Adiponectin (APN), a cytokine constitutively produced in fat tissue, has been shown to exert anti-inflammatory effects in various disease models. While the influence of APN on monocytic cells has been extensively studied in vitro, little is known about its role in T cells. In this study, we show that while o10% of human peripheral blood T cells express adiponectin receptors (AdipoRs) on their surface, most T cells store AdipoRs in intracellular compartments. AdipoRs colocalized with immune regulatory molecules CTLA-4 and TIRC7 within clathrin-coated vesicles. After stimulation, the expression of adiponectin receptor 1 (AdipoR1) and AdipoR2 was upregulated on the surface of antigen-specific T cells, as determined by tetramer or CD137 staining, and AdipoR1 and AdipoR2 coexpressed with CTLA-4. Addition of APN resulted in a significant diminution of antigenspecific T-cell expansion. Mechanistically, APN enhanced apoptosis and inhibited proliferation of antigen-specific T-cell lines. Further, APN directly inhibited cytokine production in response to antigen stimulation. In line with the in vitro data, APN-deficient (knockout, KO) mice had higher frequencies of CD137 1 T cells upon Coxsackie B virus infection. Altogether, our data suggest that APN is a novel negative T-cell regulator. In contrast to the CTLA-4 ligand B7 only expressed on APCs, APN is abundant in human plasma.

Our results implicate that APN acts as endogenously upregulated anti-inflammatory cytokine confining cardiac inflammation and progression in DCMi.

AimThe expression of leptin and resistin is known to be positively correlated with the incidence of chronic heart failure (CHF). Both adipokines have been implicated in immunomodulation and cardiac remodelling. Therefore, we performed for the first time a clinical study to elucidate the effects of leptin and resistin on progression of CHF in patients with non-ischaemic dilated (DCM) and inflammatory (DCMi) cardiomyopathy. Methods and resultsFor the clinical study 120 patients were divided into a control (n ¼ 16), DCM (n ¼ 52), and DCMi (n ¼ 52) group to determine the effect of leptin and resistin on CHF progression. Nuclear factor-kB (NF-kB) activation, reactive oxygen species generation, and tumour necrosis factor-a (TNF-a) and interleukin-6 (IL-6) expression following adipokine exposition were determined in vitro in cardiomyocytes. Leptin and resistin systemic plasma levels and not cardiac expression were significantly elevated in patients with DCM (leptin, 13.12 + 17.2 ng/mL, P , 0.05; resistin, 6.87 + 2.25 ng/mL, P , 0.05) and DCMi (leptin, 13.63 + 16 ng/mL, P , 0.05; resistin, 7.27 + 2.2 ng/mL, P , 0.05) compared with the control group (leptin, 7.34 + 5.7 ng/mL; resistin, 4.4 + 1.18 ng/mL). A multivariate linear regression model revealed low leptin and resistin plasma levels as contributors for favourable cardiac functional parameters at 6-month follow-up independent of inflammatory conditions. Cell culture experiments in vitro showed leptin and resistin to be potent regulators of TNF-a and IL-6 expression in cardiomyocytes, leading to significantly increased redox stress in cardiac cells. ConclusionsHigh leptin and resistin expression in patients with DCM and DCMi is associated with CHF progression, i.e. severe cardiac dysfunction, independent of immune responses.--

Adiponectin (APN) has been shown to exert antiinflammatory effects in various disease models but little is known concerning its regulation of NK-cell function. Here, weshow that the majority of human CD56 dim NK cells express surface Adiponectin receptor (AdipoR) 1 and 2 while most CD56 high NK cells are AdipoR-negative. Toll-like receptor (TLR) ligand-induced IFN-γ production was diminished by APN while it had no influence on NK-cell cytotoxicity. In contrast only a small subpopulation of murine NK cells expresses surface AdipoRs, but about 90% store them intracellularly. APN-deficient knockout (KO) mice had elevated frequencies of NK cells. However, cytotoxic degranulation of NK cells was decreased in APN knockout (APN-KO) animals. Accordingly, frequencies of CD11b high CD27 high and CD94 high effector NK cells and expression of NKG2D were lower in APN-KO mice. Upon CVB3 infection NK-cell function was restored in APN-KO mice. Our data suggest that in addition to its antiinflammatory effects APN also influences the numerical and differentiation status of NK cells, which may further impact the outcome of immune-mediated diseases in APN-KO mice.Keywords: Adiponectin r Adiponectin KO mice r Adiponectin receptors 1 or 2 r Immunomodulation r NK cells Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAdiponectin (APN), a cytokine, accounting for 0.01% of total plasma protein, is mainly produced by adipocytes under steadystate conditions and negatively regulated by obesity [1,2]. Adiponectin has been shown to exert antiinflammatory effects in several disease models such as sepsis, inflammatory diseases, and Correspondence: Prof. Carmen Scheibenbogen e-mail: Carmen.Scheibenbogen@charite.de transplantation. In accordance, APN-deficient mice are more prone to transplant rejection and inflammatory diseases [3][4][5].APN signaling is mediated by two receptors, adiponectin receptor (AdipoR) 1 and 2, with different affinities for existing isoforms. AdipoR1 is ubiquitous, but most prominent in skeletal muscle and heart, whereas AdipoR2 is abundantly expressed in the liver [6]. AdipoRs expression was further described in cells of the immune system [7,8]. Several studies revealed the direct action of APN on cells of the innate and adaptive immune system [1,9]. APN was shown to inhibit TLR-mediated NF-κB activation in macrophageswww.eji-journal.eu Eur. J. Immunol. 2013. 43: 1024-1033 Immunomodulation 1025[10] and to induce macrophage polarization toward the antiinflammatory M2 phenotype [11]. In a recent study we could further demonstrate that T cells store AdipoRs intracellularly, upregulate them upon T-cell receptor activation, and that APN acts as a negative T-cell regulator for antigen-activated T cells [8]. Furthermore, APN has been described as a negative regulator of hematopoiesis inhibiting directly proliferation of myelomonocytic progenitors [12] or indirectly through inducing changes in stromal cells [13]. NK cells are innate effector lymphocyte...

Our observations indicate that APN protects against inflammation and injury in autoimmune myocarditis by diminishing TLR4 signalling thereby attenuating inflammatory activation and interaction of cardiac and immune cells.

Purpose For many applications in the field of computer-assisted surgery, such as providing the position of a tumor, specifying the most probable tool required next by the surgeon or determining the remaining duration of surgery, methods for surgical workflow analysis are a prerequisite. Often machine learning based approaches serve as basis for analyzing the surgical workflow. In general, machine learning algorithms, such as convolutional neural networks (CNN), require large amounts of labeled data. While data is often available in abundance, many tasks in surgical workflow analysis need annotations by domain experts, making it difficult to obtain a sufficient amount of annotations.Methods The aim of using active learning to train a machine learning model is to reduce the annotation effort. Active learning methods determine which unlabeled data points would provide the most information according to some metric, such as prediction uncertainty. Experts will then be asked to only annotate these data points. The model is then retrained with the new data and used to select further data for annotation. Recently, active learning has been applied to CNN by means of Deep Bayesian Networks (DBN). These networks make it possible to assign uncertainties to predictions. In this paper, we present a DBN-based active learning approach adapted for image-based surgical workflow analysis task. Furthermore, by using a recurrent architecture,

Our results implicate Foxo3 in regulating NK cell function and suggest Foxo3 playing an important role in the antiviral innate immunity. Thus, enhanced FOXO3 activity such as in the polymorphism rs12212067 may be protective in chronic inflammation such as cancer and cardiovascular disease but disadvantageous to control acute viral infection.

The use of cardiopulmonary bypass (CPB) results in the activation of leukocytes, release of neutrophil extracellular traps (NETs) and severe inflammation. We hypothesize that targeting of circulating cell-free DNA (cfDNA) by DNases might represent a feasible therapeutic strategy to limit CPB-associated side effects. Male Wistar rats (n = 24) underwent CPB with deep hypothermic circulatory arrest (DHCA) and were divided into 3 groups: control (group 1), one i.v. bolus DNase I before CPB start (group 2) and a second DNase I dose before reperfusion (group 3). We found a positive correlation between plasma cfDNA/NETs levels and compromised endothelial vasorelaxation after CPB. DNase I administration significantly diminished plasma cfDNA/NETs levels. Further, a dose-dependent improvement in endothelial function accompanied by significant reduction of circulating intercellular adhesion molecule (ICAM)-1 was observed. Rats of group 3 had significantly reduced plasma IL-6 levels and downregulated expression of adhesion molecules resulting in impaired leukocyte extravasation and reduced MPO activity in lungs. Mechanistically, digestion of NETs by DNase I significantly diminished NETs-dependent upregulation of adhesion molecules in human endothelial cells. Altogether, systemic DNase I administration during CPB efficiently reduced cfDNA/NETs-mediated endothelial dysfunction and inflammation and might represent a promising therapeutic strategy for clinical practice.