Selective roles of the Nuclear Receptors LXR in the transcriptional control of classical and alternative macrophage activation = Efectos selectivos de los receptores nucleares LXR en el control transcripcional de la activación clásica y alternativa de macrófagos

Resumo

Nuclear receptor LXR is a ligand dependent transcription factor. The activating ligands of LXR are specific oxidized forms of cholesterol (oxysterols) and intermediate products of the cholesterol biosynthetic pathway. This thesis has been developed in two main parts. In the first part, we have characterized the anti-inflammatory role of LXR in foam cells, a predominant cell type in atherosclerotic plaques, activated by the endogenous cytokine Interferon-gamma (IFN-?) and the bacterial component lipopolysaccharide (LPS). We have observed that the conversion of macrophages to foam cells itself has an inhibitory effect on the inflammatory response to LPS, but not to IFN-?. These inhibitory effects on the LPS response in foam cells do not seem to be mediated by impairing activation of ERK and p38 MAPK pathways, nor by inhibiting I?B? degradation. We also compared the antiinflammatory effects of the LXR ligands with the effects mediated by ligands of another member of the nuclear receptors superfamily, PPAR-?, in peritoneal macrophages. We have found subsets of genes that are specifically repressed by PPAR-? in the absence of LXR, and another group that is only repressed by LXR. In the second part of this work we have determined the role of LXR on the (IL-4-induced) alternative activation of macrophages. The expression of the main markers of alternative activation of macrophages is not affected by LXR agonists. However, we have observed that LXR exerts specific inhibitory effects over a group of chemokines associated to inflammatory lung diseases such as asthma. We have characterized the effect of an LXR agonist in a murine model of allergic asthma and we observed that LXR ameliorates the respiratory capacity upon induction of the asthmatic response. Moreover, LXR deficient mice developed significantly worsened airway responses in comparison with the wild type animals in this type of test. Finally, in this work we have also observed that IL-4 exerts negative reciprocal effects on the induction of selective LXR target genes in a STAT-6 dependent manner. This IL-4-mediated inhibition is selective and only affects a subset of targets of LXR.