Monocarboxylate transporter 1 deficiency impacts CD8+ T lymphocytes proliferation and recruitment to adipose tissue during obesity.

Lactate sits at the crossroad of metabolism, immunity, and inflammation. The expression of cellular lactate transporter MCT1 (known as Slc16a1) increases during immune cell activation to cope with the metabolic reprogramming. We investigated the impact of MCT1 deficiency on CD8+ T cell function during obesity-related inflammatory conditions. The absence of MCT1 impaired CD8+ T cell proliferation with a shift of ATP production to mitochondrial oxidative phosphorylation. In Slc16a1 f/f Tcell cre mice fed a high-fat diet, a reduction in the number of CD8+ T cells, which infiltrated epididymal visceral adipose tissue (epiWAT) or subcutaneous adipose tissue, was observed. Adipose tissue weight and adipocyte area were significantly reduced together with downregulation of adipogenic genes only in the epiWAT. Our findings highlight a distinct effect of MCT1 deficiency in CD8+ T cells in the crosstalk with adipocytes and reinforce the concept that targeting immunometabolic reprogramming in lymphocyte could impact the immune-adipose tissue axis in obesity.

Metabolic adaptations of cells at the vascular-immune interface during atherosclerosis.

Metabolic reprogramming is a physiological cellular adaptation to intracellular and extracellular stimuli that couples to cell polarization and function in multiple cellular subsets. Pathological conditions associated to nutrients overload, such as dyslipidaemia, may disturb cellular metabolic homeostasis and, in turn, affect cellular response and activation, thus contributing to disease progression. At the vascular/immune interface, the site of atherosclerotic plaque development, many of these changes occur. Here, an intimate interaction between endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and immune cells, mainly monocytes/macrophages and lymphocytes, dictates physiological versus pathological response. Furthermore, atherogenic stimuli trigger metabolic adaptations both at systemic and cellular level that affect the EC layer barrier integrity, VSMC proliferation and migration, monocyte infiltration, macrophage polarization, lymphocyte T and B activation. Rewiring cellular metabolism by repurposing "metabolic drugs" might represent a pharmacological approach to modulate cell activation at the vascular immune interface thus contributing to control the immunometabolic response in the context of cardiovascular diseases.

Lysosomal Acid Lipase: From Cellular Lipid Handler to Immunometabolic Target.

Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters (CEs) and triglycerides (TGs) to free cholesterol (FC) and free fatty acids (FFAs), which are then used for metabolic purposes in the cell. The process also occurs in immune cells that adapt their metabolic machinery to cope with the different energetic requirements associated with cell activation, proliferation, and polarization. LAL deficiency (LALD) causes severe lipid accumulation and affects the immunometabolic signature in animal models. In humans, LAL deficiency is associated with a peculiar clinical immune phenotype, secondary hemophagocytic lymphohistiocytosis. These observations suggest that LAL might play an important role in cellular immunometabolic modulation, and availability of an effective enzyme replacement strategy makes LAL an attractive target to rewire the metabolic machinery of immune cells beyond its role in controlling cellular lipid metabolism.

Vascular pentraxin 3 controls arterial thrombosis by targeting collagen and fibrinogen induced platelets aggregation.

AIM: The long pentraxin PTX3 plays a non-redundant role during acute myocardial infarction, atherosclerosis and in the orchestration of tissue repair and remodeling during vascular injury, clotting and fibrin deposition. The aim of this work is to investigate the molecular mechanisms underlying the protective role of PTX3 during arterial thrombosis. METHODS AND RESULTS: PTX3 KO mice transplanted with bone marrow from WT or PTX3 KO mice presented a significant reduction in carotid artery blood flow following FeCl3 induced arterial thrombosis (-80.36±11.5% and -95.53±4.46%), while in WT mice transplanted with bone marrow from either WT or PTX3 KO mice, the reduction was less dramatic (-45.55±1.37% and -53.39±9.8%), thus pointing to a protective effect independent of a hematopoietic cell's derived PTX3. By using P-selectin/PTX3 double KO mice, we further excluded a role for P-selectin, a target of PTX3 released by neutrophils, in vascular protection played by PTX3. In agreement with a minor role for hematopoietic cell-derived PTX3, platelet activation (assessed by flow cytometric expression of markers of platelet activation) was similar in PTX3 KO and WT mice as were haemostatic properties. Histological analysis indicated that PTX3 localizes within the thrombus and the vessel wall, and specific experiments with the N-terminal and the C-terminal PTX3 domain showed the ability of PTX3 to selectively dampen either fibrinogen or collagen induced platelet adhesion and aggregation. CONCLUSION: PTX3 interacts with fibrinogen and collagen and, by dampening their pro-thrombotic effects, plays a protective role during arterial thrombosis.

[The percutaneous action of a heparin-allantoin-dexpanthenol combination in a specific ointment base. Thrombolytic action on the rabbit ear]. / Untersuchungen zur perkutanen Wirksamkeit von Heparin-Allantoin-Dexpanthenol-Kombinationen in spezieller Salbengrundlage. Thrombolytische Wirkung am Hasenohr.

Experimentally induced thrombi of ear veins in albino rabbits have been treated locally with heparin-containing ointments in presence or absence of allantoin and dexpanthenol, the heparin concentration varying. While the ointments, containing heparin only, induce no or only minor thrombolytic activity, the combination ointments Hepathrombin Adenylchemie containing heparin, allantoin and dexpanthenol show significant thrombolytic activity. This effect is dependent upon the heparin concentration, yet, heparin doses above 50 000 IU per 100 g of ointment do not enhance the thrombolysis furthermore. Further, the studies show that the effective components of Hepathrombin do penetrate into and through the skin, allantoin and dexpanthenol being important components of the ointment probably supporting the transdermal penetration of heparin. The studies also demonstrate the only local thrombolytic effect of the Hepathrombin ointments because the thrombus of the right ear, always treated with ointment base only, did not show any change in length as contrasted to that of the left ear of the same animal treated with the Hepathrombin ointments. Mechanisms of the locally by Hepathrombin/heparin induced thrombolysis will be discussed.