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Selective effects of Liver X Receptor activation in host-bacteria interaction

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Universitat de Barcelona. Departament de Biologia Cel·lular, Fisiologia i Immunologia

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[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.

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Tesis Doctorals - Departament - Biologia Cel·lular, Fisiologia i Immunologia

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Selective effects of Liver X Receptor activation in host-bacteria interaction