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S. Allali et al.
activation was positively correlated with pulmonary arte- rial hypertension, and activated platelets might contribute to this severe complication of SCD by promoting in situ thrombosis and releasing vasoactive molecules or mito- genic mediators.77 Recently, elevated plasma levels of sol- uble CD40L and thrombospondin-1, two platelet-derived molecules, were reported in SCD patients with a history of ACS, which suggests a role for activated platelets in the pathogenesis of this syndrome.78 In support of this hypothesis, antiplatelet agents such as the ADP receptor antagonist clopidogrel significantly improved lung injury in SCD mice.51 As described above, activated platelets can form aggregates with several cells, including RBC, mono- cytes and neutrophils, and platelet–neutrophil aggregates may contribute to pulmonary arteriole microemboli in SCD mice.52 By releasing thrombospondin, which binds CD36 on both endothelial cells and RBC, platelets also promote sickle RBC adhesion to microvascular endotheli- um, resulting in vaso-occlusion.79 These findings have sup- ported clinical trials of two antiplatelet agents in SCD patients, namely the ADP receptor antagonists prasugrel and ticagrelor. However, a phase III trial of prasugrel in SCD children did not find a significant reduction of VOC rate, and ticagrelor did not affect diary-reported pain in a phase IIb trial of young adults with SCD.80,81 A ticagrelor phase III trial on VOC rate in children with SCD is cur- rently ongoing (#NCT03615924).
Increased platelet activation in SCD may result from decreased nitric oxide bioavailability and endothelial dys- function with an abnormal prothrombotic microvascula- ture.77 However, new insights into mechanisms of platelet activation in SCD were provided by the recent demon- stration that the platelet NLRP3 inflammasome is activat- ed in SCD patients in steady-state, and even more during VOC, via HMGB1/TLR4 and Bruton tyrosine kinase (BTK).82 The NLRP3 inflammasome mediates platelet acti- vation/aggregation and thrombus formation via recogni- tion of various pathogen-associated molecular patterns (PAMP) and damage-associated molecular patterns (DAMP) from injured tissues, such as HMGB1, whose level was found to be higher in plasma from SCD patients than in plasma from healthy controls.82 The platelet NLRP3 inflammasome is involved in IL-1β signaling and platelets from SCD patients were found to produce increased amounts of pro-inflammatory cytokines, includ- ing IL-1β.83 In vitro, pharmacological or antibody-mediated inhibition of HMGB1/TLR4 and BTK decreased the ability of SCD patients’ plasma to induce caspase-1 activation in platelets from healthy controls. Similarly, in sickle mice, inhibition of NLRP3 or BTK reduced caspase-1 activity and platelet aggregation.82 These findings may open ther- apeutic perspectives in SCD, especially for the BTK inhibitor ibrutinib, which is approved by the US Food and Drug Administration to treat B-cell malignancies.
Macrophages
A polarization of liver macrophages into a M1 pro- inflammatory phenotype was recently described in SCD mice, with higher expression of TNF-α and IL-6 by these cells than by liver macrophages from control mice.84 This could contribute to the pathogenesis of SCD liver damage because pro-inflammatory activation of liver macrophages is known to induce monocyte recruitment, with enhanced cytokine production leading to hepato- cyte apoptosis and fibrosis. Additionally, administration
of hemopexin to SCD mice attenuated the pro-inflamma- tory status of liver macrophages, which strongly suggests a role for heme in inducing the SCD macrophage pheno- typic switch toward an M1 phenotype.84 Macrophages may also be a major source of IL-1β in SCD because heme induces IL-1β processing through NLRP3 inflammasome activation in macrophages.85
Infiltration of macrophages has been described in kid- neys of SCD mice, with macrophage stimulating protein 1 (MSP1) accumulation in glomerular capillaries.86 MSP1 acti- vates RON kinase on glomerular endothelial cells, leading to the phosphorylation of ERK and AKT and resulting in increased von Willebrand factor expression, cell motility and glomeruli permeability. Treating SCD mice with a RON inhibitor (BMS-777607) attenuated glomerular endothelial injury, which suggests that this molecule could be used to prevent renal disease in SCD patients.86
Another interesting finding concerns sphingosine-1- phosphate (S1P), a biolipid contributing to chronic inflam- mation, whose plasma levels are elevated in SCD patients and mice. In SCD mice, S1P induces IL-6 expression in macrophages via S1P receptor 1 (S1PR1) and IL-6 in turn promotes S1PR1 expression in macrophages of several organs, which leads to a vicious cycle promoting chronic inflammation and tissue damage.87 Treating SCD mice with a S1PR1 antagonist (FTY720) reduced systemic inflammation and improved tissue damage in the spleen, liver, kidneys and lungs, which suggests that this drug, approved by the US Food and Drug Administration to treat multiple sclerosis as an immunosuppressant, may benefit SCD patients.87
Mast cells
Growing evidence is suggesting a role for mast cells in the pathophysiology of SCD. The chronic pain in this disease shares many characteristics with that encountered in mas- tocytosis, and the clinical signs of mast cell activation syn- drome have been described in SCD patients.88 Increased plasma levels of several mast cell mediators, including his- tamine and substance P, have been reported in steady-state with further enhancement during VOC.89,90 The plasma tryptase level is also slightly increased during VOC as com- pared with the level in steady-state but without reaching pathological values, which suggests mast-cell activation rather than increased numbers of mast cells.89 In SCD patients, plasma histamine level was found to be negatively correlated with HbF level, a well-known protective factor in SCD, and positively with absolute neutrophil count, absolute platelet count and C-reactive protein level, which suggests a role for inflammation in the mechanisms leading to mast-cell activation.89 Histamine may contribute to SCD pathogenesis, because stimulation of endothelial histamine H2 and H4 receptors induced the release of von Willebrand factor and P-selectin expression by endothelial cells, thus promoting adhesion of sickle RBC.91 Furthermore, the plas- ma level of substance P was found to be negatively correlat- ed with hemoglobin concentration and positively with the levels of markers of hemolysis.90 These findings may reflect SCD hemolysis being responsible for depletion of nitric oxide, which is known to induce mast-cell activation.92
Substance P, a neuropeptide released from mast cells and from sensory nerve endings, acts as a primary pain neurotransmitter and a neuromodulator. Via neurokinin 1 receptor (NK1R), substance P contributes to neurogenic inflammation by increasing venular permeability and plas-
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haematologica | 2020; 105(2)