti-inflammatory response to heme in alloimmunized patients may result in alterations in T-cell profile with an increase in pro-inflammatory (Th1) and a decrease in anti-inflammatory (Treg) T-cell subsets. Further investigations are required as they may open new therapeutic perspectives to prevent this potentially life- threatening complication.
It has also been suggested that dendritic cells may play a role in the pathogenesis of SCD-related orthopedic com- plications, such as osteonecrosis, osteoporosis and osteopenia, with there being an overexpression of bone morphogenetic protein (BMP)-6 in monocyte-derived den- dritic cells from SCD patients with orthopedic complica- tions as compared with SCD patients without orthopedic complications and healthy controls.26 However, further
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haematologica | 2020; 105(2)