Dc. Ricote Group

Macrophages are hematopoietic cells of the myeloid lineage with important roles in development, homeostasis, tissue repair and immunity. They are found in virtually all tissues, participating in homeostasis and recovery of damaged tissues. Functional and transcriptomic studies indicate that macrophages residing in different tissues are phenotypically distinct and exhibit different gene expression programs that enable tissue-specific functions. Ontogeny and environmental signals can shape cellular identity through epigenetic modifications. Different macrophage populations express distinct transcription factors that are regulated by tissue-specific signals. However, the key signaling molecules, and the mechanisms that establish the differentiation and specialized functions of most tissue-resident and monocyte-derived macrophages are largely unknown. The studies of our group focus on investigating the transcriptional and epigenetic control of macrophages in different tissues, with special emphasis on their potential medical utility for the treatment of metabolic and inflammatory diseases. Of special interest to our group is the study of transcriptional and epigenetic regulation of macrophage identity and function by nuclear receptors. Our laboratory has demonstrated in recent years that nuclear receptors, especially the retinoid receptor (RXR), play an important regulatory role in homeostasis, inflammation and immunity.

Retinoid X receptor (RXR) is a ligand-dependent transcription factor that regulate diverse aspects of development and homeostasis. Within the nuclear receptor superfamily, RXR occupy a central position, because they form heterodimers with many other family members (including LXRs, PPARs, retinoic acid receptors [RARs], vitamin D receptor [VDR], and thyroid hormone receptor [TR]) and can form homodimers. Therefore, RXR controls developmental processes, immunity, homeostasis and metabolism. There are three RXR isotypes, RXRa (NR2B1), RXRb (NR2B2), and RXRg (NR2B3), which show tissue-specific differences in expression. RXRs are receptors for ligands such as the vitamin A derivative 9-cis-retinoic acid (9-cis-RA) and fatty acids. Several RXR-specific synthetic ligands, known as rexinoids, have also been generated. Bexarotene is a rexinoid used in cancer therapy and tested for the treatment of osteopetrosis, insulin resistance, and atherosclerosis. Our group has made important discoveries about the role of RXRs in myeloid cell biology, demonstrating that they are important regulators of myeloid cell functions with key roles in macrophage identity, bone homeostasis, inflammation and autoimmunity. Genetic deletion of these receptors in macrophages severely compromises macrophage homeostatic responses, leading to autoimmunity, osteopetrosis and cancer. In addition, our more recent studies demonstrate a key role of RXR in the control of the hematopoietic system, tissue-resident macrophage identity and the metabolic maturation of neonatal heart.

Current studies in the laboratory are aimed at studying the possible role of RXR as a regulator of metabolism in different organs, especially the heart, liver and brain. In addition, we are interested in studying the role of RXR in the processes of macrophage differentiation and activation in different tissues, as well as its role in inflammatory diseases and cancer. One of the remaining issues of nuclear receptor biology is the identity of the endogenous RXR ligands. We recently identified the long-chain fatty acid C24:5 as a natural RXRa ligand that was greatly increased in abundance in response to hematopoietic stress. In addition, we also identified the maternal-milk w-6- FA g-linoleic acid as endogenous RXR ligand.  Opening the question of whether differences in diet would regulate RXR signaling and the subsequent consequences on macrophage differentiation and function. We will further study the relevance on these ligands and the discovery of new endogenous ligands in different tissues.