Microglia Medium

Endothelial cells lining the vessel network are indispensable for vascular transport but also provide paracrine signals controlling the behavior of nearby cell types. Per... More

Endothelial cells lining the vessel network are indispensable for vascular transport but also provide paracrine signals controlling the behavior of nearby cell types. Pericytes are another essential component of the vessel wall, but little is known about their interactions with other cell populations during organ growth and patterning. Here, we use mouse genetics to address the function of three pericyte-derived factors in postnatal lung and brain. We find that inactivation of the gene for hepatocyte growth factor (HGF) or brain-derived neurotrophic factor (BDNF) in pericytes causes no overt alterations in postnatal brain but impairs lung development, which we attribute to defective interaction with AT2 epithelial cells and pulmonary endothelium, respectively. In contrast, pericyte expression of the growth factor Nodal is dispensable for lung morphogenesis but regulates vessel growth and barrier function in the postnatal brain through interactions with endothelial cells, astrocytes and microglia. Taken together, our findings establish that pericytes are a critical source of paracrine signals controlling morphogenetic processes in an organ-specific fashion. Less

Microglia are the predominant resident central nervous system (CNS) cell type productively infected by HIV-1 and play a key role in the progression of HIV-associated deme... More

Microglia are the predominant resident central nervous system (CNS) cell type productively infected by HIV-1 and play a key role in the progression of HIV-associated dementia (HAD). Moreover, neural dysfunction and progression to HAD are accelerated in opiate drug abusers. In the present study, we examined the role of the autophagy pathway in the neuropathogenesis of HIV-1 using primary human microglial cells and determined whether opiates converge at this point. Infection of microglia with the HIV-1SF162 macrophage-tropic strain resulted in increased Beclin1 expression, accompanied by an increase in LC3 protein levels and accumulation of LC3 reporter RFP GFP (yellow) puncta, suggesting that HIV-1 infection triggers autophagosome formation without promoting protein degradation by the lysosome. Conversely, coexposure with HIV-1 and morphine significantly decreased virus-induced Beclin1 expression and autophagosome formation. Exploration of the possible mechanisms used by morphine to disrupt the autophagic process unveiled a significant increase in intracellular pH, which coincided with a reduction in the formation of acidic vesicular organelles and autophagolysosome formation. Small interfering RNA targeting BECN1, a gene critical for autophagosome formation, significantly reduced viral replication and the virus-induced inflammatory responses. Conversely, morphine-enhanced viral replication and inflammatory responses were not affected by gene silencing with siBeclin1, suggesting that the interactive effect of morphine in HIV-1 pathogenesis is mediated through a Beclin1-independent mechanism. These novel findings may have important implications for the connections between autophagy and HIV-1 pathogenesis mediated by microglial cells in opioid-abusing individuals. Less