Retinoid X receptors in macrophage biology

•RXRs have novel roles in physiological and pathological hematopoiesis. •RXRs are key regulators of macrophage lipid metabolism and immune functions. •RXRs have therapeutic potential in the treatment of metabolic and inflammatory diseases. •Design of selective RXR modulators may overcome current limitations of RXR targeting in medicine. Retinoid X receptors (RXRs) form a distinct and unique subclass within the nuclear receptor (NR) superfamily of ligand-dependent transcription factors. RXRs regulate a plethora of genetic programs, including cell differentiation, the immune response, and lipid and glucose metabolism. Recent advances reveal that RXRs are important regulators of macrophages, key players in inflammatory and metabolic disorders. This review outlines the versatility of RXR action in the control of macrophage gene transcription through its heterodimerization with other NRs or through RXR homodimerization. We also highlight the potential of RXR-controlled transcriptional programs as targets for the treatment of pathologies associated with altered macrophage function, such as atherosclerosis, insulin resistance, autoimmunity, and neurodegeneration. Retinoid X receptors (RXRs) form a distinct and unique subclass within the nuclear receptor (NR) superfamily of ligand-dependent transcription factors. RXRs regulate a plethora of genetic programs, including cell differentiation, the immune response, and lipid and glucose metabolism. Recent advances reveal that RXRs are important regulators of macrophages, key players in inflammatory and metabolic disorders. This review outlines the versatility of RXR action in the control of macrophage gene transcription through its heterodimerization with other NRs or through RXR homodimerization. We also highlight the potential of RXR-controlled transcriptional programs as targets for the treatment of pathologies associated with altered macrophage function, such as atherosclerosis, insulin resistance, autoimmunity, and neurodegeneration. a synthetic rexinoid {4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl] benzoic acid} that acts as a pan-RXR agonist. It has been approved by the U.S. Food and Drug Administration (FDA) as an antineoplastic agent for the oral treatment of cutaneous T cell lymphoma (marketed name Targretin®). a term currently used to denote heterodimers formed between RXR and RARs, VDR, and TRs, which are conditionally activated by RXR ligands only in the presence of the partner agonist. a short sequence of DNA within the promoter of a gene that allows the binding of a specific nuclear receptor (NR) complex, leading to transcriptional activation. RXR may bind to direct repeats (DR), inverted repeats (IR), or everted repeats (ER) of the hexameric sequence AGGTCA separated by 1 to 5 bases, depending on the specific RXR heterodimeric partner. a synthetic rexinoid {(2E,4E,6Z)-7-[2-(2,2-difluoroethoxy)-3,5-bis(1,1-dimethylethyl)phenyl]-3-methyl-2,4,6-octatrienoic acid} that selectively activates RXR/PPARγ and RXR/PPARα, and antagonizes RXR/RAR signaling by an allosteric event that results in inhibition of RAR within the RXR/RAR heterodimer. a synthetic rexinoid (2-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)cyclopropyl]pyridine-5-carboxylic acid) that acts as a pan-RXR agonist. a synthetic rexinoid [(2E,4E,6Z)-3-methyl-7-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-propoxy-3-naphthalenyl)-2,4,6-octatrienoic acid] that selectively activates RXR/PPARγ and RXR/PPARα heterodimers and antagonizes RXR homodimers. this concept has been classically used to define heterodimers formed by RXRs and RARs, VDR and TRs, which are normally activated only by ligands specific for the partner and not by RXR ligands. It this scenario RXR acts as a 'silent' partner. RXR permissive heterodimers, formed with PPARs, LXRs, PXR, FXR, Nurr1, and Nur77, can be activated by either an RXR ligand or a ligand for the heterodimeric partner. Binding by both agonists could have additive or synergistic effects. a class of naturally found compounds chemically related to vitamin A, which can bind to RARs and RXRs. Retinoids play multiple roles in cell physiology; they regulate epithelial cell growth, cell proliferation and differentiation, immune function, as well as vision. a class of synthetic compounds that selectively bind to and activate RXRs. They are currently being tested for the treatment of metabolic syndrome due to their glucose-lowering, insulin-sensitizing, and antiobesity effects in animal models of insulin resistance and type 2 diabetes. However, some have been linked to side effects such as hypertriglyceridemia and suppression of the thyroid hormone axis. a class of synthetic compounds which include heterodimer- and homodimer-specific RXR agonists and antagonists; compounds that activate only a subset of the functions induced by the pan-RXR agonists or that act in a cell type-specific manner.