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 language | English (US) |
|---|---|
| Pages (from-to) | 1241-1255 |
| Number of pages | 15 |
| Journal | Cell Reports |
| Volume | 18 |
| Issue number | 5 |
| DOIs | |
| State | Published - Jan 31 2017 |
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Keywords
- bacterial infection
- CD38
- cytoskeleton
- LXR
- macrophage
- NAD
- nuclear receptor
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
The Nuclear Receptor LXR Limits Bacterial Infection of Host Macrophages through a Mechanism that Impacts Cellular NAD Metabolism. / Matalonga, Jonathan; Glaria, Estibaliz; Bresque, Mariana; Escande, Carlos; Carbó, José María; Kiefer, Kerstin; Vicente, Ruben; León, Theresa E.; Beceiro, Susana; Pascual-García, Mónica; Serret, Joan; Sanjurjo, Lucía; Morón-Ros, Samantha; Riera, Antoni; Paytubi, Sonia; Juarez, Antonio; Sotillo, Fernando; Lindbom, Lennart; Caelles, Carme; Sarrias, Maria Rosa; Sancho, Jaime; Castrillo, Antonio; Chini, Eduardo Nunes; Valledor, Annabel F.
In: Cell Reports, Vol. 18, No. 5, 31.01.2017, p. 1241-1255.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The Nuclear Receptor LXR Limits Bacterial Infection of Host Macrophages through a Mechanism that Impacts Cellular NAD Metabolism
AU - Matalonga, Jonathan
AU - Glaria, Estibaliz
AU - Bresque, Mariana
AU - Escande, Carlos
AU - Carbó, José María
AU - Kiefer, Kerstin
AU - Vicente, Ruben
AU - León, Theresa E.
AU - Beceiro, Susana
AU - Pascual-García, Mónica
AU - Serret, Joan
AU - Sanjurjo, Lucía
AU - Morón-Ros, Samantha
AU - Riera, Antoni
AU - Paytubi, Sonia
AU - Juarez, Antonio
AU - Sotillo, Fernando
AU - Lindbom, Lennart
AU - Caelles, Carme
AU - Sarrias, Maria Rosa
AU - Sancho, Jaime
AU - Castrillo, Antonio
AU - Chini, Eduardo Nunes
AU - Valledor, Annabel F.
PY - 2017/1/31
Y1 - 2017/1/31
N2 - 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.
AB - 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.
KW - bacterial infection
KW - CD38
KW - cytoskeleton
KW - LXR
KW - macrophage
KW - NAD
KW - nuclear receptor
UR - http://www.scopus.com/inward/record.url?scp=85011691120&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85011691120&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2017.01.007
DO - 10.1016/j.celrep.2017.01.007
M3 - Article
C2 - 28147278
AN - SCOPUS:85011691120
VL - 18
SP - 1241
EP - 1255
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 5
ER -