An Allosteric Shift in CD11c Affinity Activates a Proatherogenic State in Arrested Intermediate Monocytes.

Intermediate monocytes (iMo; CD14+CD16+) increase in number in the circulation of patients with unstable coronary artery disease (CAD), and their recruitment to inflamed arteries is implicated in events leading to mortality following MI. Monocyte recruitment to inflamed coronary arteries is initiated by high affinity ß2-integrin (CD11c/CD18) that activates ß1-integrin (VLA-4) to bind endothelial VCAM-1. How integrin binding under shear stress mechanosignals a functional shift in iMo toward an inflammatory phenotype associated with CAD progression is unknown. Whole blood samples from patients treated for symptomatic CAD including non-ST elevation MI, along with healthy age-matched subjects, were collected to assess chemokine and integrin receptor levels on monocytes. Recruitment on inflamed human aortic endothelium or rVCAM-1 under fluid shear stress was assessed using a microfluidic-based artery on a chip (A-Chip). Membrane upregulation of high affinity CD11c correlated with concomitant activation of VLA-4 within focal adhesive contacts was required for arrest and diapedesis across inflamed arterial endothelium to a greater extent in non-ST elevation MI compared with stable CAD patients. The subsequent conversion of CD11c from a high to low affinity state under fluid shear activated phospho-Syk- and ADAM17-mediated proteolytic cleavage of CD16. This marked the conversion of iMo to an inflammatory phenotype associated with nuclear translocation of NF-κB and production of IL-1ß+ We conclude that CD11c functions as a mechanoregulator that activates an inflammatory state preferentially in a majority of iMo from cardiac patients but not healthy patients.

Intensive statin treatment ameliorate the Th17/Treg functional imbalance in patients with non-ST elevation acute coronary syndrome underwent percutaneous coronary intervention.

BACKGROUND: Inflammation plays important roles in the pathogenesis of acute coronary syndrome (ACS). Statins exert positive effects on the plaque stabilization through anti-inflammation, however, the detailed mechanism is still under investigation. HYPOTHESIS: Studies suggest that the Th17/Treg functional imbalance takes key part in the plaque destabilization and the onset of ACS. We hypothesized that intensive statin therapy could ameliorate the Th17/Treg imbalance in patients with ACS. METHODS: Sixty-six patients with non-ST elevation acute coronary syndrome (NSTE-ACS) were randomized to conventional group and intensive group. Peripheral blood samples were collected on admission and after atorvastatin treatment. The frequencies of circulating Th17 cells and Treg cells, the levels of cytokines associated with Th17 cells (IL-17, IL-6 and IL-23) and associated with Treg cells (IL-10 and TGF-ß1) were measured through flow cytometry and ELISA assay respectively. RESULTS: One week after therapy, the frequencies of circulating Th17 cells of both the groups decreased and the frequencies of circulating Treg cells increased significantly, compared with the basal levels. Furthermore, the decreased frequencies of circulating Th17 cells and the increased frequencies of circulating Treg cells in the intensive group were significantly higher than those in the conventional group. In consistence, the decreased accumulation of IL-17, IL-6 and IL-23 (cytokines relevant to Th17 cells) and the increased accumulation of IL-10 and TGF-ß1 in peripheral blood were displayed in both groups. The changes are more significant in the intensive group. CONCLUSION: Intensive statins therapy could ameliorate the Th17 and Treg functional imbalance in patients with ACS.

Non-ST-Elevation Myocardial Infarction-Like Syndrome in Scombroid Tuna Fish Poisoning.

Mistreated fish products ingestion can lead to a histaminergic illness known as Scombroid Syndrome (SS). The disease usually causes cutaneous rash, stomach cramps, nausea, vomiting, breathing disorder and further histamine-related symptoms. To date, however, SS has been disregarded among the potential triggers of acute coronary syndrome (ACS), in spite of prior published occasional case reports. In the present study we describe 3 consecutive patients presenting with signs and symptoms of ACS associated to SS. Two men and a woman with no history of coronary artery disease and food allergy were studied. Clinical characteristics, electrocardiographic presentation and outcomes are described. Non-ST-elevation myocardial infarction-like pattern was observed in all patients. The 2 men underwent unremarkable coronary angiography, whereas the woman was just monitored at emergency department. All individuals had uneventful follow-up. The present study confirms non-ST-elevation myocardial infarction-like ACS as a possible histaminergic toxic, not allergic, epiphenomenon of mistreated raw tuna fish ingestion, likely due to transient epicardial and/or microvascular coronary vasospasm.

Loss of Regulatory Immune Function in Coronary Artery Disease Patients from the Indian Population.

The pathogenic roles of inflammatory T cells and monocytes subsets have not been explored in different manifestations of coronary artery disease. We studied the frequency of these cells, their response to autoantigens, regulatory cell functional assay, foam cell formation and macrophage differentiation in 181 patients (stable angina, ST-elevated myocardial infarction (STEMI), NSTEMI, and unstable angina), and 34 controls and in samples collected during recurrent cardiac events and from patients showing clinical improvement. The proportion of Th17 cells and monocytes gradually increased in patients with stable angina at one end of the spectrum followed by NSTEMI, STEMI, and unstable angina at other end. Inflammatory cells were positively and inversely associated with recurrent events and clinical improvement, respectively. Patients showed expansion of Th17 cells in response to autoantigen (HSP60) and compromised Treg function. Our results suggest that stress-induced activation of inflammatory cells expands in the absence of regulatory control in CAD patients.

Indoleamine 2,3-Dioxygenase (IDO) Enzyme Links Innate Immunity and Altered T-Cell Differentiation in Non-ST Segment Elevation Acute Coronary Syndrome.

Atherosclerosis is a chronic inflammatory disease characterized by a complex interplay between innate and adaptive immunity. Dendritic cells (DCs) play a key role in T-cell activation and regulation by promoting a tolerogenic environment through the expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme involved in tryptophan catabolism. IDO expression and activity was analyzed in monocytes derived DCs (MDDCs) from non-ST segment elevation myocardial infarction (NSTEMI) patients, stable angina (SA) patients and healthy controls (HC) by real-time quantitative polymerase chain reaction (RT-qPCR) before and after in vitro maturation with lipopolysaccharide (LPS). The amount of tryptophan catabolite; kynurenine; was evaluated in the culture supernatants of mature-MDDCs by ELISA assay. Autologous mixed lymphocyte reaction (MLR) between mature-MDDCs and naïve T-cells was carried out to study the differentiation towards T-helper 1 (Th1) and induced regulatory T-cells (iTreg). Analysis of IDO mRNA transcripts in mature-MDDCs revealed a significant reduction in cells isolated from NSTEMI (625.0 ± 128.2; mean ± SEM) as compared with those from SA (958.5 ± 218.3; p = 0.041) and from HC (1183.6 ± 231.6; p = 0.034). Furthermore; the concentration of kynurenine was lower in NSTEMI patients (2.78 ± 0.2) and SA (2.98 ± 0.25) as compared with HC (5.1 ± 0.69 ng/mL; p = 0.002 and p = 0.016; respectively). When IDO-competent mature-MDDCs were co-cultured with allogeneic naïve T-cells, the ratio between the percentage of generated Th1 and iTreg was higher in NSTEMI (4.4 ± 2.9) than in SA (1.8 ± 0.6; p = 0.056) and HC (0.9 ± 0.3; p = 0.008). In NSTEMI, the tolerogenic mechanism of the immune response related to IDO production by activated MDDCs is altered, supporting their role in T-cell dysregulation.