Red Blood Cells and Their Adhesiveness in Disease: History
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Subjects: Cell Biology
Contributor:
Robert J. Asaro
,
Elisabetta Profumo
,
Brigitta Buttari
,
Pedro Cabrales

Red blood cells (RBCs) have been implicated in the progression of a wide range of disease states where their roles have been specifically linked to their adhesiveness. Such diseases include, inter alia, atherosclerosis, tumors (in terms of its growth suppression), polycythemia vera, central retinal occlusion and diabetes mellitus, 

  • blood cell adhesiveness
  • blood cell hemolysis
  • blood cell ghosting

1. Introduction

RBCs have been implicated in the progression of a wide range of disease states where their roles have been specifically linked to their adhesiveness. Such diseases include, inter alia, atherosclerosis, particularly the thrombotic events that characterizethis disease, polycythemia vera, central retinal occlusion and diabetes mellitus [1][2][3][4][5][6][7][8][9][10]. In what follows, two examples of RBC effects, viz. on atherosclerosis and-perhaps as may seem counterintuitive-on tumor suppression are discussed, followed by briefer discussions of the role of adhered RBCs in other diseases, and finally the role RBCs play in the interactions with macrophages [11].

2. The Role of the Red Blood Cell in the Progression of Atherosclerosis

There is general agreement that the key initial step in atherosclerosis is the subendothelial retention of cholesterol rich apolipoprotein B-containing lipoproteins (apoB-LPs) in susceptible regions of non-laminar flow [12][13], see Figure 1 upper left. Retention of apoB-LPs by proteoglycans results in apoB-LP aggregates [14] and increases the susceptibility of apoB-LP oxidation [15]. A key inflammatory response to retained apoB-LPs that are prone to oxidative modification is activation of the overlying endothelial cells that leads to chemotactic recruitment of monocytes [16], see Figure 1 upper left. Accumulation of macrophages within the early plaque contributes to the secretion of apoB-LP-binding proteoglycans that further encourages LP retention; the excessive lipid accumulation in macrophages and vascular smooth muscle cells (VSMC) leads to the formation of foam cells that, in turn, contribute to the physical bulk of developing plaques by triggering multiple pathways of programmed cell death, including apoptosis, autophagy, necroptosis, and pyroptosis. All these events result in a failure of such lesions to resolve as depicted in Figure 1 [17][18][19].
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Figure 1. The interior of an atherosclerosis plaque characterized by hypoxia and unresolved, and intensifying, inflammation; the progression of the plaque development is from the upper left diagonally to the lower right and upward toward the necrotic core at the upper right. Extravasated RBCs become senescent-like, adherent, and may undergo vesiculation, hemolysis, thus producing ROS, shed membrane patches (i.e., membrane fractions), leading to calcification [20] and eventual plaque instability.
The fate of atherosclerosis plaques is highly dependent on the balance between the recruitment and activation of monocyte-derived macrophages, and their clearance from the vessel wall [21][22][23][24][25][26][27]. Macrophages are extremely plastic cells, which quickly react in response to injury, infection, and other types of noxious conditions such as hypoxia and metabolic stress by switching phenotype to fulfil a pivotal role in host defense, wound healing, and immune regulation [28]. Macrophages with different phenotypes are, hence, distributed in varying locations of the atherosclerosis plaque [29].
After stimulation by microenvironmental factors, these cells demonstrate different polarization states [30]. In human atherosclerotic plaques, macrophages with a proinflammatory phenotype, termed M1, are aggregated on the shoulders of vulnerable plaques and promote inflammation by secreting proinflammatory cytokines, whereas macrophages with an anti-inflammatory phenotype, termed M2, are present in a stable cell-rich region far from the lipid core. M2 macrophages resolve plaque inflammation by secreting anti-inflammatory cytokines and by stimulating angiogenesis and phagocytosis. Macrophages termed Mhem, a more recently identified phenotype [31], are found accumulated in regions of previous hemorrhage and show an anti-atherogenic effect via the reduction of oxidative injuries in human plaque. These cells express high levels of scavenger receptor CD163, thus being able to clear Hb more quickly and to reduce hydrogen peroxide and ROS release [31]. In a mouse model of atherosclerosis, the macrophages in early-stage (“fatty-streak”) plaques are of the M2 type, but as the plaque progresses in size and complexity, they become M1-like [32].
Among microenvironmental factors, hypoxia plays a proatherogenic role in macrophage lipid and glucose metabolism, inflammation and polarization, and especially in the necrotic core where foam cells may undergo apoptosis [13] and where plaque destabilization occurs [33]. In addition, oxygen deprivation within the plaque induces neovascularization via the vasa vasorum [33][34], as indicated in Figure 1. Causes of hypoxia include, inter alia, the high metabolic needs involved with foam cell formation, as mentioned, reduced blood flow due to intima thickening, and generally reduced blood flow through the existing vasa vasorum. Hence the adaptive response is the growth of the vasa vasorum toward the lumen to supply oxygen to the inner layers [35]; however, intraplaque neovessels tend to be fragile, i.e., leaky, and prone to hemorrhage [34], mainly due to metalloprotease (MMP) activity as well as plasminogen activators [36]. Intraplaque hemorrhage is believed to be a primary trigger of the breach in the fibrous cap of the necrotic core that releases thrombosis [37][38].
Hence, researchers envision red blood cells entering into the unresolved hypoxic, inflamed, plaque environment; assuming RBCs are not yet senescent, the plaque environment clearly induces them to become so. The oxidative stress of the plaque will, for example, promote Ca++ uptake, transient cell shrinkage and re-swelling as described above and as described specifically by Lang et al. [39] for red blood cell “death”. Senescent RBCs are characterized by the exposure of phospholipid phosphatidylserine (PS) and adhesive receptors [40][41], and so researchers thereby hypothesize that the RBCs entering the plaque via hemorrhage become adhesive, and this is due to the inflammatory activity exerted by M1-like macrophages and hypoxia that promotes exposure of PS receptor (PSR) on the endothelial cells as described by Setty and Betal [42]. Under such circumstances RBCs will tend to undergo vesiculation and hemolysis, release Hb and create additional ROS as for aged RBCs [43], thus further exasperating the inflammatory conditions within the plaque. This is, in fact, quite consistent with the general scenario suggested by Buttari et al. [44] but, as yet, with an unknown mechanistic pathway. Buttari et al. [44] discuss a variety of RBC interactions involving cross-talk with T helper (Th1) cells, dendritic cells, and thereby contributing to the inflammatory factors that promote macrophage polarization toward the M1 inflammatory phenotype, that further supports researchers hypothesis. In particular, Buttari et al. observed that RBCs obtained from patients affected by carotid atherosclerosis failed to control lipopolysaccharide-induced dendritic cell (DC) maturation, thus determining the DC maturation toward a DC profile that sustains proinflammatory Th1 cell response [45]. Furthermore, Profumo et al. [46] observed that RBCs from patients with atherosclerosis are not able to inhibit activation-induced T lymphocyte apoptosis as opposed to RBCs from healthy subjects. As an impairment of apoptotic cells phagocytosis has been hypothesized as a mechanism contributing to necrotic core formation and to plaque vulnerability, it can also be speculated that the loss of the ability to rescue T lymphocytes from activation-induced apoptosis by RBCs exposed to oxidative stress contributes to promoting the pro-atherogenic processes responsible for plaque destabilization. These results indicate that the crosstalk between RBCs and immune cells contributes to the promotion of a proinflammatory microenvironment characterized by M1-like macrophage accumulation within the atherosclerosis plaque, and represents an additional pathway through which oxidative stress contributes to the progression of atherosclerosis. The M1-like macrophages increase is also supported by Williams et al. [47] who noted that “with plaque progression, an increase in GM-CSF expression in vivo contributes to the observed increase in M1-like cells”. Researchersrefer to their discussion for further details [44][47].
Finally, researchers mention that extravasated erythrocytes arising from intraplaque hemorrhage take on a senescent-like phenotype due to the hypoxic plaque environment and its ROS composition. They are likely adherent and hence prone to lysis as described in the above paradigm and its pathway. As shown by Tziakas et al. [20], the membranes of such lysed RBCs-but not intact human erythrocytes or lipids derived therefrom-promote mineralization of human arterial smooth muscle cells. This leads to plaque progression and eventual plaque instability via increased tissue stress [48]. The mechanisms involve lysed erythrocyte membranes inducing osteoblastic differentiation and calcium deposition mediated by eNOS activity via the NO receptor [20].
Collectively, all these observations indicate that exposure of RBCs to oxidative stress alters structural and functional features of these cells that consequently may acquire a proinflammatory behavior, thus contributing to the worsening of the atherosclerosis disease state.

3. The Role of the Red Blood Cell in Tumor Necrosis

Recent studies provide evidence that adhered RBCs within tumor environments can lead to tumor mass reduction. RRx-001 treatment of human RBCs induces a senescent-like state in RBCs that promotes adhesiveness via the exposure of PS; the mechanism for this involves RRx-001 binding to the Cys93 residue of hemoglobin (Hb), and inducing oxidation of Hb that then stimulates exposure of PS to the outer bilipid leaflet, as occurs for instance in sickle cell disease [6][49] and in the vesiculation and clearance of senescent red blood cells. In the inflammatory, viz. hypoxic and acidic, state of the tumor environment, this leads to the release of ROS and the exposure of PSR, the receptor for PS [42]. 
The environment so created favors the antitumor M1 macrophage phenotype and TNF-α release, that leads to further exposure of PSR, RBC adhesion, and hemolysis [50]. Moreover, it was shown that RRx-001 induces a surface decrease of CD47 on tumor cells and SIRP-α blocking on macrophages and a reduction of the phagocytosis inhibitory effect of the CD47/SIRP-α pathway that leads to a decrease in tumor mass, involving a shift from M2 macrophage to the more anti-tumor M1 phenotype [51][52][53][54][55]. It may be that RRx-001-treated RBCs stimulate a repolarization of tumor-associated-macrophages (TAMs) to a more M1-like phenotype via contributing to oxidative stress in the tumor environment and perhaps in a yet unrecognized molecular manner [54][55]. While ROS promotion of M1 polarization has been recognized and described, it is not clear if such favored polarization is exclusive to M1- vs. M2-like phenotypes [56]. For example, Zhang et al. [57] reported that ROS, and in particular O2−, play a “vital” role in the differentiation of the M2 phenotype, but not the M1 phenotype, where O2− played little role; in fact by applying ROS inhibitors they demonstrated M2 differentiation was inhibited. This is consistent with the findings of Oršolić et al. [58] who also found that ROS production was “necessary for the differentiation of M2 macrophages”; yet they also noted that “ROS production was critical for the activation and functions of M1 macrophages”. Oršolić et al. [58] used the antioxidant caffeic acid to demonstrate blockage of differentiation of TAMs, i.e., in their view M2 phenotypes. A recent review by Virág et al. [59] has noted results, viz. those of Regdon et al. [60] that M1 polarization increases macrophage resistance to oxidative stress as a self-protective measure; the same review, however, points to the results of Dai et al. [61] that find that the M2 phenotype has increased resistance to lipid-mediated stress. On the other hand, it has been shown that free heme, a product of hemolysis of senescent RBCs, induces necrosis in macrophages and hence may result in a decrease in pro-tumor M2-like macrophages vs. the anti-tumor M1 phenotype, or a general decrease in all TAM phenotypes. Yet again, it has been reported that ROS may cause apoptosis in cancer cells [62][63] and hence the free heme released by RRx-001 affected RBCs along with the increased ROS generated may also contribute to cancer cell death.
On the other hand, the release of free heme and Fe++ during hemolysis, along with the earlier release of vesicles exposing PS, of senescent-like RBCs adhered in clusters to tumor cells may precipitate ferroptosis as described as affecting survival of cancer cells [64][65][66][67][68]. Following this hypothesis, researchers note two possibilities for more specific mechanisms. First, the senescent like phenotype induced by RRx-001 may, in turn, induce an increased erythrophagocytosis and the consequent ferroptosis in the more phagocytic M2 macrophages, thereby shifting the balance to the antitumor M1 phenotype as described by Youssef et al. [69] or by Dai et al. [70]. Secondly, the heme and Fe++ released via hemolysis of adhered RBCs may be taken up by tumors and induce ferroptosis.
Enhanced RRx-001-treated RBC adhesion to endothelial cells was in fact demonstrated, especially in the presence of TNF-α and hypoxia, this supporting the belief that the adhesion couple was PS-PSR.
In relation to oxidative stress and its involvement in the development of anticancer therapeutic strategies, it is worth mentioning the role of ion channels, transmembrane proteins regulating the permeability of cell membranes to ions. Oxidative stress occurs when there is an imbalance between the production of free radicals and the defense mechanisms implemented by antioxidant molecules. In physiological conditions, cells produce ROS that function as second messengers for intracellular signaling. The redox balance is maintained by various endogenous antioxidants. These include small molecules and enzymes such as glutathione, alpha-lipoic acid, catalase, superoxide dismutase, glutathione peroxidases. Natural antioxidant compounds can also be obtained from the diet, such as beta-carotene, ascorbic acid, and tocopherol. Antioxidant compounds counteract oxidation thus preventing cellular damage caused by free radicals. Experimental studies have demonstrated the ability of antioxidants to prevent skin cancer induced by UV exposure [71]. When ROS production exceeds the ability of antioxidant mechanisms to clear them thus determining an excessive increase of their concentration, cellular and tissue damage occurs.
Ion channels have an important role in the regulation of cell migration, cell cycle progression, and proliferation. The genetic alterations occurring in cancer cells also involve the expression and/or activity of ion channels. Ionic signaling regulates innate and adaptive immune cells functions, extracellular matrix formation and tumor vascularization, thus influencing tumor microenvironment. ROS production induces post-translational modifications of ion channels, thus altering intracellular signaling pathways. Depending on the type of modification, oxidative stress can enhance or impair ion channels activity, thus promoting or attenuating the progression of tumors such as melanoma. As ion channels are primarily expressed in the plasma membrane, they represent promising targets for the development of anti-cancer therapeutic strategies. In a recent review, Remigante and co-authors thoroughly discussed the role of ion channels as therapeutic targets in melanoma [72].

4. The Role of the Red Blood Cell in Other Diseases

Central retinal vascular occlusion: Central retinal vascular occlusion (CRVO) is the second most common cause of vision loss [73][74] and has been associated with enhanced red blood cell adhesiveness to the retinal vasculature [4] where PS and PSR exposure have been implicated in the adhesiveness [4][74]. This is consistent with the findings of local inflammatory conditions causing oxidative stress that is known to promote PS and PSR exposure [39]. Hirabayashi et al. [74] report proinflammatory (M1) macrophage activity and oxidative stress whose therapeutic mitigation led to beneficial results. Without such mitigation, classically activated M1 macrophages may release TNF-α that, along with a typically hypoxic state, also promotes PS and PSR exposure on RBCs and the microendothelium, respectively [42].
Polycythemia vera: Polycythemia vera (PV) is a chronic myeloproliferative disease in which arterial and venous thrombosis is a main cause of morbidity and mortality [75]. In polycythemia vera the muted JAK2 kinase causes phosphorylation of BCAM (CD239) which is a receptor for endothelial laminin-α5 [8][9][76], and this may well be a main source of RBC adhesiveness. On the other hand, Tan et al. [77] report of observations of erythrocyte derived PS exposing “microparticles” (MPs); these MPs were described as vesicles in the size range 0.1–1 µm in diameter and as being “procoagulant”, and hence a likely contributor to the hypercoagulable state in PV. The pathway for such adhered RBCs to produce vesicles has been described by Asaro and Cabrales [78].
Diabetes: In diabetic retinopathy (DR), the breakdown of the blood–retinal barrier (BRB) results in vascular leakage and subsequent macular edema; this constitutes a major cause of vision impairment related to diabetes [79][80]. Importantly, diabetes causes oxidative stress, and elevated levels of oxidative stress contribute to the pathogenesis of diabetic vascular dysfunction, viz. that characteristic of DR [80]. The RBC may be the victim of ROS in the BRB, and then a contributor to unresolved ischemia and inflammation that leads to, inter alia, neovascularization, apoptosis of pericytes and astrocytes by the advanced glycation end-products (AGEs) that are produced [81]. Wautier et al. [82] had, in fact, hypothesized that prolonged RBC exposure to plasma hyperglycemia could cause AGE-like modification of RBC surface membrane proteins. This would enhance the adhesiveness of diabetic erythrocytes, via RAGE exposure, to the BRB endothelium. This would set the stage for RBCs contributing to further oxidative stress as per the paradigm described herein.

5. Siderocytes and Macrophages

De Back et al. [83] describe the possible role of splenic macrophages in facilitating RBC vesiculation, a mechanism important for the removal of inclusions such as Heinz bodies (aggregates of denatured, oxidatively damaged hemoglobin) and regarding siderocytes, i.e., RBCs with one or more granular inclusion containing ferric Fe [84]. Macrophages have a pivotal role in this mechanism as they interact with aged, senescent, or diseased, RBCs that expose adhesion molecules, leading to vesiculation, lysis and ghost formation. For aged RBCs, i.e. siderocytes, the process is a self-protective mechanism that ends with vesiculation [85][86]. Adhesion strength is a fundamental factor to proceed along RBC vesiculation–lysis–ghosting pathway [1][87]. There is much to understand the details of this adhesion–hemolysis–ghost formation paradigm that influences RBCs life and the RBCs role(s) in a wide range of diseases.

6. Discussion

The paradigm of adhered RBCs subject to modest shear flows leading to vesiculation, hemolysis, and ghost formation, provides a unifying scenario of the RBCs’ road to clearance and of RBC role in disease progression and/or regression. It is possible to hypothesize that details of RBC adhesiveness may provide a diagnostic set of tools for assessing, and even designing, therapeutic strategies and methods. The combination of several technological approaches would provide more complete information useful to fully document the time scales of adhesiveness and its outcomes vis-a-vis hemolysis and ghost formation to understand RBCs adhesiveness in health and disease. 

This entry is adapted from the peer-reviewed paper 10.3390/ijms241210382

References

  1. Asaro, R.J.; Cabrales, P. Red blood cells: Tethering, vesiculation, and disease in micro-vascular flow. Diagnostics 2021, 11, 971.
  2. Pretini, V.; Koenen, M.H.; Kaestner, L.; Fens, M.H.A.M.; Schiffelers, R.M.; Bartels, M.; Van Wijk, R. Red Blood Cells: Chasing Interactions. Front. Physiol. 2019, 10, 945.
  3. Weisel, J.W.; Litvinov, R.I. Red blood cells: The forgotten player in hemostasis and thrombosis. J. Thromb. Haemost. 2019, 17, 271–282.
  4. Wautier, M.P.; Héron, E.; Picot, J.; Colin, Y.; Hermine, O.; Wautier, J.L. Red blood cell phosphatidylserine exposure is responsible for increased erythrocyte adhesion to endothelium in central retinal vein occlusion. J. Thromb. Haemost. 2011, 9, 1049–1055.
  5. Grossin, N.; Wautier, M.P.; Picot, J.; Stern, D.M.; Wautier, J.L. Differential effect of plasma or erythrocyte AGE-ligands of RAGE on expression of transcripts for receptor isoforms. Diabetes Metab. 2009, 35, 410–417.
  6. Kucukal, E.; Ilich, A.; Key, N.S.; Little, J.A.; Gurkan, U.A. Red Blood Cell Adhesion to Heme-Activated Endothelial Cells Reflects Clinical Phenotype in Sickle Cell Disease. Am. J. Hematol. 2018, 93, 1050–1060.
  7. Wautier, J.L.; Wautier, M.P. Cellular and Molecular Aspects of Blood Cell-Endothelium Interactions in Vascular Disorders. Int. J. Mol. Sci. 2020, 21, 5315–5330.
  8. Wautier, M.P.; El Nemer, W.; Gane, P.; Rain, J.D.; Cartron, J.P.; Colin, Y.; Le Van Kim, C.; Wautier, J.L. Increased adhesion to endothelial cells of erythrocytes from patients with polycythemia vera is mediated by laminin alpha5 chain and Lu/BCAM. Blood 2007, 110, 894–901.
  9. El Nemer, W.; De Grandis, M.; Brusson, M. Abnormal adhesion of red blood cells in polycythemia vera: A prothrombotic effect? Thromb. Res. 2014, 133 (Suppl. 2), S107–S111.
  10. Alapan, Y.; Little, J.A.; Gurkan, U.A. Heterogeneous red blood cell adhesion and deformability in sickle cell disease. Sci. Rep. 2014, 4, 7173.
  11. de Back, D.Z.; Kostova, E.B.; van Kraaij, M.; van den Berg, T.K.; van Bruggen, R. Of macrophages and red blood cells: A complex love story. Front. Physiol. 2014, 5, 9–17.
  12. Williams, K.J.; Tabas, I. The response-to-retention hypothesis of early atherogenesis. Arterioscler. Thromb. Vasc. Biol. 1995, 15, 551–561.
  13. Moore, K.J.; Tabas, I. Macrophages in the pathogenesis of atherosclerosis. Cell 2011, 145, 341–355.
  14. Srinivasan, S.R.; Radhakrishnamurthy, B.; Vijayagopal, P.; Berenson, G.S. Proteoglycans, lipoproteins, and atherosclerosis. Adv. Exp. Med. Biol. 1991, 285, 373–381.
  15. Hurt-Camejo, E.; Camejo, G.; Rosengren, B.; López, F.; Ahlström, C.; Fager, G.; Bondjers, G. Effect of arterial proteoglycans and glycosaminoglycans on low density lipoprotein oxidation and its uptake by human macrophages and arterial smooth muscle cells. Arterioscler. Thromb. 1992, 12, 569–583.
  16. Cushing, S.D.; Berliner, J.A.; Valente, A.J.; Territo, M.C.; Navab, M.; Parhami, F.; Gerrity, R.; Schwartz, C.J.; Fogelman, A.M. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc. Natl. Acad. Sci. USA 1990, 87, 5134–5138.
  17. Tabas, I. Macrophage death and defective inflammation resolution in atherosclerosis. Nat. Rev. Immunol. 2010, 10, 36–46.
  18. Tabas, I.; Li, Y.; Brocia, R.W.; Xu, S.W.; Swenson, T.L.; Williams, K.J. Lipoprotein lipase and sphingomyelinase synergistically enhance the association of atherogenic lipoproteins with smooth muscle cells and extracellular matrix. A possible mechanism for low density lipoprotein and lipoprotein(a) retention and macrophage foam cell formation. J. Biol. Chem. 1993, 268, 20419–20432.
  19. Kruth, H.S.; Jones, N.L.; Huang, W.; Zhao, B.; Ishii, I.; Chang, J.; Combs, C.A.; Malide, D.; Zhang, W.Y. Macropinocytosis is the endocytic pathway that mediates macrophage foam cell formation with native low density lipoprotein. J. Biol. Chem. 2005, 280, 2352–2360.
  20. Tziakas, D.N.; Chalikias, G.; Pavlaki, M.; Kareli, D.; Gogiraju, R.; Hubert, A.; Böhm, E.; Stamoulis, P.; Drosos, I.; Kikas, P.; et al. Lysed Erythrocyte Membranes Promote Vascular Calcification. Circulation 2019, 139, 2032–2048.
  21. Moore, K.J.; Sheedy, F.J.; Fisher, E.A. Macrophages in atherosclerosis: A dynamic balance. Nat. Rev. Immunol. 2013, 13, 709–721.
  22. Mosser, D.M.; Edwards, J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 2008, 8, 958–969, Erratum in: Nat. Rev. Immunol. 2010, 10, 460.
  23. Libby, P.; Ridker, P.M.; Hansson, G.K. Progress and challenges in translating the biology of atherosclerosis. Nature 2011, 473, 317–325.
  24. Mestas, J.; Ley, K. Monocyte-endothelial cell interactions in the development of atherosclerosis. Trends Cardiovasc. Med. 2008, 18, 228–232.
  25. Kamei, M.; Carman, C.V. New observations on the trafficking and diapedesis of monocytes. Curr. Opin. Hematol. 2010, 17, 43–52.
  26. Johnson, J.L.; Newby, A.C. Macrophage heterogeneity in atherosclerotic plaques. Curr. Opin. Lipidol. 2009, 20, 370–378.
  27. Paulson, K.E.; Zhu, S.N.; Chen, M.; Nurmohamed, S.; Jongstra-Bilen, J.; Cybulsky, M.I. Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis. Circ. Res. 2010, 106, 383–390.
  28. Gordon, S.; Plüddemann, A.; Martinez Estrada, F. Macrophage heterogeneity in tissues: Phenotypic diversity and functions. Immunol. Rev. 2014, 262, 36–55.
  29. Gui, T.; Shimokado, A.; Sun, Y.; Akasaka, T.; Muragaki, Y. Diverse roles of macrophages in atherosclerosis: From inflammatory biology to biomarker discovery. Mediators Inflamm. 2012, 2012, 693083.
  30. Stout, R.D.; Jiang, C.; Matta, B.; Tietzel, I.; Watkins, S.K.; Suttles, J. Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J. Immunol. 2005, 175, 342–349.
  31. Boyle, J.J.; Harrington, H.A.; Piper, E.; Elderfield, K.; Stark, J.; Landis, R.C.; Haskard, D.O. Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype. Am. J. Pathol. 2009, 174, 1097–1108.
  32. Khallou-Laschet, J.; Varthaman, A.; Fornasa, G.; Compain, C.; Gaston, A.T.; Clement, M.; Dussiot, M.; Levillain, O.; Graff-Dubois, S.; Nicoletti, A.; et al. Macrophage plasticity in experimental atherosclerosis. PLoS ONE 2010, 5, e8852.
  33. de Vries, M.R.; Quax, P.H. Plaque angiogenesis and its relation to inflammation and atherosclerotic plaque destabilization. Curr. Opin. Lipidol. 2016, 27, 499–506.
  34. Chistiakov, D.A.; Melnichenko, A.A.; Myasoedova, V.A.; Grechko, A.V.; Orekhov, A.N. Role of lipids and intraplaque hypoxia in the formation of neovascularization in atherosclerosis. Ann. Med. 2017, 49, 661–677.
  35. Zemplenyi, T.; Crawford, D.W.; Cole, M.A. Adaptation to arterial wall hypoxia demonstrated in vivo with oxygen microcathodes. Atherosclerosis 1989, 76, 173–179.
  36. Garcia-Touchard, A.; Henry, T.D.; Sangiorgi, G.; Spagnoli, L.G.; Mauriello, A.; Conover, C.; Schwartz, R.S. Extracellular proteases in atherosclerosis and restenosis. Arterioscler. Thromb. Vasc. Biol. 2005, 25, 1119–1127.
  37. Virmani, R.; Kolodgie, F.D.; Burke, A.P.; Finn, A.V.; Gold, H.K.; Tulenko, T.N.; Wrenn, S.P.; Narula, J. Atherosclerotic plaque progression and vulnerability to rupture: Angiogenesis as a source of intraplaque hemorrhage. Arterioscler. Thromb. Vasc. Biol. 2005, 25, 2054–2061.
  38. Levy, A.P.; Moreno, P.R. Intraplaque hemorrhage. Curr. Mol. Med. 2006, 6, 479–488.
  39. Lang, F.; Abed, M.; Lang, E.; Föller, M. Oxidative stress and suicidal erythrocyte death. Antioxid. Redox Signal. 2014, 21, 138–153.
  40. Borst, O.; Abed, M.; Alesutan, I.; Towhid, S.T.; Qadri, S.M.; Föller, M.; Gawaz, M.; Lang, F. Dynamic adhesion of eryptotic erythrocytes to endothelial cells via CXCL16/SR-PSOX. Am. J. Physiol. Cell Physiol. 2012, 302, C644–C651.
  41. Fadok, V.A.; Bratton, D.L.; Rose, D.M.; Pearson, A.; Ezekewitz, R.A.; Henson, P.M. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 2000, 405, 85–90.
  42. Setty, B.N.; Betal, S.G. Microvascular endothelial cells express a phosphatidylserine receptor: A functionally active receptor for phosphatidylserine-positive erythrocytes. Blood 2008, 111, 905–914.
  43. Comporti, M.; Signorini, C.; Buonocore, G.; Ciccoli, L. Iron release, oxidative stress and erythrocyte ageing. Free Radic. Biol. Med. 2002, 32, 568–576.
  44. Buttari, B.; Profumo, E.; Riganò, R. Crosstalk between red blood cells and the immune system and its impact on atherosclerosis. Biomed. Res. Int. 2015, 2015, 616834.
  45. Buttari, B.; Profumo, E.; Cuccu, B.; Straface, E.; Gambardella, L.; Malorni, W.; Genuini, I.; Capoano, R.; Salvati, B.; Riganò, R. Erythrocytes from patients with carotid atherosclerosis fail to control dendritic cell maturation. Int. J. Cardiol. 2012, 155, 484–486.
  46. Profumo, E.; Buttari, B.; Petrone, L.; Straface, E.; Gambardella, L.; Pietraforte, D.; Genuini, I.; Capoano, R.; Salvati, B.; Malorni, W.; et al. Redox imbalance of red blood cells impacts T lymphocyte homeostasis: Implication in carotid atherosclerosis. Thromb. Haemost. 2011, 106, 1117–1126.
  47. Williams, H.J.; Fisher, E.A.; Greaves, D.R. Macrophage differentiation and function in atherosclerosis: Opportunities for therapeutic intervention? J. Innate Immun. 2012, 4, 498–508.
  48. Maldonado, N.; Kelly-Arnold, A.; Vengrenyuk, Y.; Laudier, D.; Fallon, J.T.; Virmani, R.; Cardoso, L.; Weinbaum, S. A mechanistic analysis of the role of microcalcifications in atherosclerotic plaque stability: Potential implications for plaque rupture. Am. J. Physiol. Heart Circ. Physiol. 2012, 303, H619–H628.
  49. Kucukal, E.; Little, J.A.; Gurkan, U.A. Shear dependent red blood cell adhesion in microscale flow. Integr. Biol. 2018, 10, 194–206.
  50. Jani, V.P.; Asaro, R.; Oronsky, B.; Cabrales, P. RRx-001 Increases Erythrocyte Preferential Adhesion to the Tumor Vasculature. Int. J. Mol. Sci. 2021, 22, 4713–4724.
  51. Cabrales, P. RRx-001 Acts as a Dual Small Molecule Checkpoint Inhibitor by Downregulating CD47 on Cancer Cells and SIRP-α on Monocytes/Macrophages. Transl. Oncol. 2019, 12, 626–663.
  52. Cendrowicz, E.; Sas, Z.; Bremer, E.; Rygiel, T.P. The Role of Macrophages in Cancer Development and Therapy. Cancers 2021, 13, 1946–1959.
  53. Na, Y.R.; Je, S.; Seok, S.H. Metabolic features of macrophages in inflammatory diseases and cancer. Cancer Lett. 2018, 413, 46–58.
  54. Anfray, C.; Ummarino, A.; Andón, F.T.; Allavena, P. Current Strategies to Target Tumor-Associated-Macrophages to Improve Anti-Tumor Immune Responses. Cells 2019, 9, 46–69.
  55. van Dalen, F.J.; van Stevendaal, M.H.M.E.; Fennemann, F.L.; Verdoes, M.; Ilina, O. Molecular Repolarisation of Tumour-Associated Macrophages. Molecules 2018, 24, 9.
  56. Tan, H.Y.; Wang, N.; Li, S.; Hong, M.; Wang, X.; Feng, Y. The Reactive Oxygen Species in Macrophage Polarization: Reflecting Its Dual Role in Progression and Treatment of Human Diseases. Oxid. Med. Cell Longev. 2016, 2016, 2795090.
  57. Zhang, Y.; Choksi, S.; Chen, K.; Pobezinskaya, Y.; Linnoila, I.; Liu, Z.G. ROS play a critical role in the differentiation of alternatively activated macrophages and the occurrence of tumor-associated macrophages. Cell Res. 2013, 23, 898–914.
  58. Oršolić, N.; Kunštić, M.; Kukolj, M.; Gračan, R.; Nemrava, J. Oxidative stress, polarization of macrophages and tumour angiogenesis: Efficacy of caffeic acid. Chem. Biol. Interact. 2016, 256, 111–124.
  59. Virág, L.; Jaén, R.I.; Regdon, Z.; Boscá, L.; Prieto, P. Self-defense of macrophages against oxidative injury: Fighting for their own survival. Redox. Biol. 2019, 26, 101261.
  60. Regdon, Z.; Robaszkiewicz, A.; Kovács, K.; Rygielska, Ż.; Hegedűs, C.; Bodoor, K.; Szabó, É.; Virág, L. LPS protects macrophages from AIF-independent parthanatos by downregulation of PARP1 expression, induction of SOD2 expression, and a metabolic shift to aerobic glycolysis. Free Radic. Biol. Med. 2019, 131, 184–196.
  61. Dai, L.; Bhargava, P.; Stanya, K.J.; Alexander, R.K.; Liou, Y.H.; Jacobi, D.; Knudsen, N.H.; Hyde, A.; Gangl, M.R.; Liu, S.; et al. Macrophage alternative activation confers protection against lipotoxicity-induced cell death. Mol. Metab. 2017, 6, 1186–1197.
  62. Kim, B.C.; Kim, H.G.; Lee, S.A.; Lim, S.; Park, E.H.; Kim, S.J.; Lim, C.J. Genipin-induced apoptosis in hepatoma cells is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of mitochondrial pathway. Biochem. Pharmacol. 2005, 70, 1398–1407.
  63. Kuo, P.L.; Chen, C.Y.; Hsu, Y.L. Isoobtusilactone A induces cell cycle arrest and apoptosis through reactive oxygen species/apoptosis signal-regulating kinase 1 signaling pathway in human breast cancer cells. Cancer Res. 2007, 67, 7406–7420.
  64. Dixon, S.J.; Lemberg, K.M.; Lamprecht, M.R.; Skouta, R.; Zaitsev, E.M.; Gleason, C.E.; Patel, D.N.; Bauer, A.J.; Cantley, A.M.; Yang, W.S.; et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 2012, 149, 1060–1072.
  65. Jiang, X.; Stockwell, B.R.; Conrad, M. Ferroptosis: Mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol. 2021, 22, 266–282.
  66. Chen, X.; Kang, R.; Kroemer, G.; Tang, D. Broadening horizons: The role of ferroptosis in cancer. Nat. Rev. Clin. Oncol. 2021, 18, 280–296.
  67. Lei, P.; Bai, T.; Sun, Y. Mechanisms of Ferroptosis and Relations with Regulated Cell Death: A Review. Front. Physiol. 2019, 10, 139.
  68. Wu, S.; Li, T.; Liu, W.; Huang, Y. Ferroptosis and Cancer: Complex Relationship and Potential Application of Exosomes. Front. Cell Dev. Biol. 2021, 9, 733751.
  69. Youssef, L.A.; Rebbaa, A.; Pampou, S.; Weisberg, S.P.; Stockwell, B.R.; Hod, E.A.; Spitalnik, S.L. Increased erythrophagocytosis induces ferroptosis in red pulp macrophages in a mouse model of transfusion. Blood 2018, 131, 2581–2593.
  70. Dai, E.; Han, L.; Liu, J.; Xie, Y.; Kroemer, G.; Klionsky, D.J.; Zeh, H.J.; Kang, R.; Wang, J.; Tang, D. Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein. Autophagy 2020, 16, 2069–2083.
  71. Sable, K.A.; Shields, B.E. The Role of Dietary Antioxidants in Melanoma and Nonmelanoma Skin Cancer. Cutis 2023, 111, 33–48.
  72. Remigante, A.; Spinelli, S.; Marino, A.; Pusch, M.; Morabito, R.; Dossena, S. Oxidative Stress and Immune Response in Melanoma: Ion Channels as Targets of Therapy. Int. J. Mol. Sci. 2023, 24, 887.
  73. Rogers, S.; McIntosh, R.L.; Cheung, N.; Lim, L.; Wang, J.J.; Mitchell, P.; Kowalski, J.W.; Nguyen, H.; Wong, T.Y.; International Eye Disease Consortium. The prevalence of retinal vein occlusion: Pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology 2010, 117, 313–319.
  74. Hirabayashi, K.; Tanaka, M.; Imai, A.; Toriyama, Y.; Iesato, Y.; Sakurai, T.; Kamiyoshi, A.; Ichikawa-Shindo, Y.; Kawate, H.; Tanaka, M.; et al. Development of a Novel Model of Central Retinal Vascular Occlusion and the Therapeutic Potential of the Adrenomedullin-Receptor Activity-Modifying Protein 2 System. Am. J. Pathol. 2019, 189, 449–466.
  75. Spivak, J.L. Polycythemia vera: Myths, mechanisms, and management. Blood 2002, 100, 4272–4290.
  76. De Grandis, M.; Cambot, M.; Wautier, M.P.; Cassinat, B.; Chomienne, C.; Colin, Y.; Wautier, J.L.; Le Van Kim, C.; El Nemer, W. JAK2V617F activates Lu/BCAM-mediated red cell adhesion in polycythemia vera through an EpoR-independent Rap1/Akt pathway. Blood 2013, 121, 658–665.
  77. Tan, X.; Shi, J.; Fu, Y.; Gao, C.; Yang, X.; Li, J.; Wang, W.; Hou, J.; Li, H.; Zhou, J. Role of erythrocytes and platelets in the hypercoagulable status in polycythemia vera through phosphatidylserine exposure and microparticle generation. Thromb. Haemost. 2013, 109, 1025–1032.
  78. Asaro, R.J.; Cabrales, P. The RBCs road to ghost and removal: Splenic clearance. Blood Adv. 2021, 5, 4422–4425.
  79. Klaassen, I.; Van Noorden, C.J.; Schlingemann, R.O. Molecular basis of the inner blood-retinal barrier and its breakdown in diabetic macular edema and other pathological conditions. Prog. Retin. Eye Res. 2013, 34, 19–48.
  80. Kaur, C.; Foulds, W.S.; Ling, E.A. Blood-retinal barrier in hypoxic ischaemic conditions: Basic concepts, clinical features and management. Prog. Retin. Eye Res. 2008, 27, 622–647.
  81. Shin, E.S.; Sorenson, C.M.; Sheibani, N. Diabetes and retinal vascular dysfunction. J. Ophthalmic Vis. Res. 2014, 9, 362–373.
  82. Wautier, J.L.; Wautier, M.P.; Schmidt, A.M.; Anderson, G.M.; Hori, O.; Zoukourian, C.; Capron, L.; Chappey, O.; Yan, S.D.; Brett, J.; et al. Advanced glycation end products (AGEs) on the surface of diabetic erythrocytes bind to the vessel wall via a specific receptor inducing oxidant stress in the vasculature: A link between surface-associated AGEs and diabetic complications. Proc. Natl. Acad. Sci. USA 1994, 91, 7742–7746.
  83. de Back, D.Z.; Kostova, E.B.; van Kraaij, M.; van den Berg, T.K.; van Bruggen, R.; Of macrophages and red blood cells: A complex love story.. Front Physiol 2014, 5, 9-17, .
  84. Crosby, W.H.; Siderocytes and the spleen.. Blood 1957, 12, 165-170, .
  85. Willekens, F.L.; Roerdinkholder-Stoelwinder, B.; Groenen-Döpp, Y.A.; Bos, H.J.; Bosman, G.J.; van den Bos, A.G.; Verkleij, A.J.; Were, J.M; Hemoglobin loss from erythrocytes in vivo results from spleen-facilitated vesiculation.. Blood 2003, 101, 747-751, .
  86. Willekens, F.L.; Were, J.M.; Groenen-Döpp, Y.A.; Roerdinkholder-Stoelwinder, B.; de Pauw, B.; Bosman, G.J.; Erythrocyte vesiculation: A self-protective mechanism?. Br J Haematol 2008, 141, 549–556, .
  87. Asaro, R.J.; Zhu, Q.; MacDonald, I.C.; Tethering, evagination, and vesiculation via cell-cell interactions in microvascular flow. . Biomech Model Mechanobiol 2020, 20, 31-53, .
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