@article{ce1c55ee8b77498694beafbfccdfff75,
title = "The Nuclear Receptor LXR Limits Bacterial Infection of Host Macrophages through a Mechanism that Impacts Cellular NAD Metabolism",
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 = "CD38, LXR, NAD, bacterial infection, cytoskeleton, macrophage, nuclear receptor",
author = "Jonathan Matalonga and Estibaliz Glaria and Mariana Bresque and Carlos Escande and Carb{\'o}, {Jos{\'e} Mar{\'i}a} and Kerstin Kiefer and Ruben Vicente and Le{\'o}n, {Theresa E.} and Susana Beceiro and M{\'o}nica Pascual-Garc{\'i}a and Joan Serret and Luc{\'i}a Sanjurjo and Samantha Mor{\'o}n-Ros and Antoni Riera and Sonia Paytubi and Antonio Juarez and Fernando Sotillo and Lennart Lindbom and Carme Caelles and Sarrias, {Maria Rosa} and Jaime Sancho and Antonio Castrillo and Chini, {Eduardo N.} and Valledor, {Annabel F.}",
note = "Funding Information: We thank D. Mangelsdorf for the LXR-deficient mice, J.H. Brumell for the pBR.RFP.1 plasmid, M. Sorribas and M. Garc?a for technical assistance, and A. Kupz, A. Dorhoi, and J.M. Caballero for protocols and scientific discussion. 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 Fundaci? la Marat? 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).",
year = "2017",
month = jan,
day = "31",
doi = "10.1016/j.celrep.2017.01.007",
language = "English (US)",
volume = "18",
pages = "1241--1255",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}