The Nuclear Receptor LXR Limits Bacterial Infection of Host Macrophages through a Mechanism that Impacts Cellular NAD Metabolism.
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.
Nuclear Receptor Group, Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona 08028, Spain.
Jonathan
J
Matalonga
Nuclear Receptor Group, Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona 08028, Spain.
Estibaliz
E
Glaria
Metabolic Diseases and Aging Laboratory, Institut Pasteur Montevideo, Montevideo 11400, Uruguay.
Mariana
M
Bresque
Metabolic Diseases and Aging Laboratory, Institut Pasteur Montevideo, Montevideo 11400, Uruguay.
Carlos
C
Escande
Nuclear Receptor Group, Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona 08028, Spain.
José María
JM
Carbó
Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona 08003, Spain.
Kerstin
K
Kiefer
Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona 08003, Spain.
Ruben
R
Vicente
Nuclear Receptor Group, Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona 08028, Spain.
Theresa E
TE
León
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.
Susana
S
Beceiro
Nuclear Receptor Group, Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona 08028, Spain.
Mónica
M
Pascual-García
Experimental Toxicology and Ecotoxicology Unit, Parc Científic de Barcelona, Barcelona 08028, Spain.
Joan
J
Serret
Innate Immunity Group, Health Sciences Research Institute Germans Trias i Pujol, Badalona 08916, Spain.
Lucía
L
Sanjurjo
Nuclear Receptor Group, Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona 08028, Spain.
Samantha
S
Morón-Ros
Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain; Department of Organic Chemistry, School of Chemistry, University of Barcelona, Barcelona 08028, Spain.
Antoni
A
Riera
Department of Microbiology, School of Biology, University of Barcelona, Barcelona 08028, Spain.
Sonia
S
Paytubi
Department of Microbiology, School of Biology, University of Barcelona, Barcelona 08028, Spain; Institute for Bioengineering of Catalonia (IBEC), Barcelona 08028, Spain.
Antonio
A
Juarez
Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.
Fernando
F
Sotillo
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm SE-171 77, Sweden.
Lennart
L
Lindbom
Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Barcelona 08028, Spain.
Carme
C
Caelles
Innate Immunity Group, Health Sciences Research Institute Germans Trias i Pujol, Badalona 08916, Spain.
Maria-Rosa
MR
Sarrias
Institute of Parasitology and Biomedicine "López-Neyra" (IPBLN), CSIC, Granada 18016, Spain.
Jaime
J
Sancho
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.
Antonio
A
Castrillo
Laboratory of Signal Transduction, Department of Anesthesiology and Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Eduardo N
EN
Chini
Nuclear Receptor Group, Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona 08028, Spain. Electronic address: afernandezvalledor@ub.edu.
Annabel F
AF
Valledor
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D005260:Female; D000071518:Liver X Receptors / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D009243:NAD / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012480:Salmonella Infections / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000472:pathogenicity*
D000071518:Liver X Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D009243:NAD; D051997:ADP-ribosyl Cyclase 1
CD38; LXR; NAD; bacterial infection; cytoskeleton; macrophage; nuclear receptor