Dendritic cells (DCs) are the most potent APCs. Whereas immature DCs downregulate T-cell responses to induce/ maintain immunologic tolerance, mature DCs promote immunity. To amplify their functions, DCs communicate with neighboring DCs through soluble mediators, cell-to-cell contact, and vesicle exchange. Transfer of nanovesicles (< 100 nm) derived from the endocytic pathway (termed exosomes) represents a novel mechanism of DC-to-DC communication. The facts that exosomes contain exosomeshuttle miRNAs and DC functions can be regulated by exogenous miRNAs, suggest that DC-to-DC interactions could be mediated through exosome-shuttle miRNAs, a hypothesis that remains to be tested. Importantly, the mechanism of transfer of exosome-shuttle miRNAs from the exosome lumen to the cytosol of target cells is unknown. Here, we demonstrate that DCs release exosomes with different miRNAs depending on the maturation of the DCs. By visualizing spontaneous transfer of exosomes between DCs, we demonstrate that exosomes fused with the target DCs, the latter followed by release of the exosome content into the DC cytosol. Importantly, exosome-shuttle miRNAs are functional, because they repress target mRNAs of acceptor DCs. IntroductionCellular miRNAs are released membrane free 1 or packaged inside microvesicles (0.1-1 m) shed by the plasma membrane 2,3 or within nanovesicles (Ͻ 100nm) derived from the endocytic pathway known as exosomes. 4,5 Exosomes are generated as intraluminal vesicles by reverse budding of the membrane of multivesicular bodies (MVBs). Release of exosomes occurs when MVBs fuse their limiting membrane with the plasma membrane. [6][7][8][9] Dendritic cells (DCs) are APCs with the ability to regulate adaptive immunity. Whereas immature DCs down-regulate T-cell responses, mature DCs promote activation, proliferation, and differentiation of effector T cells. 10 Communication between DCs is essential to amplify their tolerogenic and immunogenic functions. 11,12 This DC-to-DC interaction is mediated through cell-tocell contact, soluble mediators, exchange of plasma membrane patches, 13,14 nanotubules, 15 and interaction with apoptotic cellderived vesicles 16 and exosomes. 17,18 Although the mechanisms have not been elucidated, it has been reported that DCs acquire proteins/peptides from other cells via exosomes. [17][18][19] Recently, it has been suggested that transfer of exosome-shuttle miRNAs might constitute a mechanism of cell-tocell communication that regulates mRNA translation 20 or, alternatively, a way to dispose of "unwanted" miRNAs. 21 An important unanswered question in the field is how exosome-shuttle miRNAs, transported inside the vesicles, are delivered into the cytosol of the acceptor cells, a problem we have investigated in this study with the use of DCs. Addressing this point has been challenging because (1) the composition of DC exosomes depends on the maturation of the DC of origin 22,23 ; (2) there is limited information on intercellular communication via "endogenous" (instead of exogenously added...

Key Points Therapeutic DCs stimulated via NK1R stimulate type 1–biased immunity.

Aberrant activation of macrophages in arterial walls by oxidized lipoproteins can lead to atherosclerosis. Oxidized lipoproteins convert macrophages to foam cells through lipid uptake and TLR signaling. To investigate the relative contributions of lipid uptake and TLR signaling in foam cell formation, we established an in vitro assay utilizing liposomes of defined lipid compositions. We found that TLRs signaling through Trif promoted foam cell formation by inducing both NF-KB signaling and Type I IFN production, whereas TLRs that do not induce IFN, like TLR2, did not enhance foam cell formation. Addition of IFNα to TLR2 activator promoted robust foam cell formation. TLR signaling further required PPARα, as inhibition of PPARα blocked foam cell formation. We then investigated the ability of endogenous microparticles (MP) to contribute to foam cell formation. We found that lipid containing MP promoted foam cell formation, which was enhanced by TLR stimulation or IFNα. These MP also stimulated foam cell formation in a human skin model. However, these MP suppressed TNFα production and T cell activation, showing that foam cell formation can occur by immunosuppressive microparticles. Taken together, the data reveal novel signaling requirements for foam cell formation and suggest that uptake of distinct types of MP in the context of activation of multiple distinct TLR can induce foam cell formation.

The National Consensus was prepared with the participation of the National Medical Association for the Study of the Multimorbidity, Russian Scientific Liver Society, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians, National Society for Preventive Cardiology, Professional Foundation for the Promotion of Medicine Fund PROFMEDFORUM. The aim of the multidisciplinary consensus is a detailed analysis of the course of non-alcoholic fatty liver disease (NAFLD) and the main associated conditions. The definition of NAFLD is given, its prevalence is described, methods for diagnosing its components such as steatosis, inflammation and fibrosis are described. The association of NAFLD with a number of cardio-metabolic diseases (arterial hypertension, atherosclerosis, thrombotic complications, type 2 diabetes mellitus (T2DM), obesity, dyslipidemia, etc.), chronic kidney disease (CKD) and the risk of developing hepatocellular cancer (HCC) were analyzed. The review of non-drug methods of treatment of NAFLD and modern opportunities of pharmacotherapy are presented. The possibilities of new molecules in the treatment of NAFLD are considered: agonists of nuclear receptors, antagonists of pro-inflammatory molecules, etc. The positive properties and disadvantages of currently used drugs (vitamin E, thiazolidinediones, etc.) are described. Special attention is paid to the multi-target ursodeoxycholic acid (UDCA) molecule in the complex treatment of NAFLD as a multifactorial disease. Its anti-inflammatory, anti-oxidant and cytoprotective properties, the ability to reduce steatosis an independent risk factor for the development of cardiovascular pathology, reduce inflammation and hepatic fibrosis through the modulation of autophagy are considered. The ability of UDCA to influence glucose and lipid homeostasis and to have an anticarcinogenic effect has been demonstrated. The Consensus statement has advanced provisions for practitioners to optimize the diagnosis and treatment of NAFLD and related common pathogenetic links of cardio-metabolic diseases.

Aim: present clinical guidelines, aimed at general practitioners, gastroenterologists, cardiologists, endocrinologists, comprise up-to-date methods of diagnosis and treatment of non-alcoholic fatty liver disease.Key points. Nonalcoholic fatty liver disease, the most wide-spread chronic liver disease, is characterized by accumulation of fat by more than 5 % of hepatocytes and presented by two histological forms: steatosis and nonalcoholic steatohepatitis. Clinical guidelines provide current views on pathogenesis of nonalcoholic fatty liver disease as a multisystem disease, methods of invasive and noninvasive diagnosis of steatosis and liver fibrosis, principles of nondrug treatment and pharmacotherapy of nonalcoholic fatty liver disease and associated conditions. Complications of nonalcoholic fatty liver disease include aggravation of cardiometabolic risks, development of hepatocellular cancer, progression of liver fibrosis to cirrhotic stage.Conclusion. Progression of liver disease can be avoided, cardiometabolic risks can be reduced and patients' prognosis — improved by the timely recognition of diagnosis of nonalcoholic fatty liver disease and associated comorbidities and competent multidisciplinary management of these patients.