Roszer t 1, menendezgutierrez mp, cedenilla m, ricote m. Retinoid x receptor rxr regulates several key functions in myeloid cells, including inflammatory responses, phagocytosis, chemokine secretion, and proangiogenic activity. A decade of molecular biology of retinoic acid receptors. Cyclodextrin promotes atherosclerosis regression via. These receptors directly act as transcription factors fig. Ppara peroxisome proliferatoractivated receptor alpha. The text is divided into five sections, the first of which examines vitamin a metabolic. There is increasing appreciation of the involvement of this receptor network in the metabolic programming of macrophages and dendritic cells dcs, essential members of. Hpr caused a greater than twofold increase in phagocytosis of igg. In addition to npff, the nuclear receptor rxr retinoid x receptor is known to control mafb levels in macrophages.
As a secreted molecule, aim is found in both human and mouse blood 97, 100 103 and increases in blood with the progression of obesity in dio mice 98. Retinoid x receptor boosts brain recovery after stroke in pre. Sep 01, 20 retinoid x receptors in macrophage biology one for all. The therapeutic role of xenobiotic nuclear receptors against. Oct 03, 20 aim is a direct target for regulation by nuclear receptor liver x receptor retinoid x receptor lxrrxr heterodimers 99, 100, and it is exclusively produced by tissue macrophages. Cholesterol esterrich ldl, on the other hand, delivers cholesterol to peripheral tissues for steroidogenesis and maintaining cell membrane integrity. The two classes of nuclear receptors mediate the action of endogenous retinoids 7. Liver x receptor how is liver x receptor abbreviated. Liver x receptor signaling pathways in cardiovascular. Rxra knockout mice revealed that loss of function in young mice caused delayed myelin debris uptake and slowed remyelination after experimentallyinduced demyelination. Roszer t, menendezgutierrez mp, cedenilla m, ricote m 20 retinoid x receptors in macrophage biology. Rxrs regulate a plethora of genetic programs, including cell differentiation, the immune response, and lipid and glucose metabolism. Retinoid x receptor rxr antagonists are not only useful as chemical tools for.
Thyroid hormone receptors often form heterodimers with retinoid x receptors. Compounds that trigger dissociation of rxr tetramers may comprise a novel class. Chapters discuss lentiviral delivery of shrna constructs and rar signaling. Transcriptional integration of metabolism by the nuclear. Genes involved in driving cholesterol efflux, including abca1 and abcg1, are under the control of the lxr retinoid x receptor lxrrxr transcription apparatus 22, 28. The mechanism of action of thyroid hormones annual. Tamas roszer research group leader pi ulm university. Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Steroldependent transactivation of theabc1 promoter by the.
Vitamin d deficiency and diabetes mellitus intechopen. Effects of retinoids on macrophage function and il. This volume explores synthetic procedures for producing receptor specific retinoids and rexinoids, molecular biology methods, and new technologies to demonstrate the therapeutic activities of molecules. Pdf alphalinolenic acid increases cholesterol efflux in. Transcriptional control of apoptotic cell clearance by macrophage. Steroldependent transactivation of theabc1 promoter by. Retinoid x receptors rxrs form a distinct and unique subclass within the nuclear receptor nr superfamily of liganddependent transcription factors. Sequential cytokine dynamics in chronic rejection of rat renal allografts. Recent advances reveal that rxrs are important regulators of macrophages, key players in inflammatory and metabolic disorders. Isolation and purification of tissue resident macrophages for. Retinoid x receptor activation reverses agerelated. Dec 16, 2020 receptors include the retinoid x receptors rxrs.
Retinoid x receptors rxrs form a distinct and unique subclass within the nuclear receptor nr superfamily of liganddependent transcription. Macrophages are effector cells of the innate immune system with primary. In mammals there are three rxr isotypes that are encoded by distinct genes. Physical and functional interactions between liver x. Retinoid x receptor rxr belongs to a family of ligandactivated. Evaluation of retinoids for induction of the redundant. Biology, biochemistry, and diseaseprovides an overview and synthesis of the retinoid molecules, from basic biology to mechanisms of diseases and therapy. Retinoid x receptor boosts brain recovery after stroke in. Jan 21, 2021 several other orphan nrs, such as peroxisome proliferatoractivated receptor ppar. Recently, we identified a cisretinol dehydrogenase crdh that oxidizes 9cisretinol to 9cisretinal. Although several members of the nuclear hormone receptor superfamily have emerged as important regulators of macrophage gene expression, the existence in.
Because the transcriptional activities of lxrs are positively regulated by oxysterols, we next analyzed whether cd can potentiate cholesterol oxidation. Retinoid x receptors in macrophage biology request pdf. Activated by the endogenous ligand 1palmitoyl2oleoylsnglycerol3phosphocholine 16. Retinoid x receptor rxr regulates several key functions in myeloid cells, including. Each isotype exists in several isoforms with specific tissue distributions and expression patterns during development 1,2. The effect of peroxisome proliferatoractivated receptor. Jun 06, 2019 camp is known to be a direct transcriptional target of vd, which is induced by binding of 1,25oh 2 dvdr retinoid x receptor rxr complex to the vd response elements vdre in the gene promoter. Retinoid x receptor rxr antagonists are not only useful as chemical tools for biological research, but are also candidate drugs for the treatment of various diseases, including diabetes and allergies, although no rxr antagonist has yet been approved for clinical use. Mapping the genomic binding sites of the activated.
Identification of receptorselective retinoids that are. Retinoids modulate the growth and differentiation of cancer cells presumably by activating gene transcription via the nuclear retinoic acid receptor rar a, b, and g and retinoid x receptor rxr a, b, and g. Cedenilla m, ricote m 20 retinoid x receptors in macrophage biology. Retinoid x receptor definition of retinoid x receptor by. Isolation and purification of tissue resident macrophages. Retinoid x receptors rxrs are members of the nr superfamily of liganddependent transcription factors 1,2. The role of retinoid x receptors in tissueresident.
Alltrans retinoic acid modulates tlr4nfkappab signaling pathway targeting tnfalpha and nitric oxide synthase 2 expression in colonic mucosa during. Both types of receptors are composed of three subtypes alpha, beta, and gamma 8. Retinoids regulate survival and antigen presentation by. Mapping the genomic binding sites of the activated retinoid x. Germain p, chambon p, eichele g, evans rm, lazar ma, et al. Other signals, such as adiponectin 86, fcmediated phagocytosis and complement activation 123, uptake of cryptococcus cells 123, and oxidized lowdensity lipoprotein oxldl 124 are also known to increase. Understanding the mysterious m2 macrophage through activation. Journal of nutritional biochemistry 23 2012 400 409 alphalinolenic acid increases cholesterol efflux in macrophage derived foam cells by decreasing stearoyl coa desaturase 1 expression. Retinoid x receptors in macrophage biology one for all. Nuclear receptors are ligandactivated transcription factors linking lipid signaling to the expression of the genome. Pdf evaluation of retinoids for induction of the redundant.
Retinoid x receptors in macrophage biology sciencedirect. Feb 05, 2020 a regulator of gene expression, retinoid x receptor rxr, can boost scavenging cells in their mission to clear the brain of dead cells and debris after a stroke, thus limiting inflammation and improving recovery, according to preclinical research led by jarek aronowski, md, phd, of the university of texas health science center at houston. Liver x receptors lxrs are important regulators of cholesterol, fatty acid, and glucose homeostasis. Inhibition of liver x receptorretinoid x receptormediated. Lxrs play diverse roles in macrophage biology fig 4.
Retinoid x receptor agonists upregulate genes responsible for the biosynthesis of alltransretinoic acid in human epidermis 14 april 2016 plos one, vol. Retinoid x receptor rxr belongs to a family of ligand activated. Phytol metabolites are circulating dietary factors that. The retinoid x receptor rxr is a type of nuclear receptor that is activated by 9cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9cis,14dihydroretinoic acid, which is likely to be the major endogenous mammalian rxrselective agonist. Pharmacol liver x receptor alpha interferes with srebp1cmediated abcd2 expression. Request pdf retinoid x receptors in macrophage biology retinoid x receptors rxrs form a distinct and unique subclass within the nuclear receptor nr superfamily of liganddependent. Thus, the concept of alternative activation or m2 emerged as an il4mediated inflammatory response promoting recruited macrophages to acquire a unique repertoire of secreted cytokines and phagocytic receptor. Transcriptional control of macrophage polarization. In cultured macrophages, abc1 mrna was induced in an additive fashion by 22rhydroxycholesterol and 9cisretinoic acid 9cra, suggesting induction by nuclear hormone receptors of the liver x receptor lxr and retinoid x receptor rxr family. Receptors are key to understanding topical retinoids. The role of lipidactivated nuclear receptors in shaping macrophage. Retinoid and rexinoid signaling methods and protocols. Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety.
Lbd tetramer through a novel hydrophobic region that is located on the surface of. A major source of diversity originates from the existence of two families of retinoid acid ra receptors r, the rar isotypes. We analyzed the effects of 38 rarselective and rxrselective retinoids on the proliferation of 10 human head and neck squamous cell. Weinhofer i, kunze m, rampler h, bookout al, forsspetter s, et al. Jun 01, 2003 lxrs bind to their target dna sequences in heterodimeric complexes with the retinoid x receptor rxr. There is increasing appreciation of the involvement of this receptor network in the metabolic programming of macrophages and dendritic cells dcs, essential members of the innate immune system. Aug 25, 2020 retinoid x receptors rxrs form a distinct and unique subclass within the nuclear receptor nr superfamily of liganddependent transcription factors. The study, published today in nature communications, demonstrates that the expansion of peritoneal macrophages after birth and their maintenance during adult life are controlled by retinoid x receptor rxr, a member of the nuclear receptor family. Profiling in binding and functional assays led to the identification of lxr modulator gsk9772 20 as a highaffinity lxr.
Retinoids inhibit interleukin12 production in macrophages through physical associations of retinoid x receptor and nfkappab. Mice carrying targeted disruption of the lxr genes have been invaluable tools for the dissection of lxr biology 9, 10. The retinoid x receptor rxr is a type of nuclear receptor that is activated by 9cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9 cis,14dihydroretinoic acid, which is likely to be the major endogenous mammalian rxrselective agonist. Lipoprotein lipase lpl, secreted by the adipocyte, muscle, and macrophage, plays an important role in vldl fatty acid release, and its subsequent conversion to lowdensity lipoprotein ldl. Lxrrxr is a socalled permissive heterodimer, in that it can be activated by ligands for either lxr or rxr. Understanding the biology of selfrenewing macrophages. Adipokines involved in macrophage recruitment intechopen. Jan 25, 20 retinoic acidrelated orphan receptors ror. Disruption of retinoid x receptor function in young macrophages, using the antagonist hx531, mimics ageing by reducing myelin debris uptake. Retinoic acid receptor retinoid x receptor heterodimers in gel shift studies, rars and rxrs in nuclear extracts from human skin and cultured keratinocytes bind exclusively as heterodimers to rare, dna sequences composed of hexameric direct repeats spaced by two dr2 or five nucleotides dr5, and to retinoid x response figure 2. Retinoid x receptor suppresses a metastasispromoting. The versatility of liver x receptors in t cell homeostasis. Nuclear receptors, such as peroxisome proliferator activated. Jul 31, 2014 ra exists in two different isomeric forms, alltransretinoic acid atra and 9cisra 9cra, and acts by binding to the nuclear retinoic acid receptor rar and retinoid x receptor rxr.
Ppar, the oxysterol receptor liver x receptor lxr, and their obligate heterodimeric partner, the retinoid x. Rxrs are key regulators of macrophage lipid metabolism and immune functions. Liver x receptor signaling pathways in cardiovascular disease. Retinoids function through conformational alterations of liganddependent nuclear transcription factors, the retinoic acid receptors, and retinoid x receptors.
Rxrs are key regulators of macrophage lipid metabolism and immune. Sep 22, 2007 the lipid transporter atp binding cassette transporter a1 abca1 promotes the efflux of cellular phospholipids and cholesterol to lipidfree apolipoprotein ai and thus initiates the biogenesis of highdensity lipoprotein hdl. These retinoid receptors are active as heterodimers typical receptors are illustrated in fig. We introduce macrophages and dendritic cells and then we focus on a group of transcription factors, nuclear receptors, which regulate gene expression upon receiving lipid signals. Vd can also modulate innate immune system by increasing chemotaxis, autophagy, and phagolysosomal fusion of phagocytic cells. This may be a novel approach to reduce inflammation and autoimmunity caused by. Heterodimerization is regulated through distinct mechanisms that together determine the specificity and flexibility of the sequence recognition. In this chapter we describe in detail the experimental method developed in our laboratory to investigate in vivo the dnabinding characteristics of a key heterodimeric nuclear receptor, the retinoid x receptor rxr in murine bone marrowderived macrophages. Physical and functional interactions between liver x receptor.
Aminoterminal regions appear to modulate thyroid hormone receptor function in an isoformdependent manner. Since the discovery of these nuclear ra receptors a little bit over 30 years ago, an enormous effort has been undertaken by the scientific community to disclose both the molecular intricacies of the ra signal and the biological readouts of its activity. Ijms free fulltext retinoid x receptor antagonists html mdpi. The liver x receptor lxr is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the ppars, fxr and rxr. Rxrs have novel roles in physiological and pathological hematopoiesis.
Nuclear hormone receptors enable macrophages and dendritic. Overview of the structurebased nongenomic effects of the nuclear. The expression of the abca1 gene is controlled, coordinately with other genes of hdl metabolism, by liver x receptor retinoid x receptor lxrrxr heterodimers and. Structureguided design of nphenyl tertiary amines as. Lxrs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they. Within a target cell, ra signaling is activated by the binding of alltrans ra, the biologically active metabolite of vitamin a, to heterodimers of two nuclear receptors, the retinoic acid receptor rar and the retinoid x receptor rxr. The molecular biology of retinoids and their receptors. Evaluation of retinoids for induction of the redundant gene. Ijms free fulltext retinoid x receptor antagonists html. The receptors we cover are the ones with a recognized physiological function in these cell types and ones which heterodimerize with the retinoid x receptor.
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