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Innate immune cells in sickle cell disease
Basophils
Few studies have focused on basophils in SCD. In a cohort of 54 SCD patients and 27 healthy controls, basophil count and degranulation, assessed by flow cytometry with the Basotest, were similar in patients and controls.65 Further studies are required to determine whether activated basophils could contribute to SCD pathophysiology.
Natural killer cells
The absolute number of NK cells has been reported to be increased in SCD patients not receiving disease-modi- fying therapy (hydroxyurea or chronic transfusions) as compared to the numbers in healthy controls and patients on hydroxyurea.4,66 Further enhancement during VOC has also been reported.67 More importantly, the cytotoxicity of NK cells from SCD patients not on disease-modifying therapy, unlike that of patients receiving hydroxyurea or exchange transfusions, seems significantly increased com- pared with the cytotoxicity of NK cells from controls.66 Because NK cells are capable of graft rejection, this obser- vation of NK cell number and function normalization with hydroxyurea may explain why SCD patients receiving hydroxyurea before bone-marrow transplantation seem to have a reduced risk of graft rejection.68 This finding raises the question of whether it would be beneficial to combine hydroxyurea with chronic transfusion in the pretransplant
period, especially with non-myeloablative or HLA-mis- matched transplants.
As for iNKT cells, a potential role for NK cells in SCD pulmonary inflammation was described in SCD mice. The mRNA level of adenosine A2A receptor (A2AR) was increased six-fold in pulmonary NK cells from SCD mice as compared with the level in control mice, and activating A2AR on NK cells decreased the number of these cells and improved baseline pulmonary function.69
Invariant natural killer T cells
iNKT cells are known to contribute to hepatic and renal ischemia-reperfusion injury in mice.70 Their role has, therefore, been investigated in SCD, which is character- ized by repeated microvascular ischemia-reperfusion injury. Lung, liver and spleen iNKT cells were found to be more numerous, more activated and more responsive to hypoxia-reoxygenation in SCD mice than in control mice.71 Similarly, SCD patients have shown enhanced lev- els of circulating iNKT cells, together with increased levels of activation markers and increased interferon (IFN)-γ pro- duction, especially during VOC.71 Treating SCD mice with anti-CD1d antibody to inhibit iNKT-cell activation ame- liorated pulmonary dysfunction and decreased pulmonary levels of IFN-γ and CXCR3, which suggests an important role of this pathway in SCD pulmonary inflammation.71 In
Figure 2. Neutrophils in sickle cell disease. Neutrophils rolling on E-selectin under shear stress promote catch-bond formation between E-selectin and L-selectin via sLex expressed on L-selectin. This interaction triggers activation of high-affinity β2-integrins, which leads to shear-resistant bonds with intercellular adhesion molecule 1. Neutrophil adhesion also occurs through interactions between P-selectin glycoprotein ligand 1 (PSGL-1) and endothelial P-selectin, which is upregulated in response to toll-like receptor 4 activation by heme released from red blood cells (RBC). E-selectin induces a secondary wave of activating signals, which leads to the clustering of activated macrophage-1 antigen (Mac-1) on the leading edge of adherent neutrophils, allowing for the capture of sickle RBC. Endothelin-1 promotes Mac-1 expression through the endothelin B receptors on neutrophils. Activated platelets express P-selectin, which binds PSGL-1, thereby enhancing the formation of platelet-neutrophil aggregates. The platelet-neutrophil association is also mediated by interactions between glycoprotein Ibα and Mac-1, which is positively regu- lated by AKT2 in neutrophils during vascular inflammation. Neutrophil aging is promoted by the microbiota via TLR/Myd88 signaling and is positively correlated with Mac-1 expression and neutrophil extracellular trap (NET) formation. Heme also promotes NET formation, possibly via generation of reactive oxygen species in neu- trophils, and induces expression of heme oxygenase-1 during neutrophilic differentiation, thereby impairing the bactericidal oxidative burst. ESL-1: E-selectin ligand- 1; ET: endothelin; GP: glycoprotein; HO-1: heme oxygenase-1; ICAM-1: intercellular adhesion molecule 1; ROS: reactive oxygen species; TLR: toll-like receptor.
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