Selective effects of Liver X Receptor activation in host-bacteria interaction
[eng] 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 transcriptio...
| Author: | |
|---|---|
| Format: | Doctoral thesis |
| Status: | Published version |
| Publication date: | 2021 |
| Country: | España |
| Institution: | Universidad de Barcelona |
| Repository: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/183925 |
| Online Access: | https://hdl.handle.net/2445/183925 http://hdl.handle.net/10803/673708 |
| Access Level: | Open access |
| Keyword: | Sistema immunitari Macròfags Metabolisme Bacteris Receptors cel·lulars Fetge Immune system Macrophages Metabolism Bacteria Cell receptors Liver |
| _version_ | 1878742688637911040 |
|---|---|
| author | Glaría Percaz, Estibaliz |
| author_browse | Glaría Percaz, Estibaliz |
| author_facet | Glaría Percaz, Estibaliz |
| author_role | author |
| collection | Dipòsit Digital de la UB |
| description | [eng] 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. |
| eu_rights_str_mv | openAccess |
| format | doctoralThesis |
| id | ES_fa717dcb1befd1f2c941a8a6f347bcdb |
| institution | Universidad de Barcelona |
| instname_str | Universidad de Barcelona |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:diposit.ub.edu:2445/183925 |
| publishDate | 2021 |
| publishDateSort | 2021 |
| publisher | Universitat de Barcelona |
| publisherStr | Universitat de Barcelona |
| reponame_str | Dipòsit Digital de la UB |
| spelling | Selective effects of Liver X Receptor activation in host-bacteria interaction Glaría Percaz, Estibaliz Sistema immunitari Macròfags Metabolisme Bacteris Receptors cel·lulars Fetge Immune system Macrophages Metabolism Bacteria Cell receptors Liver [eng] 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. Universitat de Barcelona https://hdl.handle.net/2445/183925 http://hdl.handle.net/10803/673708 |
| spellingShingle | Selective effects of Liver X Receptor activation in host-bacteria interaction Glaría Percaz, Estibaliz Sistema immunitari Macròfags Metabolisme Bacteris Receptors cel·lulars Fetge Immune system Macrophages Metabolism Bacteria Cell receptors Liver |
| status_str | publishedVersion |
| title | 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_short | Selective effects of Liver X Receptor activation in host-bacteria interaction |
| title_sort | Selective effects of Liver X Receptor activation in host-bacteria interaction |
| topic | Sistema immunitari Macròfags Metabolisme Bacteris Receptors cel·lulars Fetge Immune system Macrophages Metabolism Bacteria Cell receptors Liver |
| topic_facet | Sistema immunitari Macròfags Metabolisme Bacteris Receptors cel·lulars Fetge Immune system Macrophages Metabolism Bacteria Cell receptors Liver |
| url | https://hdl.handle.net/2445/183925 http://hdl.handle.net/10803/673708 |