Liver X receptors (LXRs) regulate the expression of genes involved in cholesterol and fatty acid homeostasis, including the genes for ATP-binding cassette transporter A1 (ABCA1) and sterol response element binding protein 1 (SREBP1). Loss of LXR leads to derepression of the ABCA1 gene in macrophages and the intestine, while the SREBP1c gene remains transcriptionally silent. Here we report that high-density-lipoprotein (HDL) cholesterol levels are increased in LXR-deficient mice, suggesting that derepression of ABCA1 and possibly other LXR target genes in selected tissues is sufficient to result in enhanced HDL biogenesis at the whole-body level. We provide several independent lines of evidence indicating that the repressive actions of LXRs are dependent on interactions with the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptors (SMRT). While dissociation of NCoR and SMRT results in derepression of the ABCA1 gene in macrophages, it is not sufficient for derepression of the SREBP1c gene. These findings reveal differential requirements for corepressors in the regulation of genes involved in cholesterol and fatty acid homeostasis and raise the possibility that these interactions may be exploited to develop synthetic ligands that selectively modulate LXR actions in vivo.

Microbe-macrophage interactions play a central role in the pathogenesis of many infections. The ability of some bacterial pathogens to induce macrophage apoptosis has been suggested to contribute to their ability to elude innate immune responses and successfully colonize the host. Here, we provide evidence that activation of liver X receptors (LXRs) and retinoid X receptors (RXRs) inhibits apoptotic responses of macrophages to macrophage colony-stimulating factor (M-CSF) withdrawal and several inducers of apoptosis. In addition, combined activation of LXR and RXR protected macrophages from apoptosis caused by infection withBacillus anthracis, Escherichia coli, andSalmonella typhimurium. Expression-profiling studies demonstrated that LXR and RXR agonists induced the expression of antiapoptotic regulators, including AIM/CT2, Bcl-X_L, and Birc1a. Conversely, LXR and RXR agonists inhibited expression of proapoptotic regulators and effectors, including caspases 1, 4/11, 7, and 12; Fas ligand; and Dnase1l3. The combination of LXR and RXR agonists was more effective than either agonist alone at inhibiting apoptosis in response to various inducers of apoptosis, and it acted synergistically to induce expression of AIM/CT2. Inhibition of AIM/CT2 expression in response to LXR/RXR agonists partially reversed their antiapoptotic effects. These findings reveal unexpected roles of LXRs and RXRs in the control of macrophage survival and raise the possibility that LXR/RXR agonists may be exploited to enhance innate immunity to bacterial pathogens that induce apoptotic programs as a strategy for evading host responses.

Although all the cells in an organism contain the same genetic information, differences in the cell phenotype arise from the expression of lineage‐specific genes. During myelopoiesis, external differentiating signals regulate the expression of a set of transcription factors. The combined action of these transcription factors subsequently determines the expression of myeloid‐specific genes and the generation of monocytes and macrophages. In particular, the transcription factor PU.1 has a critical role in this process. We review the contribution of several transcription factors to the control of macrophage development. J. Leukoc. Biol. 63: 405–417; 1998.

CD5L, a soluble protein belonging to the SRCR superfamily, is expressed mostly by macrophages in lymphoid and inflamed tissues. The expression of this protein is transcriptionally controlled by LXRs, members of the nuclear receptor family that play major roles in lipid homeostasis. Research undertaken over the last decade has uncovered critical roles of CD5L as a PRR of bacterial and fungal components and in the control of key mechanisms in inflammatory responses, with involvement in processes, such as infection, atherosclerosis, and cancer. In this review, we summarize the current knowledge of CD5L, its roles at the intersection between lipid homeostasis and immune response, and its potential use as a diagnostic biomarker in a variety of diseases, such as TB and liver cirrhosis.

Macrophages play essential roles in immunity and homeostasis. As professional scavengers, macrophages phagocytose microbes and apoptotic and necrotic cells and take up modified lipoprotein particles. These functions require tightly regulated mechanisms for the processing and disposal of cellular lipids. Under pathological conditions, arterial wall macrophages become foam cells by accumulating large amounts of cholesterol, contributing to the development of atherosclerosis. Peroxisome proliferator–activated receptors (PPARs) and liver X receptors (LXRs) are members of the nuclear receptor superfamily of transcription factors that have emerged as key regulators of macrophage homeostasis. PPARs and LXRs control transcriptional programs involved in processes of lipid uptake and efflux, lipogenesis, and lipoprotein metabolism. In addition, PPARs and LXRs negatively regulate transcriptional programs involved in the development of inflammatory responses. This review summarizes recent efforts to decode the differential and overlapping roles of PPARs and LXRs in the context of macrophage lipid homeostasis and the control of inflammation.