Selective effects of Liver X Receptor activation in host-bacteria interaction
Macrophages exert potent microbicidal functions against pathogens; however, some intracellular bacteria have developed strategies to survive within intracellular phagolysosomes and use macrophages as a preferential niche to replicate. Liver X receptors (LXRs) are ligand- activated transcription fact...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/673708 |
| Acceso en línea: | http://hdl.handle.net/10803/673708 |
| Access Level: | acceso abierto |
| Palabra clave: | Sistema immunitari Sistema inmunológico Immune system Macròfags Macrófagos Macrophages Metabolisme Metabolismo Metabolism Bacteris Bacterias Bacteria Receptors cel·lulars Receptores celulares Cell receptors Fetge Hígado Liver Ciències Experimentals i Matemàtiques 577 |
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España |
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Selective effects of Liver X Receptor activation in host-bacteria interaction |
| title |
Selective effects of Liver X Receptor activation in host-bacteria interaction |
| spellingShingle |
Selective effects of Liver X Receptor activation in host-bacteria interaction Glaría Percaz, Estibaliz Sistema immunitari Sistema inmunológico Immune system Macròfags Macrófagos Macrophages Metabolisme Metabolismo Metabolism Bacteris Bacterias Bacteria Receptors cel·lulars Receptores celulares Cell receptors Fetge Hígado Liver Ciències Experimentals i Matemàtiques 577 |
| title_short |
Selective effects of Liver X Receptor activation in host-bacteria interaction |
| title_full |
Selective effects of Liver X Receptor activation in host-bacteria interaction |
| title_fullStr |
Selective effects of Liver X Receptor activation in host-bacteria interaction |
| title_full_unstemmed |
Selective effects of Liver X Receptor activation in host-bacteria interaction |
| title_sort |
Selective effects of Liver X Receptor activation in host-bacteria interaction |
| dc.creator.none.fl_str_mv |
Glaría Percaz, Estibaliz |
| author |
Glaría Percaz, Estibaliz |
| author_facet |
Glaría Percaz, Estibaliz |
| author_role |
author |
| dc.contributor.none.fl_str_mv |
Valledor Fernández, Annabel Valledor Fernández, Annabel Universitat de Barcelona. Departament de Biologia Cel·lular, Fisiologia i Immunologia |
| dc.subject.none.fl_str_mv |
Sistema immunitari Sistema inmunológico Immune system Macròfags Macrófagos Macrophages Metabolisme Metabolismo Metabolism Bacteris Bacterias Bacteria Receptors cel·lulars Receptores celulares Cell receptors Fetge Hígado Liver Ciències Experimentals i Matemàtiques 577 |
| topic |
Sistema immunitari Sistema inmunológico Immune system Macròfags Macrófagos Macrophages Metabolisme Metabolismo Metabolism Bacteris Bacterias Bacteria Receptors cel·lulars Receptores celulares Cell receptors Fetge Hígado Liver Ciències Experimentals i Matemàtiques 577 |
| description |
Macrophages exert potent microbicidal functions against pathogens; however, some intracellular bacteria have developed strategies to survive within intracellular phagolysosomes and use macrophages as a preferential niche to replicate. Liver X receptors (LXRs) are ligand- activated transcription factors of the nuclear receptor superfamily that regulate metabolic and immune functions. In this study, we explored the impact of LXR activation on host–bacteria interactions and its consequences on infection. In a murine model of orally-acquired salmonellosis, the pharmacological activation of LXRs reduced extraintestinal bacterial dissemination and attenuated the clinical signs of infection. The beneficial effects of LXR activation in the control of infection required the expression of the multifunctional protein CD38 in bone marrow-derived cells. We had previously described CD38 as a new LXR target gene that is synergistically induced by the combination of LXR agonists and inflammatory stimuli in macrophages. Here, we have identified the transcription factor C/EBPβ as an essential mediator of Cd38 induction by TNFα, IFNγ, or LPS, as well as by the combination of these inflammatory signals and an LXR agonist. In murine macrophages, LXR activation reduced the internalisation of Salmonella Typhimurium, uropathogenic E. coli, and enteroinvasive E. coli (EIEC) but not of Listeria monocytogenes, Staphylococcus aureus, or latex microspheres. After analysing several LXR-mediated activities, we found that S. Typhimurium infection correlated with the abundance of free cholesterol in macrophages, indicating that the reduction in cellular cholesterol caused by LXR activation might mediate the inhibitory effect on bacterial entry. In primary human macrophages, LXR activation reduced the infection by S. Typhimurium but not by EIEC or S. aureus. Strikingly, LXR activation caused either no effect or a reduction in the internalisation of L. monocytogenes and latex microspheres depending on the donor. In conclusion, this work delves into the mechanisms by which LXRs modulate host interactions with bacteria. Given that the ability of many bacteria to invade host cells largely depends on initial surface contacts, modulating these events through LXR-targeting compounds opens new potential therapeutic opportunities for antibacterial drug development. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 2022 2022 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/doctoralThesis info:eu-repo/semantics/publishedVersion |
| format |
doctoralThesis |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10803/673708 |
| url |
http://hdl.handle.net/10803/673708 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
238 p. application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
Universitat de Barcelona |
| publisher.none.fl_str_mv |
Universitat de Barcelona |
| dc.source.none.fl_str_mv |
TDX (Tesis Doctorals en Xarxa) reponame:TDR. Tesis Doctorales en Red instname:CBUC, CESCA |
| instname_str |
CBUC, CESCA |
| reponame_str |
TDR. Tesis Doctorales en Red |
| collection |
TDR. Tesis Doctorales en Red |
| repository.name.fl_str_mv |
|
| repository.mail.fl_str_mv |
|
| _version_ |
1869421773852770304 |
| spelling |
Selective effects of Liver X Receptor activation in host-bacteria interactionGlaría Percaz, EstibalizSistema immunitariSistema inmunológicoImmune systemMacròfagsMacrófagosMacrophagesMetabolismeMetabolismoMetabolismBacterisBacteriasBacteriaReceptors cel·lularsReceptores celularesCell receptorsFetgeHígadoLiverCiències Experimentals i Matemàtiques577Macrophages exert potent microbicidal functions against pathogens; however, some intracellular bacteria have developed strategies to survive within intracellular phagolysosomes and use macrophages as a preferential niche to replicate. Liver X receptors (LXRs) are ligand- activated transcription factors of the nuclear receptor superfamily that regulate metabolic and immune functions. In this study, we explored the impact of LXR activation on host–bacteria interactions and its consequences on infection. In a murine model of orally-acquired salmonellosis, the pharmacological activation of LXRs reduced extraintestinal bacterial dissemination and attenuated the clinical signs of infection. The beneficial effects of LXR activation in the control of infection required the expression of the multifunctional protein CD38 in bone marrow-derived cells. We had previously described CD38 as a new LXR target gene that is synergistically induced by the combination of LXR agonists and inflammatory stimuli in macrophages. Here, we have identified the transcription factor C/EBPβ as an essential mediator of Cd38 induction by TNFα, IFNγ, or LPS, as well as by the combination of these inflammatory signals and an LXR agonist. In murine macrophages, LXR activation reduced the internalisation of Salmonella Typhimurium, uropathogenic E. coli, and enteroinvasive E. coli (EIEC) but not of Listeria monocytogenes, Staphylococcus aureus, or latex microspheres. After analysing several LXR-mediated activities, we found that S. Typhimurium infection correlated with the abundance of free cholesterol in macrophages, indicating that the reduction in cellular cholesterol caused by LXR activation might mediate the inhibitory effect on bacterial entry. In primary human macrophages, LXR activation reduced the infection by S. Typhimurium but not by EIEC or S. aureus. Strikingly, LXR activation caused either no effect or a reduction in the internalisation of L. monocytogenes and latex microspheres depending on the donor. In conclusion, this work delves into the mechanisms by which LXRs modulate host interactions with bacteria. Given that the ability of many bacteria to invade host cells largely depends on initial surface contacts, modulating these events through LXR-targeting compounds opens new potential therapeutic opportunities for antibacterial drug development.Universitat de BarcelonaValledor Fernández, AnnabelValledor Fernández, AnnabelUniversitat de Barcelona. Departament de Biologia Cel·lular, Fisiologia i Immunologia202220222021info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion238 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/673708TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésADVERTIMENT. Tots els drets reservats. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/6737082026-06-14T12:46:07Z |
| score |
15,301603 |