Plasmacytoid dendritic cells (pDCs) are antigen-presenting cells that develop into type-I interferon (IFN-I IntroductionPlasmacytoid dendritic cells (pDCs) are major type I interferon (IFN-I) producing cells in response to viral infections 1 as a result of selective expression of Toll-like receptors 7 and 9 and constitutive expression of interferon response factor 7. They migrate to inflamed lymph nodes (LN) through high endothelium venules during viral and bacterial infections 2,3 and provide an important link between innate and adaptive immunity, enhancing natural killer (NK) cell activity and adaptive immune responses.Blood pDC counts and pDC-dependent IFN-I production levels in vitro decrease in patients infected with human immunodeficiency virus (HIV). [4][5][6][7][8] These decreases are generally correlated with a fall in CD4 ϩ T-cell counts, inversely correlated with plasma viral load, and are associated with opportunistic infections. 5,6,[9][10][11][12] The reduction in circulating pDC numbers during HIV infection may be related to their direct infection, 6,9,13 or to redistribution to lymphoid organs, as suggested in the chronic asymptomatic stage of HIV infection. 14 In nonhuman primate models of HIV infection, the IFN-I innate response is an early immunologic event. [15][16][17] Rhesus macaque (Macaca mulatta) pDCs are activated and produce IFN-I in vitro in response to pathogenic simian immunodeficiency virus (SIV) 18,19 like their human counterparts in response to HIV. 20,21 Strong depletion of pDCs from blood and lymphoid tissues are reported in the end stage of SIV infection 19,22 and attributed to infection and to higher levels of apoptosis.However, although the HIV/SIV interplay with the host immune response during primary infection is a key event, probably determining the later progression to disease, little is known about the role of pDCs in immune regulation at this early stage.We predicted that HIV/SIV infection may have an impact on the dynamics of circulating and LN dendritic cells (DCs) and on their functions in the first few days of infection 23,24 and that it may induce immune suppression through IFN-I production and indoleamine-2,3-dioxygenase (IDO) activity. IDO is the ratelimiting enzyme responsible for the extrahepatic catabolism of the essential amino acid tryptophan (Trp) and is triggered by type I and type II interferons. [25][26][27] Abnormal production/activation of IDO is associated with inefficient immunologic responses to infections, including HIV/SIV and cancer 26,[28][29][30] and is induced by HIV in human pDCs in vitro. 20,21 Growing evidence suggests that pDCs are involved in the induction of tolerance through IDO-dependent mechanisms. 31 This suggests that pDCs may target immune suppression during the acute phase of HIV/SIV infection.We focused on the dynamics of pDCs during primary infection by carrying out fine time-resolution sampling of blood, and a longitudinal analysis of peripheral lymph nodes, using absolute quantification, to investigate the possible homing of ...

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Aims: Oxidative stress and mitochondrial dysfunction participate together in the development of heart failure (HF). mRNA levels of monoamine oxidase-A (MAO-A), a mitochondrial enzyme that produces hydrogen peroxide (H 2 O 2 ), increase in several models of cardiomyopathies. Therefore, we hypothesized that an increase in cardiac MAO-A could cause oxidative stress and mitochondrial damage, leading to cardiac dysfunction. In the present study, we evaluated the consequences of cardiac MAO-A augmentation on chronic oxidative damage, cardiomyocyte survival, and heart function, and identified the intracellular pathways involved. Results: We generated transgenic (Tg) mice with cardiac-specific MAO-A overexpression. Tg mice displayed cardiac MAO-A activity levels similar to those found in HF and aging. As expected, Tg mice showed a significant decrease in the cardiac amounts of the MAO-A substrates serotonin and norepinephrine. This was associated with enhanced H 2 O 2 generation in situ and mitochondrial DNA oxidation. As a consequence, MAO-A Tg mice demonstrated progressive loss of cardiomyocytes by necrosis and ventricular failure, which were prevented by chronic treatment with the MAO-A inhibitor clorgyline and the antioxidant N-acetyl-cystein. Interestingly, Tg hearts exhibited p53 accumulation and downregulation of peroxisome proliferator-activated receptor-c coactivator-1a (PGC-1a), a master regulator of mitochondrial function. This was concomitant with cardiac mitochondrial ultrastructural defects and ATP depletion. In vitro, MAO-A adenovirus transduction of neonatal cardiomyocytes mimicked the results in MAO-A Tg mice, triggering oxidative stress-dependent p53 activation, leading to PGC-1a downregulation, mitochondrial impairment, and cardiomyocyte necrosis. Innovation and Conclusion: We provide the first evidence that MAO-A upregulation in the heart causes oxidative mitochondrial damage, p53-dependent repression of PGC-1a, cardiomyocyte necrosis, and chronic ventricular dysfunction. Antioxid. Redox Signal. 18, 5-18.

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