The Nuclear Receptor LXR Limits Bacterial Infection of Host Macrophages through a Mechanism that Impacts Cellular NAD Metabolism

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 SarriasJaime Sancho, Antonio Castrillo, Eduardo N. Chini, Annabel F. Valledor

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1241-1255
Number of pages15
JournalCell reports
Volume18
Issue number5
DOIs
StatePublished - Jan 31 2017

Keywords

  • CD38
  • LXR
  • NAD
  • bacterial infection
  • cytoskeleton
  • macrophage
  • nuclear receptor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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