Where the Action Is—Leukocyte Recruitment in Atherosclerosis

Mauersberger, Carina; Hinterdobler, Julia; Schunkert, Heribert; Kessler, Thorsten; Sager, Hendrik B.

doi:10.3389/fcvm.2021.813984

Cited by 29 publications

(21 citation statements)

References 398 publications

(451 reference statements)

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“…Leukocyte recruitment refers to a process in which endothelial cells and circulating leukocytes need to interact closely to mediate leukocytes rolling, adhesion and transmigration/extravasation ( 13 , 14 ). To investigate how colchicine treatment limited myeloid cell recruitment from blood to atherosclerotic aortas, we used flow cytometry to assess levels of leukocyte adhesion molecules on endothelial cells from atherosclerotic aortas.…”

Section: Resultsmentioning

confidence: 99%

Colchicine Impacts Leukocyte Trafficking in Atherosclerosis and Reduces Vascular Inflammation

et al. 2022

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BackgroundInflammation strongly contributes to atherosclerosis initiation and progression. Consequently, recent clinical trials pharmacologically targeted vascular inflammation to decrease the incidence of atherosclerosis-related complications. Colchicine, a microtubule inhibitor with anti-inflammatory properties, reduced cardiovascular events in patients with recent acute coronary syndrome and chronic coronary disease. However, the biological basis of these observations remains elusive. We sought to explore the mechanism by which colchicine beneficially alters the course of atherosclerosis.Methods and ResultsIn mice with early atherosclerosis (Apoe-/- mice on a high cholesterol diet for 8 weeks), we found that colchicine treatment (0.25 mg/kg bodyweight once daily over four weeks) reduced numbers of neutrophils, inflammatory monocytes and macrophages inside atherosclerotic aortas using flow cytometry and immunohistochemistry. Consequently, colchicine treatment resulted in a less inflammatory plaque composition and reduced plaque size. We next investigated how colchicine prevented plaque leukocyte expansion and found that colchicine treatment mitigated recruitment of blood neutrophils and inflammatory monocytes to plaques as revealed by adoptive transfer experiments. Causally, we found that colchicine reduced levels of both leukocyte adhesion molecules and receptors for leukocyte chemoattractants on blood neutrophils and monocytes. Further experiments showed that colchicine treatment reduced vascular inflammation also in post-myocardial infarction accelerated atherosclerosis through similar mechanisms as documented in early atherosclerosis. When we examined whether colchicine also decreased numbers of macrophages inside atherosclerotic plaques by impacting monocyte/macrophage transitioning or in-situ proliferation of macrophages, we report that colchicine treatment did not influence macrophage precursor differentiation or macrophage proliferation using cell culture experiments with bone marrow derived macrophages.ConclusionsOur data reveal that colchicine prevents expansion of plaque inflammatory leukocytes through lowering recruitment of blood myeloid cells to plaques. These data provide novel mechanistic clues on the beneficial effects of colchicine in the treatment of atherosclerosis and may inform future anti-inflammatory interventions in patients at risk.

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Section: Resultsmentioning

confidence: 99%

Colchicine Impacts Leukocyte Trafficking in Atherosclerosis and Reduces Vascular Inflammation

et al. 2022

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“…Treatment of human monocytes with HG promotes the phosphorylation of p38 MAPK and ERK1/2, leading to NF-κB transactivation and related monocyte inflammatory activation [ 44 ]. GPRCs can regulate leukocyte activation and binding to the vessel wall through the endothelial-mediated expression of chemokines [ 45 ]. Despite controversy existing on the role of GPCRs as pro- or anti-inflammatory molecules, especially in diabetic patients, emerging evidence suggests that GPCRs and NF-κB might be connected in the regulation of inflammatory diseases [ 46 ].…”

Section: Resultsmentioning

confidence: 99%

Orphan GPR26 Counteracts Early Phases of Hyperglycemia-Mediated Monocyte Activation and Is Suppressed in Diabetic Patients

et al. 2022

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Diabetes is the ninth leading cause of death, with an estimated 1.5 million deaths worldwide. Type 2 diabetes (T2D) results from the body’s ineffective use of insulin and is largely the result of excess body weight and physical inactivity. T2D increases the risk of cardiovascular diseases, retinopathy, and kidney failure by two-to three-fold. Hyperglycemia, as a hallmark of diabetes, acts as a potent stimulator of inflammatory condition by activating endothelial cells and by dysregulating monocyte activation. G-protein couple receptors (GPCRs) can both exacerbate and promote inflammatory resolution. Genome-wide association studies (GWAS) indicate that GPCRs are differentially regulated in inflammatory and vessel cells from diabetic patients. However, most of these GPCRs are orphan receptors, for which the mechanism of action in diabetes is unknown. Our data indicated that orphan GPCR26 is downregulated in the PBMC isolated from T2D patients. In contrast, GPR26 was initially upregulated in human monocytes and PBMC treated with high glucose (HG) levels and then decreased upon chronic and prolonged HG exposure. GPR26 levels were decreased in T2D patients treated with insulin compared to non-insulin treated patients. Moreover, GPR26 inversely correlated with the BMI and the HbA1c of diabetic compared to non-diabetic patients. Knockdown of GPR26 enhanced monocyte ROS production, MAPK signaling, pro-inflammatory activation, monocyte adhesion to ECs, and enhanced the activity of Caspase 3, a pro-apoptotic molecule. The same mechanisms were activated by HG and exacerbated when GPR26 was knocked down. Hence, our data indicated that GPR26 is initially activated to protect monocytes from HG and is inhibited under chronic hyperglycemic conditions.

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“…Similar processes may be at play during atherogenesis, when P-selectin deficiency in platelets partially protects from atherosclerotic plaque development in ApoE-deficient mice, whereas endothelial P-selectin deficiency has a more profound atheroprotective effect [ 8 ]. In myocardial infarction, however, myocardial injury develops in a large ischemic area distal to the site of an occluding coronary artery plaque, and leukocyte infiltration into the infarct tissue occurs via post-capillary venules distinct from arterial recruitment in atherosclerosis [ 15 , 35 ]. Hence, mesenteric venule intravital microscopy and sterile peritonitis are valid complementary models for gaining insight into inflammatory cell recruitment into infarct tissue.…”

Section: Discussionmentioning

confidence: 99%

Elevated platelet–leukocyte complexes are associated with, but dispensable for myocardial ischemia–reperfusion injury

et al. 2022

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Aims P-selectin is an activatable adhesion molecule on platelets promoting platelet aggregation, and platelet–leukocyte complex (PLC) formation. Increased numbers of PLC are circulating in the blood of patients shortly after acute myocardial infarction and predict adverse outcomes. These correlations led to speculations about whether PLC may represent novel therapeutic targets. We therefore set out to elucidate the pathomechanistic relevance of PLC in myocardial ischemia and reperfusion injury. Methods and results By generating P-selectin deficient bone marrow chimeric mice, the post-myocardial infarction surge in PLC numbers in blood was prevented. Yet, intravital microscopy, flow cytometry and immunohistochemical staining, echocardiography, and gene expression profiling showed unequivocally that leukocyte adhesion to the vessel wall, leukocyte infiltration, and myocardial damage post-infarction were not altered in response to the lack in PLC. Conclusion We conclude that myocardial infarction associated sterile inflammation triggers PLC formation, reminiscent of conserved immunothrombotic responses, but without PLC influencing myocardial ischemia and reperfusion injury in return. Our experimental data do not support a therapeutic concept of selectively targeting PLC formation in myocardial infarction.

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Where the Action Is—Leukocyte Recruitment in Atherosclerosis

Cited by 29 publications

References 398 publications

Colchicine Impacts Leukocyte Trafficking in Atherosclerosis and Reduces Vascular Inflammation

Colchicine Impacts Leukocyte Trafficking in Atherosclerosis and Reduces Vascular Inflammation

Orphan GPR26 Counteracts Early Phases of Hyperglycemia-Mediated Monocyte Activation and Is Suppressed in Diabetic Patients

Elevated platelet–leukocyte complexes are associated with, but dispensable for myocardial ischemia–reperfusion injury

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