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Prolonged hematopoietic and myeloid cellular response in patients after an acute coronary syndrome measured with 18F-DPA-714 PET/CT.
Verweij, SL, Stiekema, LCA, Delewi, R, Zheng, KH, Bernelot Moens, SJ, Kroon, J, Stroes, CI, Versloot, M, Piek, JJ, Verberne, HJ, et al
European journal of nuclear medicine and molecular imaging. 2018;(11):1956-1963
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Abstract
PURPOSE An acute coronary syndrome (ACS) is characterized by a multi-level inflammatory response, comprising activation of bone marrow and spleen accompanied by augmented release of leukocytes into the circulation. The duration of this response after an ACS remains unclear. Here, we assessed the effect of an ACS on the multi-level inflammatory response in patients both acutely and after 3 months. METHODS We performed 18F-DPA-714 PET/CT acutely and 3 months post-ACS in eight patients and eight matched healthy controls. DPA-714, a PET tracer binding the TSPO receptor and highly expressed in myeloid cells, was used to assess hematopoietic activity. We also characterized circulating monocytes and hematopoietic stem and progenitor cells (HSPCs) by flow cytometry in 20 patients acutely and 3 months post-ACS and in 19 healthy controls. RESULTS In the acute phase, patients displayed a 1.4-fold and 1.3-fold higher 18F-DPA-714 uptake in, respectively, bone marrow (p = 0.012) and spleen (p = 0.039) compared with healthy controls. This coincided with a 2.4-fold higher number of circulating HSPCs (p = 0.001). Three months post-ACS, 18F-DPA-714 uptake in bone marrow decreased significantly (p = 0.002), but no decrease was observed for 18F-DPA-714 uptake in the spleen (p = 0.67) nor for the number of circulating HSPCs (p = 0.75). CONCLUSIONS 18F-DPA-714 PET/CT reveals an ACS- triggered hematopoietic organ activation as initiator of a prolonged cellular inflammatory response beyond 3 months, characterized by a higher number of circulating leukocytes and their precursors. This multi-level inflammatory response may provide an attractive target for novel treatment options aimed at reducing the high recurrence rate post-ACS.
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P2Y12 receptor modulation of ADP-evoked intracellular Ca2+ signalling in THP-1 human monocytic cells.
Micklewright, JJ, Layhadi, JA, Fountain, SJ
British journal of pharmacology. 2018;(12):2483-2491
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Abstract
BACKGROUND AND PURPOSE The Gi -coupled, ADP-activated P2Y12 receptor is well characterized as playing a key role in platelet activation via crosstalk with the P2Y1 receptor in ADP-evoked intracellular Ca2+ responses. However, there is limited knowledge on the role of P2Y12 receptors in ADP-evoked Ca2+ responses in other blood cells. Here, we investigated the role of P2Y12 receptor activation in the modulation of ADP-evoked Ca2+ responses in human THP-1 monocytic cells. EXPERIMENTAL APPROACH A combination of intracellular Ca2+ measurements, RT-PCR, immunocytochemistry, leukocyte isolation and siRNA-mediated gene knockdown were used to identify the role of P2Y12 receptor activation. KEY RESULTS ADP-evoked intracellular Ca2+ responses (EC50 2.7 μM) in THP-1 cells were abolished by inhibition of PLC (U73122) or sarco/endoplasmic reticulum Ca2+ -ATPase (thapsigargin). Loss of ADP-evoked Ca2+ responses following treatment with MRS2578 (IC50 200 nM) revealed a major role for P2Y6 receptors in mediating ADP-evoked Ca2+ responses. ADP-evoked responses were attenuated either with pertussis toxin treatment, or P2Y12 receptor inhibition with two chemically distinct antagonists (ticagrelor, IC50 5.3 μM; PSB-0739, IC50 5.6 μM). ADP-evoked responses were suppressed following siRNA-mediated P2Y12 gene knockdown. The inhibitory effects of P2Y12 antagonists were fully reversed following adenylate cyclase inhibition (SQ22536). P2Y12 receptor expression was confirmed in freshly isolated human CD14+ monocytes. CONCLUSIONS AND IMPLICATIONS Taken together, these data suggest that P2Y12 receptor activation positively regulates P2Y6 receptor-mediated intracellular Ca2+ signalling through suppression of adenylate cyclase activity in human monocytic cells.
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BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity.
Arts, RJW, Moorlag, SJCFM, Novakovic, B, Li, Y, Wang, SY, Oosting, M, Kumar, V, Xavier, RJ, Wijmenga, C, Joosten, LAB, et al
Cell host & microbe. 2018;(1):89-100.e5
Abstract
The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects against non-related infections. The basis of these effects has been poorly explored in humans. In a randomized placebo-controlled human challenge study, we found that BCG vaccination induced genome-wide epigenetic reprograming of monocytes and protected against experimental infection with an attenuated yellow fever virus vaccine strain. Epigenetic reprogramming was accompanied by functional changes indicative of trained immunity. Reduction of viremia was highly correlated with the upregulation of IL-1β, a heterologous cytokine associated with the induction of trained immunity, but not with the specific IFNγ response. The importance of IL-1β for the induction of trained immunity was validated through genetic, epigenetic, and immunological studies. In conclusion, BCG induces epigenetic reprogramming in human monocytes in vivo, followed by functional reprogramming and protection against non-related viral infections, with a key role for IL-1β as a mediator of trained immunity responses.
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Monocyte-to-high density lipoprotein ratio is associated with a decreased compound muscle action potential amplitude in patients with diabetic axonal polyneuropathy.
Vural, G, Gümüsyayla, Ş
Medicine. 2018;(42):e12857
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Abstract
The monocyte-to-high density lipoprotein ratio (MHR) has recently been implemented as an indicator of inflammation and oxidative stress. The present study characterized MHR in patients with diabetic polyneuropathy (DPN), in which oxidative stress and microvascular damage play a role in pathogenesis, relative to patients with non-DPN, diabetic patients without polyneuropathy, and healthy individuals. We further aimed to evaluate the association between MHR and the decreased compound muscle action potential (CMAP) amplitude of patients with diabetic axonal polyneuropathy.We enrolled 90 patients with DPN, 75 patients with nonDPN, 92 diabetic patients without polyneuropathy, and 67 healthy individuals; The monocyte, high-density lipoprotein cholesterol (HDL-C) values were obtained for all participants and MHR was calculated for each individual. Intergroup comparison was performed. The relationship between MHR and the posterior tibial nerve CMAP amplitudes was examined.Statistically significant negative correlation was observed between MHR and the posterior tibial nerve CMAP amplitudes of patients with DPN. The MHR values of the patients with DPN were significantly higher than those of the patients with non-DPN, diabetic patients without polyneuropathy and the control group.This study demonstrated that diabetic patients with higher MHR values may be more likely to develop polyneuropathy.
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Young adult binge drinkers have immunophenotypic changes in peripheral polymorphonuclear cells and monocytes.
Pérez-García, A, Arroyo-Valerio, AG, Zaldivar-Fujigaki, JL, Bustos-Esquivel, MA, Gastelum-Strozzi, A, Padilla-Castañeda, MA, Reding-Bernal, A, Kershenobich, D, Hernández-Ruiz, J
The American journal of drug and alcohol abuse. 2018;(3):403-412
Abstract
BACKGROUND High alcohol intake on weekends (binge drinking) is more frequent in young adults, who could undergo early liver damage. Alcohol-induced liver damage is characterized by polymorphonuclear cell (PMN) infiltration, which can be represented in the peripheral blood by altered trafficking and activation profiles. OBJECTIVE To evaluate the PMN trafficking and activation immunophenotypic profiles in people with a binge drinking pattern. METHODS People with binge drinking (n = 18, 8 females) or at low risk (n = 16, 13 females) based on their AUDIT and HEPCA scores were studied. Hematic biometry and liver enzyme tests were conducted. Peripheral blood leukocytes were stained for CCR5, CCR4, and CXCR4 (trafficking) and CD69 and CD127 (activation). PMNs and monocytes were analyzed by FACS. The data were analyzed using the T-test and Mann-Whitney's U-test for contrasts and principal component and Fuzzy C means analyses for clustering, with p < 0.05 considered significant. RESULTS Compared to the low-risk group, the binge group showed higher CCR5 expression on PMNs, decreases in the CD69 percentage and positive PMNs per microliter, and decreased CXCR4 expression on monocytes. Six immunophenotypical clusters were identified, all of which were distributed following the CCR5 and CXCR4 main vectors. CONCLUSION Young adult binge drinkers have differential PMN trafficking and activation immunophenotypes, which could be related to the initial onset of alcoholic liver disease and a systemic inflammatory state in response to their alcohol consumption pattern. These findings could lead to the future development of an early diagnostic tool.
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High-Density Lipoprotein Reduction Differentially Modulates to Classical and Nonclassical Monocyte Subpopulations in Metabolic Syndrome Patients and in LPS-Stimulated Primary Human Monocytes In Vitro.
Grün, JL, Manjarrez-Reyna, AN, Gómez-Arauz, AY, Leon-Cabrera, S, Rückert, F, Fragoso, JM, Bueno-Hernández, N, Islas-Andrade, S, Meléndez-Mier, G, Escobedo, G
Journal of immunology research. 2018;:2737040
Abstract
The effect of metabolic syndrome on human monocyte subpopulations has not yet been studied. Our main goal was to examine monocyte subpopulations in metabolic syndrome patients, while also identifying the risk factors that could directly influence these cells. Eighty-six subjects were divided into metabolic syndrome patients and controls. Monocyte subpopulations were quantified by flow cytometry, and interleukin- (IL-) 1β secretion levels were measured by ELISA. Primary human monocytes were cultured in low or elevated concentrations of high-density lipoprotein (HDL) and stimulated with lipopolysaccharide (LPS). The nonclassical monocyte (NCM) percentage was significantly increased in metabolic syndrome patients as compared to controls, whereas classical monocytes (CM) were reduced. Among all metabolic syndrome risk factors, HDL reduction exhibited the most important correlation with monocyte subpopulations and then was studied in vitro. Low HDL concentration reduced the CM percentage, whereas it increased the NCM percentage and IL-1β secretion in LPS-treated monocytes. The LPS effect was abolished when monocytes were cultured in elevated HDL concentrations. Concurring with in vitro results, IL-1β serum values significantly increased in metabolic syndrome patients with low HDL levels as compared to metabolic syndrome patients without HDL reduction. Our data demonstrate that HDL directly modulates monocyte subpopulations in metabolic syndrome.
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Platelet-Derived MRP-14 Induces Monocyte Activation in Patients With Symptomatic Peripheral Artery Disease.
Dann, R, Hadi, T, Montenont, E, Boytard, L, Alebrahim, D, Feinstein, J, Allen, N, Simon, R, Barone, K, Uryu, K, et al
Journal of the American College of Cardiology. 2018;(1):53-65
Abstract
BACKGROUND Peripheral artery disease (PAD), a diffuse manifestation of atherothrombosis, is a major cardiovascular threat. Although platelets are primary mediators of atherothrombosis, their role in the pathogenesis of PAD remains unclear. OBJECTIVES The authors sought to investigate the role of platelets in a cohort of symptomatic PAD. METHODS The authors profiled platelet activity, mRNA, and effector roles in patients with symptomatic PAD and in healthy controls. Patients with PAD and carotid artery stenosis were recruited into ongoing studies (NCT02106429 and NCT01897103) investigating platelet activity, platelet RNA, and cardiovascular disease. RESULTS Platelet RNA sequence profiling mapped a robust up-regulation of myeloid-related protein (MRP)-14 mRNA, a potent calcium binding protein heterodimer, in PAD. Circulating activated platelets were enriched with MRP-14 protein, which augmented the expression of the adhesion mediator, P-selectin, thereby promoting monocyte-platelet aggregates. Electron microscopy confirmed the firm interaction of platelets with monocytes in vitro and colocalization of macrophages with MRP-14 confirmed their cross talk in atherosclerotic manifestations of PAD in vivo. Platelet-derived MRP-14 was channeled to monocytes, thereby fueling their expression of key PAD lesional hallmarks and increasing their directed locomotion, which were both suppressed in the presence of antibody-mediated blockade. Circulating MRP-14 was heightened in the setting of PAD, significantly correlated with PAD severity, and was associated with incident limb events. CONCLUSIONS The authors identified a heightened platelet activity profile and unraveled a novel immunomodulatory effector role of platelet-derived MRP-14 in reprograming monocyte activation in symptomatic PAD. (Platelet Activity in Vascular Surgery and Cardiovascular Events [PACE]; NCT02106429; and Platelet Activity in Vascular Surgery for Thrombosis and Bleeding [PIVOTAL]; NCT01897103).
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Apheresis buffy coat collection without photoactivation has no effect on apoptosis, cell proliferation, and total viability of mononuclear cells collected using photopheresis systems.
Szczepiorkowski, ZM, Burnett, CA, Dumont, LJ, Abhyankar, SH
Transfusion. 2018;(4):943-950
Abstract
BACKGROUND Extracorporeal photopheresis (ECP) has been approved for the treatment of advanced cutaneous T-cell lymphoma since 1988. While the precise mechanisms resulting in clinical effects are not fully understood, the photoactivation of mononuclear cells (MNCs) using ultraviolet A (UVA) light and methoxsalen is believed to be the predominant initiating process. The effects of MNC passage through the instrument without photoactivation are unknown. The objective of this study was to evaluate the effect of cell processing through the photopheresis instruments on MNCs. STUDY DESIGN AND METHODS Fourteen healthy male subjects underwent one simulated ECP procedure without reinfusion of buffy coats (BCs) in a two-center, open-label, prospective trial. Baseline peripheral blood BC, apheresis-separated untreated BC (BC1), and photoactivated BC (BC2) were evaluated in culture for viability by dye exclusion, apoptosis by annexin V binding, and cell proliferation response to phytohemagglutinin (PHA) stimulation by bromodeoxyuridine (BrdU) incorporation. RESULTS Photoactivation (BC2) resulted in 88% expression of annexin V by Day 1 of culture compared with 37 and 39% for baseline and untreated BC1. Cell viability by propidium iodide exclusion was reduced to 10% in BC2 on Day 1 versus 65 and 60% for baseline and BC1. The proliferative response to PHA stimulation was 97% inhibited in the photoactivated BC2. CONCLUSIONS These results demonstrate that the mechanical processes used for cell separation and processing of the BC in the absence of photoactivation do not induce a significant amount of apoptosis compared to the standard ECP with methoxsalen and UVA photoactivation.
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Resistance Exercise Selectively Mobilizes Monocyte Subsets: Role of Polyphenols.
Jajtner, AR, Townsend, JR, Beyer, KS, Varanoske, AN, Church, DD, Oliveira, LP, Herrlinger, KA, Radom-Aizik, S, Fukuda, DH, Stout, JR, et al
Medicine and science in sports and exercise. 2018;(11):2231-2241
Abstract
PURPOSE To examine the impact of polyphenol supplementation on the recruitment, mobilization, and activation of monocyte subsets after resistance exercise. METHODS Thirty-eight recreationally active males (22.1 ± 3.1 yr; 173.9 ± 7.9 cm; 77.8 ± 14.5 kg) were assigned to 28 d of polyphenol blend (PPB) supplementation, placebo (PL), or control (CON). Blood samples were obtained before (PRE) postresistance exercise, immediately (IP) postresistance exercise, 1 h (1H) postresistance exercise, 5 h (5H) postresistance exercise, 24 h (24H) postresistance exercise, and 48 h (48H) postresistance exercise (PPB/PL) or rest (CON). Fine-needle biopsies were obtained from the vastus lateralis at PRE, 1H, 5H, and 48H. Circulating concentrations of macrophage chemoattractant protein-1 (MCP-1) and fractalkine, as well as intramuscular MCP-1 were analyzed via multiplex assay. Changes in the proportions and expression of CD11b on monocyte subsets were assessed via flow cytometry. RESULTS Circulating MCP-1 increased in PPB and PL at IP with further increases at 5H. Intramuscular MCP-1 was increased at 1H, 5H, and 48H in all groups. Classical monocyte proportions were reduced in PPB and PL at IP, and increased at 1H. Nonclassical monocytes were increased in PPB and PL at IP, whereas intermediate monocytes were increased at IP, and reduced at 1H. Intermediate monocytes were increased in PPB at 24H and 48H. CD11b expression was reduced on PPB compared with PL and CON at PRE on intermediate and nonclassical monocytes. CONCLUSIONS Resistance exercise may elicit selective mobilization of intermediate monocytes at 24H and 48H, which may be mediated by tissue damage. Additionally, polyphenol supplementation may suppress CD11b expression on monocyte subsets at rest.
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Altered microRNA expression profile in the peripheral lymphoid compartment of multiple myeloma patients with bisphosphonate-induced osteonecrosis of the jaw.
Musolino, C, Oteri, G, Allegra, A, Mania, M, D'Ascola, A, Avenoso, A, Innao, V, Allegra, AG, Campo, S
Annals of hematology. 2018;(7):1259-1269
Abstract
Bisphosphonates are formidable inhibitors of osteoclast-mediated bone resorption employed for therapy of multiple myeloma (MM) subjects with osteolytic lesions. Osteonecrosis of the jaw (ONJ) is an uncommon drug-induced adverse event of these agents. MicroRNAs (miRNAs) are a group of small, noncoding RNAs nucleotides, which are essential post-transcriptional controllers of gene expression. They have a central role in the normal bone development. The goal of our study was to investigate 18 miRNAs, whose targets were previously validated and described in MM subjects without ONJ, in peripheral lymphocytes of MM subjects with bisphosphonate-induced ONJ. Utilizing reverse transcription quantitative polymerase chain reaction, we evaluated miRNAs in five healthy subjects and in five MM patients with ONJ. Our experimental data revealed that a diverse miRNA signature for ONJ subjects emerged with respect to control subjects. Using the filter for in silico analysis, among the 18 miRNAs, we recognized 14 dysregulated miRNAs. All these miRNAs were significantly over-expressed in patients vs controls (MIR-16-1, MIR-21, MIR-23A, MIR-28, MIR-101-1, MIR-124-1, MIR-129, MIR-139, MIR-145, MIR-149, MIR-202, MIR-221, MIR-424, MIR-520). Among them, six were strongly upregulated (fourfold upregulated and more). These miRNAs target numerous pathways and genes implicated in calcium ion binding, bone resorption, mineralization of bone matrix, and differentiation and maintenance of bone tissue. A modified microRNA expression profile after zoledronate therapy could participate to the onset of ONJ. Targeting these miRNAs could provide a new opportunity for the prevention or treatment of ONJ.