Obesity and diabetes are major risk factors for epicardial adipose tissue inflammation

BACKGROUND. Epicardial adipose tissue (EAT) directly overlies the myocardium, with changes in its morphology and volume associated with myriad cardiovascular and metabolic diseases. However, EAT's immune structure and cellular characterization remain incompletely described. We aimed to define the immune phenotype of EAT in humans and compare such profiles across lean, obese, and diabetic patients. METHODS. We recruited 152 patients undergoing open-chest coronary artery bypass grafting (CABG), valve repair/replacement (VR) surgery, or combined CABG/VR. Patients' clinical and biochemical data and EAT, subcutaneous adipose tissue (SAT), and preoperative blood samples were collected. Immune cell profiling was evaluated by flow cytometry and complemented by gene expression studies of immune mediators. Bulk RNA-Seq was performed in EAT across metabolic profiles to assess whole-transcriptome changes observed in lean, obese, and diabetic groups. RESULTS. Flow cytometry analysis demonstrated EAT was highly enriched in adaptive immune (T and B) cells. Although overweight/obese and diabetic patients had similar EAT cellular profiles to lean control patients, the EAT exhibited significantly (P ≤ 0.01) raised expression of immune mediators, including IL-1, IL-6, TNF-α, and IFN-γ. These changes were not observed in SAT or blood. Neither underlying coronary artery disease nor the presence of hypertension significantly altered the immune profiles observed. Bulk RNA-Seq demonstrated significant alterations in metabolic and inflammatory pathways in the EAT of overweight/obese patients compared with lean controls. CONCLUSION. Adaptive immune cells are the predominant immune cell constituent in human EAT and SAT. The presence of underlying cardiometabolic conditions, specifically obesity and diabetes, rather than cardiac disease phenotype appears to alter the inflammatory profile of EAT. Obese states markedly alter EAT metabolic and inflammatory signaling genes, underlining the impact of obesity on the EAT transcriptome profile

Circulating c-Met-Expressing Memory T Cells Define Cardiac Autoimmunity

BACKGROUND: Autoimmunity is increasingly recognized as a key contributing factor in heart muscle diseases. The functional features of cardiac autoimmunity in humans remain undefined because of the challenge of studying immune responses in situ. We previously described a subset of c-mesenchymal epithelial transition factor (c-Met)-expressing (c-Met+) memory T lymphocytes that preferentially migrate to cardiac tissue in mice and humans. METHODS: In-depth phenotyping of peripheral blood T cells, including c-Met+ T cells, was undertaken in groups of patients with inflammatory and noninflammatory cardiomyopathies, patients with noncardiac autoimmunity, and healthy controls. Validation studies were carried out using human cardiac tissue and in an experimental model of cardiac inflammation. RESULTS: We show that c-Met+ T cells are selectively increased in the circulation and in the myocardium of patients with inflammatory cardiomyopathies. The phenotype and function of c-Met+ T cells are distinct from those of c-Met-negative (c-Met-) T cells, including preferential proliferation to cardiac myosin and coproduction of multiple cytokines (interleukin-4, interleukin-17, and interleukin-22). Furthermore, circulating c-Met+ T cell subpopulations in different heart muscle diseases identify distinct and overlapping mechanisms of heart inflammation. In experimental autoimmune myocarditis, elevations in autoantigen-specific c-Met+ T cells in peripheral blood mark the loss of immune tolerance to the heart. Disease development can be halted by pharmacologic c-Met inhibition, indicating a causative role for c-Met+ T cells. CONCLUSIONS: Our study demonstrates that the detection of circulating c-Met+ T cells may have use in the diagnosis and monitoring of adaptive cardiac inflammation and definition of new targets for therapeutic intervention when cardiac autoimmunity causes or contributes to progressive cardiac injury

The glucose transporter 2 regulates CD8⁺ T cell function via environment sensing

T cell activation is associated with a profound and rapid metabolic response to meet increased energy demands for cell division, differentiation and development of effector function. Glucose uptake and engagement of the glycolytic pathway are major checkpoints for this event. Here we show that the low-affinity, concentration-dependent glucose transporter 2 (Glut2) regulates the development of CD8+ T cell effector responses in mice by promoting glucose uptake, glycolysis and glucose storage. Expression of Glut2 is modulated by environmental factors including glucose and oxygen availability and extracellular acidification. Glut2 is highly expressed by circulating, recently primed T cells, allowing efficient glucose uptake and storage. In glucose-deprived inflammatory environments, Glut2 becomes downregulated, thus preventing passive loss of intracellular glucose. Mechanistically, Glut2 expression is regulated by a combination of molecular interactions involving hypoxia-inducible factor-1 alpha, galectin-9 and stomatin. Finally, we show that human T cells also rely on this glucose transporter, thus providing a potential target for therapeutic immunomodulation

Direct Type I IFN but Not MDA5/TLR3 Activation of Dendritic Cells Is Required for Maturation and Metabolic Shift to Glycolysis after Poly IC Stimulation

We thank the Rockefeller University Center for Clinical and Translational Science (UL1 TR000043 NCATS, NIH) for technical support

CLUSTER ANALYSIS IN SEASONAL DECIDUOUS FOREST REMNANTS

Floresta Estacional Decidual, caracterizado como um enclave c\uf4ncavo, em terreno com declividade acentuada e solo arenoso, entre campos caracter\uedsticos da regi\ue3o. As esp\ue9cies arb\uf3reas e arbustivas com CAP (circunfer\ueancia a altura de 1,3 m do solo) 65 15 cm foram amostradas em duas classes de tamanho. Na amostragem dos indiv\uedduos da Classe I (CAP 65 30 cm) foram utilizadas 14 parcelas de 20 x 100 m, divididas em subparcelas (10 x 10 m). Os indiv\uedduos da Classe II (15 64 CAP < 30 cm) foram observados em 70 subparcelas. Para an\ue1lise de agrupamentos foi utilizado o programa TWINSPAN, que indicou dois grupos (G1 e G2) bem definidos na Classe I e um grupo relativamente homog\ueaneo na Classe II (sub-bosque). No grupo G1 ocorreram as esp\ue9cies indicadoras Trichilia claussenii , Cupania vernalis e Crysophyllum marginatum ; e no grupo G2 Luehea divaricata e Sebastiania commersoniana . Em rela\ue7\ue3o \ue0 estrutura horizontal, essas esp\ue9cies estiveram entre as tr\ueas mais importantes nos respectivos grupos. No sub-bosque, as esp\ue9cies com maior valor de import\ue2ncia foram Actinostemon concolor , Trichilia claussenii, Trichilia elegans , Eugenia rostrifolia e Sorocea bonplandii . Essas esp\ue9cies, por predominarem na vegeta\ue7\ue3o arb\uf3rea, apresentam papel fundamental na estabiliza\ue7\ue3o de encostas, considerando que est\ue3o adaptadas \ue0s \ue1reas com declividade acentuada e solos rasos, destacando-se Cupania vernalis e Trichilia claussenii em ambientes menos alterados e Luehea divaricata e Sebastiania commersoniana em ambientes mais suscept\uedveis \ue0s interfer\ueancias.This study intended to analyze the presence of clusters in the vegetation of Seasonal Deciduous Forest remnants, characterized as a concave enclave, on steep sandy soil, among the region\u2019s characteristic fields. Shrub and tree specimens with CBH (circumference at breast height) 65 15 cm were sampled in two size classes. In class I (CBH 65 30 cm) specimen sampling, we used fourteen 20 x 100 m plots, divided into sub-plots (10 x 10 m). Class II (15 64 CBH < 30 cm) specimens were observed in 70 sub-portions. We used the TWINSPAN program to analyze the clusters, which indicated two well-defined clusters in class I (G1 and G2) and one relatively homogenous cluster in class II (understorey). There were Trichilia claussenii , Cupania vernalis and Crysophyllum marginatum indicator species in the G1 cluster; and Luehea divaricata and Sebastiania commersoniana in the G2 cluster. Regarding to horizontal structure, these species were among the three most important ones in both clusters. In the understorey, the most important species were Actinostemon concolor , Trichilia claussenii, Trichilia elegans , Eugenia rostrifolia and Sorocea bonplandii . Since these species prevail in the tree vegetation, they are fundamental to stabilize hillsides, considering that they are adapted to steep and shallow soil areas, pointing out the Cupania vernalis and Trichilia claussenii in less modified environments and the Luehea divaricata and Sebastiania commersoniana in environments more susceptible to interference

Visceral adipose tissue immune homeostasis is regulated by the crosstalk between adipocytes and dendritic cell subsets

Visceral adipose tissue (VAT) has multiple roles in orchestrating whole-body energy homeostasis. In addition, VAT is now considered an immune site harboring an array of innate and adaptive immune cells with a direct role in immune surveillance and host defense. We report that conventional dendritic cells (cDCs) in VAT acquire a tolerogenic phenotype through upregulation of pathways involved in adipocyte differentiation. While activation of the Wnt/β-catenin pathway in cDC1 DCs induces IL-10 production, upregulation of the PPARγ pathway in cDC2 DCs directly suppresses their activation. Combined, they promote an anti-inflammatory milieu in vivo delaying the onset of obesity-induced chronic inflammation and insulin resistance. Under long-term over-nutrition, changes in adipocyte biology curtail β-catenin and PPARγ activation, contributing to VAT inflammation

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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