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Innate immune cells in sickle cell disease
ma extravasation, but it also acts on the mast cells them- selves, promoting a vicious cycle of mast-cell activation and substance P release.93 Furthermore, tryptase released from mast cells activates protease-activated receptor 2 (PAR-2) on peripheral nerve endings, thus contributing to nociceptor sensitization and stimulating the release of substance P, which in turn activates mast cells.94 Substance P and tryptase levels were higher in the skin of SCD mice than in that of control mice and both proteins colocalized with activated mast cells.93,95 Inhibition of mast cells, with the mast-cell stabilizer cromolyn or the c-kit/tyrosine kinase inhibitor imatinib, decreased substance P and tryptase levels as well as systemic inflammation, neuro- genic inflammation, reflected by Evans blue leakage, and hyperalgesia. Importantly, these results were confirmed in transgenic SCD mice lacking mast cells.93 In the same line of evidence, in an SCD patient with chronic myeloid leukemia, imatinib treatment completely resolved repeat- ed VOC, and discontinuation of the treatment coincided with VOC recurrence.96 However, this may be explained, at least in part, by a decrease in leukocyte and neutrophil counts during imatinib treatment, and further studies are needed. A clinical trial of imatinib or another c-kit/tyrosine kinase inhibitor in SCD patients may be considered.
Treating SCD mice with a high-affinity opioid nocicep- tion receptor agonist, AT-200, known to inhibit the release of substance P from sensory nerve endings, inhibited mast- cell activation/degranulation as well as neurogenic inflam- mation, with a greater antinociceptive effect than that of morphine.97 In SCD mice, morphine was found to stimulate the release of substance P from mast cells, thereby promot- ing neurogenic inflammation and hyperalgesia mediated by mast-cell activation.93 In SCD patients, morphine is consid- ered a reference analgesic for VOC but it may actually have deleterious effects by inducing the release of mast-cell medi- ators, including substance P and histamine.89 Importantly, human mast-cell degranulation in response to morphine was recently found to be mediated by MAS-related G-pro- tein-coupled receptor X2 (MRGPRX2), which is also a major receptor for substance P, mediating innate immune cell recruitment, neurogenic inflammation, and pain.98,99
Mast-cell activation may have an additional role in pro- moting blood-brain barrier dysfunction in SCD. In vitro, activated mast cells from SCD mice induced endoplasmic reticulum stress in brain endothelial cells, with increased P-selectin expression and increased endothelial permeabil- ity.100 Hence, mast-cell activation may contribute to endothelial dysfunction in SCD via endoplasmic reticu- lum stress-mediated P-selectin expression.
The main findings on the involvement of mast cells in SCD pathophysiology are summarized in Figure 3.
The main potential therapeutic agents targeting innate immune cells in SCD are described in Table 1.
Conclusion
Findings from our review suggest that innate immune cells do indeed play important roles in SCD in promoting inflammation, adhesion and pain, the hallmarks of the dis- ease (Figure 4).
Among suspected mechanisms underlying innate immune cell activation, free hemoglobin and heme released by hemolysis may play a crucial role by activating TLR4 or generating ROS that can activate the inflamma- some.85 Nitric oxide depletion by free hemoglobin may also contribute, especially to platelet and mast-cell activa- tion. Innate immune cells usually possess a large repertoire of receptors, including cytokine and chemokine receptors, which enables them to respond to various inflammatory signals. Hence, their activation in SCD is likely promoted by chronic and acute inflammation. SCD patients have increased susceptibility to infections, and PAMP, such as bacterial lipopolysaccharides or endotoxins, could also contribute, as could DAMP originating from injured tis- sues following ischemia/reperfusion.
Once activated, innate immune cells release a wide range of cytokines and chemokines, thus promoting a vicious cycle of immune cell recruitment and activation. Pro-inflammatory cytokines produced mainly by mono- cytes and macrophages, but also by platelets and other innate immune cells, can activate the endothelium togeth- er with heme, resulting in increased expression of adhe- sion molecules. Neutrophils are crucial factors in endothe- lial adhesion but monocytes and platelets also contribute to decreased blood flow and vaso-occlusion via the forma- tion of RBC–monocyte, platelet–monocyte and platelet– neutrophil aggregates. However, activated innate immune cells are not just deleterious protagonists in SCD, as illus- trated by patrolling monocytes, which scavenge endothe- lial debris and adherent sickle RBC.
Innate immune cells may play a specific role in SCD. For example, mast cells promote neurogenic inflammation via substance P release. However, the main complications of SCD, such as VOC, ACS and stroke, likely result from interlinked actions of innate immune cells. Further inves- tigations are required to better understand the involve- ment of these novel, important protagonists in SCD pathophysiology, their respective roles in acute and chron- ic complications, as well as the mechanisms underlying their activation, in order to develop innovative treatments targeting innate immune cells in SCD.
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