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Hyperglycemia Induces Inflammatory Response: History
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Subjects: Immunology | Endocrinology & Metabolism
Contributor: Laura Matuschik

Hyperglycemia, a hallmark of diabetes, can induce inflammatory programming of macrophages. The macrophage scavenger receptor CD163 controls inflammation by the internalization and degradation of hemoglobin-haptoglobin (Hb-Hp) complexes built due to intravascular hemolysis. Clinical studies have demonstrated a correlation between impaired scavenging of Hb-Hp complexes via CD163 and diabetic vascular complications. Hyperglycemia induces an inflammatory response of innate immune cells to Hb-Hp1-1 and Hb-Hp2-2 uptake, converting the silent Hb-Hp complex clearance that prevents vascular damage into an inflammatory process, hereby increasing the susceptibility of diabetic patients to vascular complications.

  • diabetes mellitus
  • hyperglycemia
  • inflammation
  • macrophages
  • CD163
  • scavenger receptor
  • hemoglobin-haptoglobin complexes

1. Introduction

Diabetes mellitus is a heterogeneous group of metabolic disorders sharing the common ground of chronic hyperglycemia that induces micro- and macrovascular complications [1][2]. Large clinical trials, i.e., the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS), found that the duration and degree of hyperglycemia correlates with the extent of microvascular complications [3][4]. Hyperglycemia can cause vascular complications by direct and indirect mechanisms, by the activation of detrimental inflammatory pathways in endothelial cells or by activation of immune cells, primarily of myeloid origin [5][6][7][8]. It was suggested that subclinical chronic systemic inflammation creates conditions for vascular damage [9][10][11]. Chronic inflammation is characterized by only moderate elevation of inflammatory cytokines, e.g., TNFα, IL-1β, and IL-6, induced by exogenous or endogenous factors [12]. The major source of inflammatory cytokines in chronic inflammation are macrophages. We have demonstrated previously that human macrophages respond to hyperglycemia by elevated production of predominantly proinflammatory cytokines [6][13]. Hyperglycemia can induce an inflammatory program in innate immune cells on the epigenetic level, as we showed for the enhanced presence of activating histone marks on the promoters of S100A9 and S100A12 genes, responsible for vascular inflammation in diabetes [7][14][15][16]. However, macrophages control inflammation not only by the release of proinflammatory factors, but also by their complex scavenging activity, which can be silent and tolerogenic, or can provoke additional inflammation. The effect of hyperglycemia on this essential function of monocytes and macrophages is unexplored.
CD163 is a scavenger receptor expressed on circulating monocytes and on tissue macrophages in different pathologies [17][18][19][20]. CD163 controls inflammation by the internalization and degradation of hemoglobin-haptoglobin (Hb-Hp) complexes [21]. Expression of CD163 is controlled by pro- and anti-inflammatory factors, where anti-inflammatory agents, such as glucocorticoids and IL-10, stimulate CD163 expression, and proinflammatory cytokines, such as IFNγ and TNFα, suppress CD163 expression [22][23][24][25][26]. The anti-inflammatory cytokine IL-4 had no effect on CD163 protein expression [23][27].
The most comprehensively characterized function of CD163 is its homeostatic role in the scavenging of Hb-Hp complexes formed as a result of intravascular hemolysis. This mechanism physiologically occurs for 10–20% of erythrocytes and increases considerably in pathological conditions, e.g., hemoglobinopathies or inflammation [21][28]. The formation of Hb-Hp complexes protects the endothelium and kidneys from the toxicity of free hemoglobin by preventing renal deposition of free hemoglobin resulting in parenchymal and vascular damage [28][29].
Hb-Hp complexes bind with high affinity to membrane-bound CD163 of both circulating monocytes and tissue macrophages, leading to their internalization and degradation via the cytoprotective and anti-inflammatory heme oxygenase-1 [21][30][31]. This anti-inflammatory capacity is decreased in diabetes mellitus, as CD163 mRNA expression in peripheral blood mononuclear cells (PBMCs) is significantly suppressed in newly diagnosed diabetic patients [32]. Moreover, the percentage of macrophages in atherosclerotic plaques and PBMC expressing CD163 was significantly reduced in diabetic patients compared to non-diabetic individuals [28][33]. Haptoglobin, the protein binding to free extracorpuscular hemoglobin, exists in two known allelic variants: Hp1 and Hp2, leading to three possible phenotypes: Hp1-1, Hp1-2, and Hp2-2 [34]. Haptoglobin serum levels differ considerably from 0.3–3.0 mg/mL between healthy individuals but stay reasonably constant for one individual, and are saturated when 500–1500 mg/L free hemoglobin is present in serum [34][35]. During inflammation, haptoglobin, which is a hepatocyte-produced acute-phase protein, is induced 2–5-fold by the acute-phase mediators IL-1 and IL-6 and can be released locally from storage granules by active neutrophils [36][37]. The clearance and antioxidant capacity of individuals expressing Hp1-1 has been observed to be superior to Hp2-2 individuals [38][39]. Longitudinal prospective studies have demonstrated that the Hp2-2 phenotype is an independent risk factor for the development of cardiovascular disease and increased susceptibility to vascular complications in diabetic individuals in comparison with the homozygous Hp1-1 variant [33][34][40]. As a possible mechanism for the proneness to vascular complications, it has been demonstrated that CD163 is downregulated in macrophages in atherosclerotic plaques of diabetic patients with the Hp2-2 genotype, indicating a compromised hemoglobin clearing capability [33].

2. Hyperglycemia Induces Inflammatory Response of Human Macrophages to CD163-Mediated Scavenging of Hemoglobin-Haptoglobin Complexes

In order to sustainably treat the skyrocketing number of patients affected by microvascular complications of diabetes mellitus, it is crucial to broaden our understanding of the immunological mechanisms leading to a derogated control of vascular damage [5][41].
So far, a number of studies have tried to elucidate the role and regulation of CD163 in pathological conditions, such as diabetes mellitus or inflammation, altogether [32][33][42][43]. In recent studies, mainly samples of already differentiated tissue macrophages [33][44], undifferentiated peripheral blood mononuclear cells [32], or the plasma concentration of the shed receptor, soluble CD163 [45][46], were used. Compared to them, our group used human primary peripheral blood macrophages derived from circulating monocytes.
IFNγ alone is an effective suppressor of CD163 expression on human primary macrophages, thus impairing the scavenging capacity of proinflammatory macrophages. These results, although being observed after a longer duration of cultivation (6 days), correlate with the findings of other studies in which CD163 mRNA and surface expression were decreased on freshly isolated or one-day old peripheral blood monocytes from healthy individuals after IFNγ stimulation [22][26].
Whereas the mRNA expression of CD163 was significantly downregulated in M(IL-4) compared to M0, the surface expression of CD163 was not affected by stimulation with IL-4. In agreement with this observation, Staples et al. described a downregulation of CD163 mRNA expression upon stimulation with IL-4 [47] and both Sulahian et al. and van den Heuvel et al. demonstrated that stimulation with IL-4 did not alter CD163 surface expression compared to M0 [23][27]. Thus, healing macrophages should possess a compensatory mechanism to ensure sufficient levels of surface CD163 to ensure control over the inflammatory response.
Apart from IFNγ- and IL-4-mediated regulation of CD163, hyperglycemia elicited an additional suppression of CD163 mRNA in M(IFNγ) compared to normoglycemia. This finding is in line with the observation that CD163 mRNA expression in PBMCs of diabetic individuals was significantly lower compared to PBMCs of healthy subjects [32]. Additionally, clinical studies not only found that pre-diabetic subjects displayed a significant increase in proinflammatory M(IFNγ), but also showed that diabetic patients had an elevated M1/M2 ratio correlating with a higher prevalence of microangiopathy [41][48].
The decrease of CD163 surface expression in hyperglycemia is congruent with the results of Levy et al., who found that PBMCs acquired from diabetic individuals expressed significantly less CD163 on their cell surface than those from healthy donors [33]. This reduced scavenging capacity might lead to an elevated heme toxicity contributing to endothelial damage and indicating the susceptibility of the diabetic patient to vascular complications due to dysfunctional control of tissue damage [5][49]. The clinically observed heterogeneity of manifestation and onset of vascular diabetic complications correlates with the observed donor-dependent response of macrophages to hyperglycemia. Cytokines, such as IFNγ and IL-4, define the direction of macrophage response, whereas hyperglycemia interferes by enhancing or annulating this cytokine effect.
Suppression of CD163 expression in M(IFNγ) in hyperglycemia raised the question of whether high-glucose conditions additionally have a direct impact on the scavenging function of CD163. Although the two tested variants of CD163′s ligand haptoglobin Hp1-1 and Hp2-2 differ considerably in their molecular structure [34][50], the uptake patterns of Hb-Hp complexes matched CD163 mRNA and surface expression patterns. Remarkably, higher uptake was found for Hb-Hp2-2 complexes compared to Hb-Hp1-1 complexes in all three macrophage subpopulations, correlating with a higher affinity of the Hp2-2 variant for the CD163-binding site located in the scavenger receptor cysteine-rich (SRCR) domain 3 [21][51]. Whether the structure of haptoglobin itself is the crucial factor in the process of Hb-Hp complex internalization is still controversial. An in vitro study performed on monocytes showed that the uptake of Hb-Hp complexes is competitively inhibited by free hemoglobin, thus indicating a common binding site of free and complexed hemoglobin and demonstrating that CD163–hemoglobin interactions are not affected by changes in structure resulting from the binding process of hemoglobin to haptoglobin [52]. This seems to be in contradiction to various other studies describing CD163 as the specific receptor for hemoglobin complexed to haptoglobin but not the free hemoglobin molecule [21][39].
There have not been any studies reporting a qualitative derogation of the CD163 scavenging function. However, the clinically observed proneness to vascular complications in diabetic patients is enhanced by the limited availability—and therefore limited capacity to mitigate vessel damage—of CD163 in proinflammatory conditions [49].
In vitro studies showed the activation of protein-kinase C- and casein-kinase-dependent macrophage pathways by cross-linking of cell surface CD163, triggering the release of proinflammatory cytokines, such as IL-1β and IL-6 [23][53][54]. Moreover, it was found in human atherosclerotic plaques that the exposure to Hb-Hp complexes leads to a particular macrophage phenotype, named M(Hb) or Mhem [55][56]. This phenotype is characterized by an abundant expression of surface CD163, downregulated cytokine production, and the lack of lipid withholding [57][58][59]. As these macrophages are particularly present in areas of hemorrhage and neoangiogenesis, a role in plaque vascularization, microvessel leakage, and inflammation of the surrounding endothelium has been suggested [55], thus questioning the long-established notion that CD163+ macrophages are involved in the resolution of inflammation [26][49]. Adding to a possible role of CD163 in proinflammatory macrophage activation, alveolar spaces of severely infected COVID-19 lungs contained a large amount of CD163+ macrophages as a sign of altered airway macrophage populations and correlating with diffuse alveolar damage and worse patient outcomes [60]. Moreover, the serum levels of soluble CD163, as a marker of macrophage activation, were enhanced in COVID-19 patients [61][62].
As a possible factor contributing to diverging results, the haptoglobin variants Hp1-1 and Hp2-2 were found to have not only differences in function, but also in the involvement in pathological conditions. For instance, the clearance and antioxidant capacity of Hp1-1 by binding hemoglobin was superior to the clearance of Hp2-2 [38][39]. The release of anti-inflammatory IL-10 in response to the binding of Hb-Hp1-1 complexes to CD163 was increased compared to Hb-Hp2-2 complexes [63]. Regarding the clinical significance of the different haptoglobin variants, it has been shown in longitudinal prospective studies that the Hp2-2 phenotype is an independent risk factor for the development of cardiovascular disease in diabetic individuals in comparison with the homozygous Hp1 variant [34][40]. Additionally, it has been demonstrated that CD163 is downregulated in macrophages of atherosclerotic plaques of diabetic patients with the Hp2-2 genotype, indicating a constrained hemoglobin clearing capacity [33].
To detect the inflammatory response of Hb-Hp scavenging in hyperglycemic conditions, we selected a number of read-out cytokines displaying the complex interaction and different stages of an inflammatory reaction. In healthy individuals, the process of inflammation serves a homeostatic purpose, containing pro- and anti-inflammatory phases [64]. In individuals suffering from type 2 diabetes mellitus, however, the balance is tilted towards the proinflammatory side, manifested by an upregulation of proinflammatory intracellular pathways [65] and an elevation in circulating inflammatory markers, such as C-reactive protein, IL-6, and TNFα [66][67][68].
Hyperglycemia enhanced the proinflammatory response of M(IFNγ) to Hb-Hp complex uptake by stimulating the production of TNFα, IL-1β, IL-6, IL-8, and IL-1RA, supporting the observation that hyperglycemia itself can induce the secretion of proinflammatory cytokines [6].
A statistically significant increase in TNFα secretion, the ‘classical player’ of the acute-phase immune response [69], could only be detected 6 h after the stimulation with Hb-Hp complexes in hyperglycemia, regardless of the present haptoglobin variant. This finding corresponded to the clinical observation of elevated TNFα-levels being detected in newly diagnosed diabetic patients compared to a healthy cohort [70][71].
Elevated IL-6 release might contribute to diabetes progression, as an in vitro study reported the induction of cellular insulin resistance of hepatocytes by IL-6-triggered impairment of insulin receptor signal transduction [72]. Another in vitro study showed that lower concentrations (20 µg/mL) of Hb-Hp1-1 complexes induced the secretion of proinflammatory IL-6 while higher concentrations (100 µg/mL) of Hb-Hp1-1 complexes, however, led to increased CD163 surface expression on monocytes, in terms of a positive anti-inflammatory feedback loop [73].
Hyperglycemia increased the secretion of both IL-1β and its natural inhibitor IL-1RA, confirming our previous data [6]. Increased IL-1RA secretion could be a possible compensation mechanism or negative feedback for the enhanced release of IL-1β, whose serum level was found to be elevated in diabetic patients, contributing to insulin resistance and progression of atherosclerotic lesions in obesity [74]. A compensatory role of IL-1RA might also be an explanation for the controversial observations concerning IL-1RA levels in hyperglycemia: on the one hand, elevated IL-1RA levels could be correlated with insulin resistance [73][75]; on the other hand, IL-1RA was found to diminish markers of inflammation in the blood samples of diabetic patients and enhance beta cell function [76].
In general, Hb-Hp1-1 complex uptake was the strongest stimulus for M(IFNγ) for acute (6 h) cytokine release; however, cytokine secretion was diminished after 24 h. Contrarily, Hb-Hp2-2 complex uptake resulted in the increased secretion of all read-out cytokines after 24 h, indicating a transcriptional upregulation of cytokine production. Hb-Hp2-2 complex uptake is able to create a long-lasting elevated release of proinflammatory cytokines is in line with the numerous clinical observations of Hp2-2 possessing a lesser antioxidative capacity than Hp1-1 [38][39], inducing a lesser anti-inflammatory response than Hp1-1 [63] and even being an independent risk factor for the development of cardiovascular disease in diabetic patients [34][40].
As an element of the pathophysiology of diabetes, these mechanisms promote the low-grade chronic inflammation present in the vascular system of diabetic patients and support the development of vascular complications. This shows that—in addition to a more proinflammatory setting—diabetes mellitus is a disease characterized by less effective anti-inflammatory damage control [5][64].
Further research using monocytes isolated from patients with non-compensated hyperglycemia is needed to validate our findings, and to determine the level of contribution of the Hp-Hb-induced inflammatory monocyte response to systemic inflammation. We also believe that in the future, the effect of currently used medications for diabetic patients should also be analyzed for their ability to minimize Hp-Hb-induced inflammation.

This entry is adapted from the peer-reviewed paper 10.3390/ijms23031385

References

  1. Alberti, K.G.; Zimmet, P.Z.; Aschner, P.; Assal, P.-J.; Bennet, P.H.; Groop, L.; Jervell, J.; Kanazawa, Y.; Keen, H.; Klein, R.; et al. Diagnosis and Classification of Diabetes Mellitus; Report of a WHO Consultation; WHO, Department of Noncommunicable Disease Surveillance: Geneva, Switzerland, 1999.
  2. Powers, A.; Niswender, K.; Evans-Molina, C. Diabetes: Diagnosis, Classification, and Pathophysiology. In Harrison’s Principles of Internal Medicine, 20th ed.; Jameson, F., Kasper, H., Longo, L., Eds.; McGraw-Hill Education: New York, NY, USA, 2018; Volume I, pp. 2850–2859.
  3. DCCT. The Diabetes Control and Complications Trial (DCCT). Design and methodologic considerations for the feasibility phase. Diabetes 1986, 35, 530–545.
  4. Stevens, R.J.; Kothari, V.; Adler, A.I.; Stratton, I.M.; United Kingdom Prospective Diabetes Study (UKPDS) Group. The UKPDS risk engine: A model for the risk of coronary heart disease in Type II diabetes (UKPDS 56). Clin. Sci. 2001, 101, 671–679.
  5. Schaper, N.C.; Havekes, B. Diabetes: Impaired damage control. Diabetologia 2012, 55, 18–20.
  6. Moganti, K.; Li, F.; Schmuttermaier, C.; Riemann, S.; Kluter, H.; Gratchev, A.; Harmsen, M.C.; Kzhyshkowska, J. Hyperglycemia induces mixed M1/M2 cytokine profile in primary human monocyte-derived macrophages. Immunobiology 2017, 222, 952–959.
  7. Mossel, D.M.; Moganti, K.; Riabov, V.; Weiss, C.; Kopf, S.; Cordero, J.; Dobreva, G.; Rots, M.G.; Kluter, H.; Harmsen, M.C.; et al. Epigenetic Regulation of S100A9 and S100A12 Expression in Monocyte-Macrophage System in Hyperglycemic Conditions. Front. Immunol. 2020, 11, 1071.
  8. Dasu, M.R.; Devaraj, S.; Park, S.; Jialal, I. Increased toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects. Diabetes Care 2010, 33, 861–868.
  9. Lorenzi, M. The polyol pathway as a mechanism for diabetic retinopathy: Attractive, elusive, and resilient. Exp. Diabetes Res. 2007, 2007, 61038.
  10. Ishibashi, Y.; Matsui, T.; Maeda, S.; Higashimoto, Y.; Yamagishi, S. Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor. Cardiovasc. Diabetol. 2013, 12, 125.
  11. Wendt, T.M.; Tanji, N.; Guo, J.; Kislinger, T.R.; Qu, W.; Lu, Y.; Bucciarelli, L.G.; Rong, L.L.; Moser, B.; Markowitz, G.S.; et al. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am. J. Pathol. 2003, 162, 1123–1137.
  12. Mathur, N.; Pedersen, B.K. Exercise as a mean to control low-grade systemic inflammation. Mediat. Inflamm 2008, 2008, 109502.
  13. Torres-Castro, I.; Arroyo-Camarena, U.D.; Martinez-Reyes, C.P.; Gomez-Arauz, A.Y.; Duenas-Andrade, Y.; Hernandez-Ruiz, J.; Bejar, Y.L.; Zaga-Clavellina, V.; Morales-Montor, J.; Terrazas, L.I.; et al. Human monocytes and macrophages undergo M1-type inflammatory polarization in response to high levels of glucose. Immunol. Lett. 2016, 176, 81–89.
  14. Heizmann, C.W.; Fritz, G.; Schafer, B.W. S100 proteins: Structure, functions and pathology. Front. Biosci. 2002, 7, d1356–d1368.
  15. Chellan, B.; Sutton, N.R.; Bowman, M.A.H. S100/RAGE-Mediated Inflammation and Modified Cholesterol Lipoproteins as Mediators of Osteoblastic Differentiation of Vascular Smooth Muscle Cells. Front. Cardiovasc. Med. 2018, 5, 163.
  16. Xiao, X.; Yang, C.; Qu, S.L.; Shao, Y.D.; Zhou, C.Y.; Chao, R.; Huang, L.; Zhang, C. S100 proteins in atherosclerosis. Clin. Chim. Acta 2020, 502, 293–304.
  17. Buechler, C.; Eisinger, K.; Krautbauer, S. Diagnostic and prognostic potential of the macrophage specific receptor CD163 in inflammatory diseases. Inflamm. Allergy Drug Targets 2013, 12, 391–402.
  18. Fuentes-Duculan, J.; Suarez-Farinas, M.; Zaba, L.C.; Nograles, K.E.; Pierson, K.C.; Mitsui, H.; Pensabene, C.A.; Kzhyshkowska, J.; Krueger, J.G.; Lowes, M.A. A subpopulation of CD163-positive macrophages is classically activated in psoriasis. J. Investig. Dermatol. 2010, 130, 2412–2422.
  19. Larionova, I.; Tuguzbaeva, G.; Ponomaryova, A.; Stakheyeva, M.; Cherdyntseva, N.; Pavlov, V.; Choinzonov, E.; Kzhyshkowska, J. Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers. Front. Oncol. 2020, 10, 566511.
  20. Bengtsson, E.; Hultman, K.; Edsfeldt, A.; Persson, A.; Nitulescu, M.; Nilsson, J.; Goncalves, I.; Bjorkbacka, H. CD163+ macrophages are associated with a vulnerable plaque phenotype in human carotid plaques. Sci. Rep. 2020, 10, 14362.
  21. Kristiansen, M.; Graversen, J.; Jacobsen, C.; Sonne, O.; Hoffman, H.J.; Lawk, A.; Moestrup, S. Identifcation of the haemoglobin scavenger receptor. Nature 2001, 409, 198–201.
  22. Buechler, C.; Ritter, M.; Orso, E.; Langmann, T.; Klucken, J.; Schmitz, G. Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. J. Leukoc. Biol. 2000, 67, 97–103.
  23. Van den Heuvel, M.M.; Tensen, C.P.; van As, J.H.; Van den Berg, T.K.; Fluitsma, D.M.; Dijkstra, C.D.; Dopp, E.A.; Droste, A.; Van Gaalen, F.A.; Sorg, C.; et al. Regulation of CD 163 on human macrophages: Cross-linking of CD163 induces signaling and activation. J. Leukoc. Biol. 1999, 66, 858–866.
  24. Hogger, P.; Dreier, J.; Droste, A.; Buck, F.; Sorg, C. Identification of the integral membrane protein RM3/1 on human monocytes as a glucocorticoid-inducible member of the scavenger receptor cysteine-rich family (CD163). J. Immunol. 1998, 161, 1883–1890.
  25. Philippidis, P.; Mason, J.C.; Evans, B.J.; Nadra, I.; Taylor, K.M.; Haskard, D.O.; Landis, R.C. Hemoglobin scavenger receptor CD163 mediates interleukin-10 release and heme oxygenase-1 synthesis: Antiinflammatory monocyte-macrophage responses in vitro, in resolving skin blisters in vivo, and after cardiopulmonary bypass surgery. Circ. Res. 2004, 94, 119–126.
  26. Zwadlo, G.; Voegeli, R.; Schulze Osthoff, K.; Sorg, C. A monoclonal antibody to a novel differentiation antigen on human macrophages associated with the down-regulatory phase of the inflammatory process. Pathobiology 1987, 55, 295–304.
  27. Sulahian, T.H.; Hogger, P.; Wahner, A.E.; Wardwell, K.; Goulding, N.J.; Sorg, C.; Droste, A.; Stehling, M.; Wallace, P.K.; Morganelli, P.M.; et al. Human monocytes express CD163, which is upregulated by IL-10 and identical to p155. Cytokine 2000, 12, 1312–1321.
  28. Asleh, R.; Levy, A.P. In vivo and in vitro studies establishing haptoglobin as a major susceptibility gene for diabetic vascular disease. Vasc. Health Risk Manag. 2005, 1, 19–28.
  29. Everse, J.; Hsia, N. The toxicities of native and modified hemoglobins. Free Radic. Biol. Med. 1997, 22, 1075–1099.
  30. Schaer, C.A.; Vallelian, F.; Imhof, A.; Schoedon, G.; Schaer, D.J. CD163-expressing monocytes constitute an endotoxin-sensitive Hb clearance compartment within the vascular system. J. Leukoc. Biol. 2007, 82, 106–110.
  31. Nielsen, M.J.; Andersen, C.B.; Moestrup, S.K. CD163 binding to haptoglobin-hemoglobin complexes involves a dual-point electrostatic receptor-ligand pairing. J. Biol. Chem. 2013, 288, 18834–18841.
  32. Dubayee, M.S.A.; Alayed, H.; Almansour, R.; Alqaoud, N.; Alnamlah, R.; Obeid, D.; Alshahrani, A.; Zahra, M.M.; Nasr, A.; Al-Bawab, A.; et al. Differential Expression of Human Peripheral Mononuclear Cells Phenotype Markers in Type 2 Diabetic Patients and Type 2 Diabetic Patients on Metformin. Front. Endocrinol. 2018, 9, 537.
  33. Levy, A.; Purushothaman, K.R.; Levy, N.S.; Purushothaman, M.; Strauss, M.; Asleh, R.; Marsh, S.; Cohen, O.; Moestrup, S.K.; Moller, H.J.; et al. Downregulation of the hemoglobin scavenger receptor in individuals with diabetes and the Hp 2-2 genotype: Implications for the response to intraplaque hemorrhage and plaque vulnerability. Circ. Res. 2007, 101, 106–110.
  34. Levy, A.; Asleh, R.; Blum, S.; Levy, N.S.; Miller-Lotan, R.; Kalet-Litman, S.; Anbinder, Y.; Lache, O.; Nakhoul, F.M.; Asaf, R.; et al. Haptoglobin: Basic and clinical aspects. Antioxid. Redox Signal. 2010, 12, 293–304.
  35. Langlois, M.R.; Delanghe, J.R. Biological and clinical significance of haptoglobin polymorphism in humans. Clin. Chem. 1996, 42, 1589–1600.
  36. Thomsen, J.H.; Etzerodt, A.; Svendsen, P.; Moestrup, S.K. The Haptoglobin-CD163-Heme Oxygenase-1 Pathway for Hemoglobin Scavenging. Oxid. Med. Cell. Longev. 2013, 2013, 523652.
  37. Gabay, C.; Kushner, I. Acute-phase proteins and other systemic responses to inflammation. N. Engl. J. Med. 1999, 340, 448–454.
  38. Melamed-Frank, M.; Lache, O.; Enav, B.I.; Szafranek, T.; Levy, N.S.; Ricklis, R.M.; Levy, A.P. Structure-function analysis of the antioxidant properties of haptoglobin. Blood 2001, 98, 3693–3698.
  39. Asleh, R.; Marsh, S.; Shilkrut, M.; Binah, O.; Guetta, J.; Lejbkowicz, F.; Enav, B.; Shehadeh, N.; Kanter, Y.; Lache, O.; et al. Genetically determined heterogeneity in hemoglobin scavenging and susceptibility to diabetic cardiovascular disease. Circ. Res. 2003, 92, 1193–1200.
  40. Levy, A.P.; Hochberg, I.; Jablonski, K.; Resnick, H.E.; Lee, E.T.; Best, L.; Howard, B.V.; Strong Heart, S. Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: The Strong Heart Study. J. Am. Coll. Cardiol. 2002, 40, 1984–1990.
  41. Fadini, G.P.; de Kreutzenberg, S.V.; Boscaro, E.; Albiero, M.; Cappellari, R.; Krankel, N.; Landmesser, U.; Toniolo, A.; Bolego, C.; Cignarella, A.; et al. An unbalanced monocyte polarisation in peripheral blood and bone marrow of patients with type 2 diabetes has an impact on microangiopathy. Diabetologia 2013, 56, 1856–1866.
  42. Etzerodt, A.; Moestrup, S.K. CD163 and Inflammation: Biological, Diagnostic, and Therapeutic Aspects. Antioxid. Redox Signal. 2013, 18, 2352–2363.
  43. Moller, H.J.; Frikke-Schmidt, R.; Moestrup, S.K.; Nordestgaard, B.; Tybjærg-Hansen, A. Serum soluble CD163 predicts risk of type 2 diabetes in the general population. Clin. Chem. 2011, 57, 291–297.
  44. Fink, L.N.; Oberbach, A.; Costford, S.R.; Chan, K.L.; Sams, A.; Bluher, M.; Klip, A. Expression of anti-inflammatory macrophage genes within skeletal muscle correlates with insulin sensitivity in human obesity and type 2 diabetes. Diabetologia 2013, 56, 1623–1628.
  45. Aristoteli, L.; Møller, H.J.; Bailey, B.; Moestrup, S.K.; Kritharides, L. The monocytic lineage specific soluble CD163 is a plasma marker of coronary atherosclerosis. Atherosclerosis 2006, 184, 342–347.
  46. Zanni, M.V.; Burdo, T.H.; Makimura, H.; Williams, K.C.; Grinspoon, S.K. Relationship between monocyte/macrophage activation marker soluble CD163 and insulin resistance in obese and normal-weight subjects. Clin. Endocrinol. 2012, 77, 385–390.
  47. Staples, K.J.; Hinks, T.S.; Ward, J.A.; Gunn, V.; Smith, C.; Djukanovic, R. Phenotypic characterization of lung macrophages in asthmatic patients: Overexpression of CCL17. J. Allergy Clin. Immunol. 2012, 130, 1404–1412.
  48. Fadini, G.P.; Cappellari, R.; Mazzucato, M.; Agostini, C.; Vigili de Kreutzenberg, S.; Avogaro, A. Monocyte-macrophage polarization balance in pre-diabetic individuals. Acta Diabetol. 2013, 50, 977–982.
  49. Schaer, C.A.; Schoedon, G.; Imhof, A.; Kurrer, M.O.; Schaer, D.J. Constitutive endocytosis of CD163 mediates hemoglobin-heme uptake and determines the noninflammatory and protective transcriptional response of macrophages to hemoglobin. Circ. Res. 2006, 99, 943–950.
  50. Wejman, J.C.; Hovsepian, D.; Wall, J.S.; Hainfeld, J.F.; Greer, J. Structure and assembly of haptoglobin polymers by electron microscopy. J. Mol. Biol. 1984, 174, 343–368.
  51. Andersen, C.B.; Torvund-Jensen, M.; Nielsen, M.J.; de Oliveira, C.L.; Hersleth, H.P.; Andersen, N.H.; Pedersen, J.S.; Andersen, G.R.; Moestrup, S.K. Structure of the haptoglobin-haemoglobin complex. Nature 2012, 489, 456–459.
  52. Schaer, D.J.; Schaer, C.A.; Buehler, P.W.; Boykins, R.A.; Schoedon, G.; Alayash, A.I.; Schaffner, A. CD163 is the macrophage scavenger receptor for native and chemically modified hemoglobins in the absence of haptoglobin. Blood 2006, 107, 373–380.
  53. Schaer, D.J. The macrophage hemoglobin scavenger receptor (CD163) as a genetically determined disease modifying pathway in atherosclerosis. Atherosclerosis 2002, 163, 199–201.
  54. Ritter, M.; Buechler, C.; Kapinsky, M.; Schmitz, G. Interaction of CD163 with the regulatory subunit of casein kinase II (CKII) and dependence of CD163 signaling on CKII and protein kinase C. Eur. J. Immunol. 2001, 31, 999–1009.
  55. Guo, L.; Akahori, H.; Harari, E.; Smith, S.L.; Polavarapu, R.; Karmali, V.; Otsuka, F.; Gannon, R.L.; Braumann, R.E.; Dickinson, M.H.; et al. CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis. J. Clin. Investig. 2018, 128, 1106–1124.
  56. Guo, L.; Harari, E.; Virmani, R.; Finn, A.V. Linking Hemorrhage, Angiogenesis, Macrophages, and Iron Metabolism in Atherosclerotic Vascular Diseases. Arterioscler. Thromb. Vasc. Biol. 2017, 37, e33–e39.
  57. Liberale, L.; Dallegri, F.; Montecucco, F.; Carbone, F. Pathophysiological relevance of macrophage subsets in atherogenesis. Thromb. Haemost. 2017, 117, 7–18.
  58. Finn, A.V.; Nakano, M.; Polavarapu, R.; Karmali, V.; Saeed, O.; Zhao, X.; Yazdani, S.; Otsuka, F.; Davis, T.; Habib, A.; et al. Hemoglobin directs macrophage differentiation and prevents foam cell formation in human atherosclerotic plaques. J. Am. Coll. Cardiol. 2012, 59, 166–177.
  59. 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.
  60. Szabo, P.A.; Dogra, P.; Gray, J.I.; Wells, S.B.; Connors, T.J.; Weisberg, S.P.; Krupska, I.; Matsumoto, R.; Poon, M.M.L.; Idzikowski, E.; et al. Longitudinal profiling of respiratory and systemic immune responses reveals myeloid cell-driven lung inflammation in severe COVID-19. Immunity 2021, 54, 797–814.
  61. Abers, M.S.; Delmonte, O.M.; Ricotta, E.E.; Fintzi, J.; Fink, D.L.; de Jesus, A.A.A.; Zarember, K.A.; Alehashemi, S.; Oikonomou, V.; Desai, J.V.; et al. An immune-based biomarker signature is associated with mortality in COVID-19 patients. JCI Insight 2021, 6, e144455.
  62. Gomez-Rial, J.; Curras-Tuala, M.J.; Rivero-Calle, I.; Gomez-Carballa, A.; Cebey-Lopez, M.; Rodriguez-Tenreiro, C.; Dacosta-Urbieta, A.; Rivero-Velasco, C.; Rodriguez-Nunez, N.; Trastoy-Pena, R.; et al. Increased Serum Levels of sCD14 and sCD163 Indicate a Preponderant Role for Monocytes in COVID-19 Immunopathology. Front. Immunol. 2020, 11, 560381.
  63. Guetta, J.; Strauss, M.; Levy, N.S.; Fahoum, L.; Levy, A.P. Haptoglobin genotype modulates the balance of Th1/Th2 cytokines produced by macrophages exposed to free hemoglobin. Atherosclerosis 2007, 191, 48–53.
  64. Guest, C.B.; Park, M.J.; Johnson, D.R.; Freund, G.G. The implication of proinflammatory cytokines in type 2 diabetes. Front. Biosci. 2008, 13, 5187–5194.
  65. Collier, B.; Dossett, L.A.; May, A.K.; Diaz, J.J. Glucose control and the inflammatory response. Nutr. Clin. Pract. 2008, 23, 3–15.
  66. Esposito, K.; Nappo, F.; Marfella, R.; Giugliano, G.; Giugliano, F.; Ciotola, M.; Quagliaro, L.; Ceriello, A.; Giugliano, D. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: Role of oxidative stress. Circulation 2002, 106, 2067–2072.
  67. Pickup, J.C. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 2004, 27, 813–823.
  68. Esser, N.; Legrand-Poels, S.; Piette, J.; Scheen, A.J.; Paquot, N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res. Clin. Pract. 2014, 105, 141–150.
  69. Gresser, I.; Delers, F.; Tran Quangs, N.; Marion, S.; Engler, R.; Maury, C.; Soria, C.; Soria, J.; Fiers, W.; Tavernier, J. Tumor necrosis factor induces acute phase proteins in rats. J. Biol. Regul. Homeost. Agents 1987, 1, 173–176.
  70. Stentz, F.B.; Umpierrez, G.E.; Cuervo, R.; Kitabchi, A.E. Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises. Diabetes 2004, 53, 2079–2086.
  71. Mirza, S.; Hossain, M.; Mathews, C.; Martinez, P.; Pino, P.; Gay, J.L.; Rentfro, A.; McCormick, J.B.; Fisher-Hoch, S.P. Type 2-diabetes is associated with elevated levels of TNF-alpha, IL-6 and adiponectin and low levels of leptin in a population of Mexican Americans: A cross-sectional study. Cytokine 2012, 57, 136–142.
  72. Senn, J.J.; Klover, P.J.; Nowak, I.A.; Mooney, R.A. Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes 2002, 51, 3391–3399.
  73. Feve, B.; Bastard, J.P. The role of interleukins in insulin resistance and type 2 diabetes mellitus. Nat. Rev. Endocrinol. 2009, 5, 305–311.
  74. Maedler, K.; Dharmadhikari, G.; Schumann, D.M.; Storling, J. Interleukin-1 beta targeted therapy for type 2 diabetes. Expert Opin. Biol. Ther. 2009, 9, 1177–1188.
  75. Strandberg, L.; Lorentzon, M.; Hellqvist, A.; Nilsson, S.; Wallenius, V.; Ohlsson, C.; Jansson, J.O. Interleukin-1 system gene polymorphisms are associated with fat mass in young men. J. Clin. Endocrinol. Metab. 2006, 91, 2749–2754.
  76. Larsen, C.M.; Faulenbach, M.; Vaag, A.; Volund, A.; Ehses, J.A.; Seifert, B.; Mandrup-Poulsen, T.; Donath, M.Y. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 2007, 356, 1517–1526.
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