Cell Reports (Jan 2017)
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 Sarrias,
- Jaime Sancho,
- Antonio Castrillo,
- Eduardo N. Chini,
- Annabel F. Valledor
Affiliations
- Jonathan Matalonga
- Nuclear Receptor Group, Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona 08028, Spain
- Estibaliz Glaria
- Nuclear Receptor Group, Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona 08028, Spain
- Mariana Bresque
- Metabolic Diseases and Aging Laboratory, Institut Pasteur Montevideo, Montevideo 11400, Uruguay
- Carlos Escande
- Metabolic Diseases and Aging Laboratory, Institut Pasteur Montevideo, Montevideo 11400, Uruguay
- José María Carbó
- Nuclear Receptor Group, Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona 08028, Spain
- Kerstin Kiefer
- Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona 08003, Spain
- Ruben Vicente
- Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona 08003, Spain
- Theresa E. León
- Nuclear Receptor Group, Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona 08028, Spain
- Susana Beceiro
- Instituto de Investigaciones Biomédicas “Alberto Sols” de Madrid and Unidad Asociada de Biomedicina CSIC-Universidad de las Palmas de Gran Canaria (CSIC-ULPGC), Madrid 28029, Spain
- Mónica Pascual-García
- Nuclear Receptor Group, Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona 08028, Spain
- Joan Serret
- Experimental Toxicology and Ecotoxicology Unit, Parc Científic de Barcelona, Barcelona 08028, Spain
- Lucía Sanjurjo
- Innate Immunity Group, Health Sciences Research Institute Germans Trias i Pujol, Badalona 08916, Spain
- Samantha Morón-Ros
- Nuclear Receptor Group, Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona 08028, Spain
- Antoni Riera
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain
- Sonia Paytubi
- Department of Microbiology, School of Biology, University of Barcelona, Barcelona 08028, Spain
- Antonio Juarez
- Department of Microbiology, School of Biology, University of Barcelona, Barcelona 08028, Spain
- Fernando Sotillo
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain
- Lennart Lindbom
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE-171 77, Sweden
- Carme Caelles
- Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Barcelona 08028, Spain
- Maria-Rosa Sarrias
- Innate Immunity Group, Health Sciences Research Institute Germans Trias i Pujol, Badalona 08916, Spain
- Jaime Sancho
- Institute of Parasitology and Biomedicine “López-Neyra” (IPBLN), CSIC, Granada 18016, Spain
- Antonio Castrillo
- Instituto de Investigaciones Biomédicas “Alberto Sols” de Madrid and Unidad Asociada de Biomedicina CSIC-Universidad de las Palmas de Gran Canaria (CSIC-ULPGC), Madrid 28029, Spain
- Eduardo N. Chini
- Laboratory of Signal Transduction, Department of Anesthesiology and Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
- Annabel F. Valledor
- Nuclear Receptor Group, Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona 08028, Spain
- DOI
- https://doi.org/10.1016/j.celrep.2017.01.007
- Journal volume & issue
-
Vol. 18,
no. 5
pp. 1241 – 1255
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.
Keywords
