LXR transcription factors in the specialization on tissue resident macrophages and their role in iron homeostasis

Resumen

The liver X receptors (LXRα and LXRβ) are members of the nuclear receptor superfamily of transcription factors. In macrophages, LXRs play essential roles in the coordination of both metabolic and immune responses, such as the transcriptional control of lipid metabolism or the modulation of innate and adaptive immune responses. Tissue resident macrophages are professional phagocytes that orchestrate innate immune responses, but also participate in the maintenance of tissue homeostasis by regulating different metabolic processes. Consequently, they acquire considerable genetic and phenotypic diversity at different anatomical locations. In the spleen, there are four different macrophage subpopulations, including white and red pulp macrophages (WPM and RPM), marginal metallophilic macrophages (MMM) and marginal zone macrophages (MZM), and all of them play specific roles in homeostasis and disease. Red pulp macrophages (RPMs, identified as CD45+CD11bloF4/80hiVCAMhi by flow cytometry) are specialized cells, important for the maintenance of iron homeostasis. They actively phagocytose injured and senescent red blood cells (RBCs), thus being critical for the recycling of hemoglobin iron. The iron recycled by these macrophages contributes to meet the iron requirements of the whole organism, like the generation of new erythrocytes in the bone marrow or the correct functioning of several enzymes in the cells. Previous reports established that LXRα is crucial for the differentiation of both splenic marginal zone macrophages. Here we now show the importance of this nuclear receptor in the correct development of the red pulp compartment of the spleen. LXR-null mice present a markedly reduced RPM population, despite elevated proportion of resident monocytes, and transcriptional profiling of isolated RPMs showed that these mice presented defective expression of many genes associated with the identity of RPMs, including CD163, the hemoglobin scavenger receptor. Further flow cytometry analysis revealed the existence of two resident macrophage subpopulations within the red pulp of the spleen, defined by their expression of CD163 receptor. Strikingly, the cell reduction observed in the RPM compartment of LXR-deficient mice corresponded with the absence of the CD163+ RPM subset. Presumably as a result of these alterations, iron handling is impaired in LXR-deficient mice, that accumulate RBCs and excessive iron in the splenic red pulp. Additionally, these mice presented a similar defect in the bone marrow resident macrophage population (BMMs), with a concomitant monocyte accumulation. Studies using LXRα-/- and LXRα-GFP mouse models revealed that the absence of LXRα, and not LXRβ, was the cause for the RPM and BMM deficiency and the malfunctioning of the iron machinery in the spleen of these mice. These results indicate a novel role for LXRα in the regulation of iron homeostasis, possibly in part through the generation of an appropriate splenic RPM compartment.