The Nuclear Receptor LXR Limits Bacterial Infection of Host Macrophages through a Mechanism that Impacts Cellular NAD Metabolism
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- dc.contributor.author Matalonga, Jonathanca
- dc.contributor.author Kiefer, Kerstin, 1986-ca
- dc.contributor.author Vicente García, Rubén, 1978-ca
- dc.contributor.author Valledor, Annabel F.ca
- dc.date.accessioned 2017-05-09T08:11:49Z
- dc.date.available 2017-05-09T08:11:49Z
- dc.date.issued 2017
- dc.description.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.
- dc.description.sponsorship This work was supported by grants from the Spanish MICINN to A.F.V. (SAF2010-14989, SAF2011-23402, and SAF2014-57856), R.V. (SAF2010-16725), and the NuRCaMeIn network (SAF2015-71878-REDT); from Fundació la Marató de TV3 to A.F.V. (080930) and R.V. (20134030); and from COST Action BM1404 (Mye-EUNITER). M.R.S. is a Miguel Servet II researcher (ISCIII CPII14/00021), and C.E. is supported by a grant from ANII (INNOVA II, FCE_1_2014_1_104002, Uruguay). J.M. received fellowships from the Spanish MICINN (FPI, BES-2009-014828) and from the Institut Pasteur-Pierre Ledoux Jeunesse Internationale Foundation, M.P. received fellowships from the Spanish MEC (FPU, AP 2007-00821), J.M.C. received fellowships from the UB (APIF), and M.B. received fellowships from ANII (Uruguay).
- dc.format.mimetype application/pdfca
- dc.identifier.citation Matalonga J, Glaria E, Bresque M, Escande C, Carbó JM, Kiefer K et al. The Nuclear Receptor LXR Limits Bacterial Infection of Host Macrophages through a Mechanism that Impacts Cellular NAD Metabolism. Cell Reports. 2017;18(5):1241-55. DOI: 10.1016/j.celrep.2017.01.007
- dc.identifier.doi http://dx.doi.org/10.1016/j.celrep.2017.01.007
- dc.identifier.issn 2211-1247
- dc.identifier.uri http://hdl.handle.net/10230/32108
- dc.language.iso eng
- dc.publisher Elsevierca
- dc.relation.ispartof Cell Reports. 2017;18(5):1241-55
- dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2010-16725
- dc.rights © Elsevier This is the published version of an article http://dx.doi.org/10.1016/j.celrep.2017.01.007 that appeared in the journal Cell Reports. It is published in an Open Archive under an Elsevier user license. Details of this licence are available here: http://www.elsevier.com/about/open-access/open-access-policies/oa-license-policy/elsevier-user-license
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.subject.keyword Macrophage
- dc.subject.keyword Nuclear receptor
- dc.subject.keyword LXR
- dc.subject.keyword Bacterial infection
- dc.subject.keyword NAD
- dc.subject.keyword Cytoskeleton
- dc.subject.keyword CD38
- dc.title The Nuclear Receptor LXR Limits Bacterial Infection of Host Macrophages through a Mechanism that Impacts Cellular NAD Metabolismca
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion