Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Jonathan Matalonga, Estibaliz Glaria, Mariana Bresque, Carlos Escande, José María Carbó, Kerstin Kiefer, Ruben Vicente, Theresa E. León, Susana Beceiro, Mónica Pascual-García, Joan Serret, Lucía Sanjurjo, Samantha Morón-Ros, Antoni Riera, Sonia Paytubi, Antonio Juarez, Fernando Sotillo, Lennart Lindbom, Carme Caelles, Maria-Rosa Sarrias, Jaime Sancho, Antonio Castrillo, Eduardo N. Chini, Annabel F. Valledor
Macrophages exert potent effector functions against invading microorganisms but constitute, paradoxically, a preferential niche for many bacterial strains to replicate. Using a model of infection by Salmonella Typhimurium, we have identified a molecular mechanism regulated by the nuclear receptor LXR that limits infection of host macrophages through transcriptional activation of the multifunctional enzyme CD38. LXR agonists reduced the intracellular levels of NAD+ in a CD38-dependent manner, counteracting pathogen-induced changes in macrophage morphology and the distribution of the F-actin cytoskeleton and reducing the capability of non-opsonized Salmonella to infect macrophages. Remarkably, pharmacological treatment with an LXR agonist ameliorated clinical signs associated with Salmonella infection in vivo, and these effects were dependent on CD38 expression in bone-marrow-derived cells. Altogether, this work reveals an unappreciated role for CD38 in bacterial-host cell interaction that can be pharmacologically exploited by activation of the LXR pathway.
Graphical abstract
Teaser
Macrophages constitute a preferential niche for intracellular bacteria to replicate. Matalonga et al. identified an antibacterial circuit mediated by pharmacological targeting of the liver X receptor (LXR) pathway that impacts intracellular NAD metabolism and interferes with macrophage cytoskeletal rearrangements subverted by invasive bacteria.http://ift.tt/2kMW9pR
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