The Role of the Nrf2 Pathway in Airway Tissue Damage Due to Viral Respiratory Infections.

Respiratory viruses constitute a significant cause of illness and death worldwide. Respiratory virus-associated injuries include oxidative stress, ferroptosis, inflammation, pyroptosis, apoptosis, fibrosis, autoimmunity, and vascular injury. Several studies have demonstrated the involvement of the nuclear factor erythroid 2-related factor 2 (Nrf2) in the pathophysiology of viral infection and associated complications. It has thus emerged as a pivotal player in cellular defense mechanisms against such damage. Here, we discuss the impact of Nrf2 activation on airway injuries induced by respiratory viruses, including viruses, coronaviruses, rhinoviruses, and respiratory syncytial viruses. The inhibition or deregulation of Nrf2 pathway activation induces airway tissue damage in the presence of viral respiratory infections. In contrast, Nrf2 pathway activation demonstrates protection against tissue and organ injuries. Clinical trials involving Nrf2 agonists are needed to define the effect of Nrf2 therapeutics on airway tissues and organs damaged by viral respiratory infections.

Nuclear receptor Nr1d1 alleviates asthma by abating GATA3 gene expression and Th2 cell differentiation.

Nuclear receptors are a unique family of transcription factors that play cardinal roles in physiology and plethora of human diseases. The adopted orphan nuclear receptor Nr1d1 is a constitutive transcriptional repressor known to modulate several biological processes. In this study, we found that Nr1d1 plays a decisive role in T helper (Th)-cell polarization and transcriptionally impedes the formation of Th2 cells by directly binding to the promoter region of GATA binding protein 3 (GATA3) gene. Nr1d1 interacts with its cellular companion, the nuclear receptor corepressor and histone deacetylase 3 to form a stable repression complex on the GATA3 promoter. The presence of Nr1d1 also imparts protection against associated inflammatory responses in murine model of asthma and its ligand SR9011 eased disease severity by suppressing Th2 responses. Moreover, Chip-seq profiling uncovered Nr1d1 interactions with other gene subsets that impedes Th2-linked pathways and regulates metabolism, immunity and brain functions, therefore, providing empirical evidence regarding the genetic link between asthma and other comorbid conditions. Thus, Nr1d1 emerges as a molecular switch that could be targeted to subdue asthma.

Biological Functions of HMGN Chromosomal Proteins.

Chromatin plays a key role in regulating gene expression programs necessary for the orderly progress of development and for preventing changes in cell identity that can lead to disease. The high mobility group N (HMGN) is a family of nucleosome binding proteins that preferentially binds to chromatin regulatory sites including enhancers and promoters. HMGN proteins are ubiquitously expressed in all vertebrate cells potentially affecting chromatin function and epigenetic regulation in multiple cell types. Here, we review studies aimed at elucidating the biological function of HMGN proteins, focusing on their possible role in vertebrate development and the etiology of disease. The data indicate that changes in HMGN levels lead to cell type-specific phenotypes, suggesting that HMGN optimize epigenetic processes necessary for maintaining cell identity and for proper execution of specific cellular functions. This manuscript contains tables that can be used as a comprehensive resource for all the English written manuscripts describing research aimed at elucidating the biological function of the HMGN protein family.

A human xenobiotic nuclear receptor contributes to nonresponsiveness of Mycobacterium tuberculosis to the antituberculosis drug rifampicin.

Mycobacterium tuberculosis is the causative agent of tuberculosis (TB). It acquires phenotypic drug resistance inside macrophages, and this resistance mainly arises from host-induced stress. However, whether cellular drug-efflux mechanisms in macrophages contribute to nonresponsiveness of M. tuberculosis to anti-TB drugs is unclear. Here, we report that xenobiotic nuclear receptors mediate TB drug nonresponsiveness by modulating drug-efflux transporters in macrophages. This was evident from expression analysis of drug-efflux transporters in macrophages isolated from TB patients. Among patients harboring rifampicin-susceptible M. tuberculosis, we observed increased intracellular survival of M. tuberculosis upon rifampicin treatment of macrophages isolated from patients not responding to anti-TB drugs compared with macrophages from patients who did respond. Of note, M. tuberculosis infection and rifampicin exposure synergistically modulated macrophage drug-efflux transporters in vitro We also found that the xenobiotic nuclear receptor pregnane X receptor (PXR) modulates macrophage drug-efflux transporter expression and activity, which compromised the anti-TB efficacy of rifampicin. We further validated this finding in a TB mouse model in which use of the PXR antagonist ketoconazole rescued rifampicin anti-TB activity. We conclude that PXR activation in macrophages compromises the efficacy of the anti-TB drug rifampicin. Alternative therapeutic strategies, such as use of the rifampicin derivatives rifapentine and rifabutin, which do not activate PXR, or of a PXR antagonist, may be effective for tackling drug nonresponsiveness of M. tuberculosis that arises from drug-efflux systems of the host.

Human Xenobiotic Nuclear Receptor PXR Augments Mycobacterium tuberculosis Survival.

Mycobacterium tuberculosis can evade host defense processes, thereby ensuring its survival and pathogenesis. In this study, we investigated the role of nuclear receptor, pregnane X receptor (PXR), in M. tuberculosis infection in human monocyte-derived macrophages. In this study, we demonstrate that PXR augments M. tuberculosis survival inside the host macrophages by promoting the foamy macrophage formation and abrogating phagolysosomal fusion, inflammation, and apoptosis. Additionally, M. tuberculosis cell wall lipids, particularly mycolic acids, crosstalk with human PXR (hPXR) by interacting with its promiscuous ligand binding domain. To confirm our in vitro findings and to avoid the reported species barrier in PXR function, we adopted an in vivo mouse model expressing hPXR, wherein expression of hPXR in mice promotes M. tuberculosis survival. Therefore, pharmacological intervention and designing antagonists to hPXR may prove to be a promising adjunct therapy for tuberculosis.

The Active Form of Vitamin D Transcriptionally Represses Smad7 Signaling and Activates Extracellular Signal-regulated Kinase (ERK) to Inhibit the Differentiation of a Inflammatory T Helper Cell Subset and Suppress Experimental Autoimmune Encephalomyelitis.

The ability of the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), to transcriptionally modulate Smads to inhibit Th17 differentiation and experimental autoimmune encephalomyelitis (EAE) has not been adequately studied. This study reports modulation of Smad signaling by the specific binding of the VDR along with its heterodimeric partner RXR to the negative vitamin D response element on the promoter of Smad7, which leads to Smad7 gene repression. The vitamin D receptor-mediated increase in Smad3 expression partially explains the IL10 augmentation seen in Th17 cells. Furthermore, the VDR axis also modulates non-Smad signaling by activating ERK during differentiation of Th17 cells, which inhibits the Th17-specific genes il17a, il17f, il22, and il23r. In vivo EAE experiments revealed that, 1,25(OH)2D3 suppression of EAE correlates with the Smad7 expression in the spleen and lymph nodes. Furthermore, Smad7 expression also correlates well with IL17 and IFNγ expression in CNS infiltered inflammatory T cells. We also observed similar gene repression of Smad7 in in vitro differentiated Th1 cells when cultured in presence of 1,25(OH)2D3. The above canonical and non-canonical pathways in part address the ability of 1,25(OH)2D3-VDR to inhibit EAE.

Nuclear Receptor Nr4a2 Promotes Alternative Polarization of Macrophages and Confers Protection in Sepsis.

The orphan nuclear receptor Nr4a2 is known to modulate both inflammatory and metabolic processes, but the mechanism by which it regulates innate inflammatory homeostasis has not been adequately addressed. This study shows that exposure to ligands for Toll-like receptors (TLRs) robustly induces Nr4a2 and that this induction is tightly regulated by the PI3K-Akt signaling axis. Interestingly, exogenous expression of Nr4a2 in macrophages leads to their alternative phenotype with induction of genes that are prototypical M2 markers. Moreover, Nr4a2 transcriptionally activates arginase 1 expression by directly binding to its promoter. Adoptive transfer experiments revealed that increased survival of animals in endotoxin-induced sepsis is Nr4a2-dependent. Thus our data identify a previously unknown role for Nr4a2 in the regulation of macrophage polarization.

Oleic acid complex of bovine α-lactalbumin induces eryptosis in human and other erythrocytes by a Ca(2+)-independent mechanism.

BACKGROUND: Complexes of oleic acid (OA) with milk α-lactalbumin, received remarkable attention in view of their selective toxicity towards a spectrum of tumors during the last two decades. OA complexes of some structurally related/unrelated proteins are also tumoricidal. Erythrocytes are among the few differentiated cells that are sensitive and undergo hemolysis when exposed to the complexes. METHODS: The effects of OA complex of bovine α-lactalbumin (Bovine Alpha-lactalbumin Made LEthal to Tumor cells, BAMLET) on human, goat and chicken erythrocytes on calcein leakage, phosphatidylserine exposure, morphological changes and hemolysis were studied by confocal microscopy, FACS analysis, scanning electron microscopy and measuring hemoglobin release. RESULTS: Erythrocytes exposed to BAMLET undergo eryptosis-like alterations as revealed by calcein leakage, surface phosphatidylserine exposure and transformation to echinocytes at low concentrations and hemolysis when the concentration of the complex was raised. Ca(2+) was not essential and restricted the alterations when included in the medium. The BAMLET-induced alterations in human erythrocytes were prevented by the cation channel inhibitors, amiloride and BaCl2 but not by inhibitors of thiol proteases, sphingomyelinase and by the antioxidant N-acetyl cysteine. CONCLUSIONS: The work shows for the first time that low concentrations of BAMLET induces eryptosis in erythrocytes by a novel mechanism not requiring Ca(2+) and hemolysis by detergent-like action by the released OA at higher concentrations. GENERAL SIGNIFICANCE: The study points out to the need for a comprehensive evaluation of the toxicity of OA complexes of α-lactalbumin and other proteins towards erythrocytes and other differentiated cells before being considered for therapy.

Mycobacterium tuberculosis keto-mycolic acid and macrophage nuclear receptor TR4 modulate foamy biogenesis in granulomas: a case of a heterologous and noncanonical ligand-receptor pair.

The cell wall of Mycobacterium tuberculosis is configured of bioactive lipid classes that are essential for virulence and potentially involved in the formation of foamy macrophages (FMs) and granulomas. Our recent work established crosstalk between M. tuberculosis cell wall lipids and the host lipid-sensing nuclear receptor TR4. In this study, we have characterized, identified, and adopted a heterologous ligand keto-mycolic acid from among M. tuberculosis lipid repertoire for the host orphan NR TR4. Crosstalk between cell wall lipids and TR4 was analyzed by transactivation and promoter reporter assays. Mycolic acid (MA) was found to transactivate TR4 significantly compared with other cell wall lipids. Among the MA, the oxygenated form, keto-MA, was responsible for transactivation, and the identity was validated by TR4 binding assays followed by TLC and nuclear magnetic resonance. Isothermal titration calorimetry revealed that keto-MA binding to TR4 is energetically favorable. This keto-MA-TR4 axis seems to be essential to this oxygenated MA induction of FMs and granuloma formation as evaluated by in vitro and in vivo model of granuloma formation. TR4 binding with keto-MA features a unique association of host nuclear receptor with a bacterial lipid and adds to the presently known ligand repertoire beyond dietary lipids. Pharmacologic modulation of this heterologous axis may hold promise as an adjunct therapy to frontline tuberculosis drugs.

Human IL10 gene repression by Rev-erbα ameliorates Mycobacterium tuberculosis clearance.

Nuclear receptors modulate macrophage effector functions, which are imperative for clearance or survival of mycobacterial infection. The adopted orphan nuclear receptor Rev-erbα is a constitutive transcriptional repressor as it lacks AF2 domain and was earlier shown to be present in macrophages. In the present study, we highlight the differences in the relative subcellular localization of Rev-erbα in monocytes and macrophages. The nuclear localization of Rev-erbα in macrophages is subsequent to monocyte differentiation. Expression analysis of Rev-erbα elucidated it to be considerably more expressed in M1 phenotype in comparison with M2. Rev-erbα overexpression augments antimycobacterial properties of macrophage by keeping IL10 in a basal repressed state. Further, promoter analysis revealed that IL10 promoter harbors a Rev-erbα binding site exclusive to humans and higher order primates and not mouse, demonstrating a species barrier in its functionality. This direct gene repression is mediated by recruitment of co-repressors NCoR and HDAC3. In addition, our data elucidate that its overexpression reduced the survival of intracellular pathogen Mycobacterium tuberculosis by enhancing phagosome lysosome maturation, an event resulting from IL10 repression. Thus, these findings suggest that Rev-erbα bestows protection against mycobacterial infection by direct gene repression of IL10 and thus provide a novel target in modulating macrophage microbicidal properties.

Mycobacterium tuberculosis modulates macrophage lipid-sensing nuclear receptors PPARγ and TR4 for survival.

Mycobacterium tuberculosis-macrophage interactions are key to pathogenesis and clearance of these bacteria. Although interactions between M. tuberculosis-associated lipids and TLRs, non-TLRs, and opsonic receptors have been investigated, interactions of these lipids and infected macrophage lipid repertoire with lipid-sensing nuclear receptors expressed in macrophages have not been addressed. In this study, we report that M. tuberculosis-macrophage lipids can interact with host peroxisome proliferator-activated receptor γ and testicular receptor 4 to ensure survival of the pathogen by modulating macrophage function. These two lipid-sensing nuclear receptors create a foamy niche within macrophage by modulating oxidized low-density lipoprotein receptor CD36, phagolysosomal maturation block by induction of IL-10, and a blunted innate response by alternative polarization of the macrophages, which leads to survival of M. tuberculosis. These results also suggest possible heterologous ligands for peroxisome proliferator-activated receptor γ and testicular receptor 4 and are suggestive of adaptive or coevolution of the host and pathogen. Relative mRNA expression levels of these receptors in PBMCs derived from clinical samples convincingly implicate them in tuberculosis susceptibility. These observations expose a novel paradigm in the pathogenesis of M. tuberculosis amenable for pharmacological modulation.

Nuclear receptor Rev-erbα role in fine-tuning erythropoietin gene expression.

ABSTRACT: The regulation of red blood cell (RBC) homeostasis by erythropoietin (EPO) is critical for O2 transport and maintaining the adequate number of RBCs in vertebrates. Therefore, dysregulation in EPO synthesis results in disease conditions such as polycythemia in the case of excessive EPO production and anemia, which occurs when EPO is inadequately produced. EPO plays a crucial role in treating anemic patients; however, its overproduction can increase blood viscosity, potentially leading to fatal heart failure. Consequently, the identification of druggable transcription factors and their associated ligands capable of regulating EPO offers a promising therapeutic approach to address EPO-related disorders. This study unveils a novel regulatory mechanism involving 2 pivotal nuclear receptors (NRs), Rev-ERBA (Rev-erbα, is a truncation of reverse c-erbAa) and RAR-related orphan receptor A (RORα), in the control of EPO gene expression. Rev-erbα acts as a cell-intrinsic negative regulator, playing a vital role in maintaining erythropoiesis at the correct level. It accomplishes this by directly binding to newly identified response elements within the human and mouse EPO gene promoter, thereby repressing EPO production. These findings are further supported by the discovery that a Rev-erbα agonist (SR9011) effectively suppresses hypoxia-induced EPO expression in mice. In contrast, RORα functions as a positive regulator of EPO gene expression, also binding to the same response elements in the promoter to induce EPO production. Finally, the results of this study revealed that the 2 NRs, Rev-erbα and RORα, influence EPO synthesis in a negative and positive manner, respectively, suggesting that the modulating activity of these 2 NRs could provide a method to target disorders linked with EPO dysregulation.

Stem bromelain-induced macrophage apoptosis and activation curtail Mycobacterium tuberculosis persistence.

BACKGROUND: Mycobacterium tuberculosis, the causative agent of tuberculosis, has a remarkable ability to usurp its host's innate immune response, killing millions of infected people annually. One approach to manage infection is prevention through the use of natural agents. In this regard, stem bromelain (SBM), a pharmacologically active member of the sulfhydryl proteolytic enzyme family, obtained from Ananas comosus and possessing a remarkable ability to induce the innate and acquired immune systems, is important. METHODS: We evaluated SBM's ability to induce apoptosis and free-radical generation in macrophages. We also studied antimycobacterial properties of SBM and its effect on foamy macrophages. RESULTS: SBM treatment of peritoneal macrophages resulted in the upregulation of proapoptotic proteins and downregulation of antiapoptotic proteins. Additionally, SBM treatment activated macrophages, curtailed the levels of free glutathione, and augmented the production of hydrogen peroxide, superoxide anion, peroxynitrite, and nitric oxide. SBM cleaves CD36 and reduced the formation of foam cells, the hallmark of M. tuberculosis infection. These conditions created an environment for the increased clearance of M. tuberculosis. CONCLUSIONS: Together these data provide a mechanism for antimycobacterial activity of SBM and provide important insights for the use of cysteine proteases as immunomodulatory agents.

The Role of the NRF2 Pathway in the Pathogenesis of Viral Respiratory Infections.

In humans, acute and chronic respiratory infections caused by viruses are associated with considerable morbidity and mortality. Respiratory viruses infect airway epithelial cells and induce oxidative stress, yet the exact pathogenesis remains unclear. Oxidative stress activates the transcription factor NRF2, which plays a key role in alleviating redox-induced cellular injury. The transcriptional activation of NRF2 has been reported to affect both viral replication and associated inflammation pathways. There is complex bidirectional crosstalk between virus replication and the NRF2 pathway because virus replication directly or indirectly regulates NRF2 expression, and NRF2 activation can reversely hamper viral replication and viral spread across cells and tissues. In this review, we discuss the complex role of the NRF2 pathway in the regulation of the pathogenesis of the main respiratory viruses, including coronaviruses, influenza viruses, respiratory syncytial virus (RSV), and rhinoviruses. We also summarize the scientific evidence regarding the effects of the known NRF2 agonists that can be utilized to alter the NRF2 pathway.

Multiple epigenetic factors co-localize with HMGN proteins in A-compartment chromatin.

BACKGROUND: Nucleosomal binding proteins, HMGN, is a family of chromatin architectural proteins that are expressed in all vertebrate nuclei. Although previous studies have discovered that HMGN proteins have important roles in gene regulation and chromatin accessibility, whether and how HMGN proteins affect higher order chromatin status remains unknown. RESULTS: We examined the roles that HMGN1 and HMGN2 proteins play in higher order chromatin structures in three different cell types. We interrogated data generated in situ, using several techniques, including Hi-C, Promoter Capture Hi-C, ChIP-seq, and ChIP-MS. Our results show that HMGN proteins occupy the A compartment in the 3D nucleus space. In particular, HMGN proteins occupy genomic regions involved in cell-type-specific long-range promoter-enhancer interactions. Interestingly, depletion of HMGN proteins in the three different cell types does not cause structural changes in higher order chromatin, i.e., in topologically associated domains (TADs) and in A/B compartment scores. Using ChIP-seq combined with mass spectrometry, we discovered protein partners that are directly associated with or neighbors of HMGNs on nucleosomes. CONCLUSIONS: We determined how HMGN chromatin architectural proteins are positioned within a 3D nucleus space, including the identification of their binding partners in mononucleosomes. Our research indicates that HMGN proteins localize to active chromatin compartments but do not have major effects on 3D higher order chromatin structure and that their binding to chromatin is not dependent on specific protein partners.

Epigenetic regulation of white adipose tissue plasticity and energy metabolism by nucleosome binding HMGN proteins.

White adipose tissue browning is a key metabolic process controlled by epigenetic factors that facilitate changes in gene expression leading to altered cell identity. We find that male mice lacking the nucleosome binding proteins HMGN1 and HMGN2 (DKO mice), show decreased body weight and inguinal WAT mass, but elevated food intake, WAT browning and energy expenditure. DKO white preadipocytes show reduced chromatin accessibility and lower FRA2 and JUN binding at Pparγ and Pparα promoters. White preadipocytes and mouse embryonic fibroblasts from DKO mice show enhanced rate of differentiation into brown-like adipocytes. Differentiating DKO adipocytes show reduced H3K27ac levels at white adipocyte-specific enhancers but elevated H3K27ac levels at brown adipocyte-specific enhancers, suggesting a faster rate of change in cell identity, from white to brown-like adipocytes. Thus, HMGN proteins function as epigenetic factors that stabilize white adipocyte cell identity, thereby modulating the rate of white adipose tissue browning and affecting energy metabolism in mice.

Epigenetic Regulators of White Adipocyte Browning.

Adipocytes play an essential role in maintaining energy homeostasis in mammals. The primary function of white adipose tissue (WAT) is to store energy; for brown adipose tissue (BAT), primary function is to release fats in the form of heat. Dysfunctional or excess WAT can induce metabolic disorders such as dyslipidemia, obesity, and diabetes. Preadipocytes or adipocytes from WAT possess sufficient plasticity as they can transdifferentiate into brown-like beige adipocytes. Studies in both humans and rodents showed that brown and beige adipocytes could improve metabolic health and protect from metabolic disorders. Brown fat requires activation via exposure to cold or ß-adrenergic receptor (ß-AR) agonists to protect from hypothermia. Considering the fact that the usage of ß-AR agonists is still in question with their associated side effects, selective induction of WAT browning is therapeutically important instead of activating of BAT. Hence, a better understanding of the molecular mechanisms governing white adipocyte browning is vital. At the same time, it is also essential to understand the factors that define white adipocyte identity and inhibit white adipocyte browning. This literature review is a comprehensive and focused update on the epigenetic regulators crucial for differentiation and browning of white adipocytes.

Vitamin D3-VDR-PTPN6 axis mediated autophagy contributes to the inhibition of macrophage foam cell formation.

Macrophage derived foam cells in atherosclerotic plaques are the major factor responsible for the pathogenesis of atherosclerosis (AS). During advanced AS, macrophage-specific macroautophagy/autophagy is dysfunctional. 1, 25-dihydroxy vitamin D3 (VitD3) and its receptor VDR (vitamin D receptor) are reported to inhibit foam cell formation and induce autophagy; however, the role of VitD3-VDR-induced autophagy and foam cell formation in AS has not been explored. Here we find that VitD3 significantly recovered oxidized low-density lipoprotein-impaired autophagy, as well as increased autophagy-mediated lipid breakdown in mouse bone marrow-derived macrophages and human monocyte-derived macrophages, thus inhibiting the conversion of macrophages into foam cells. Importantly, VitD3 functions through its receptor VDR to upregulate autophagy and attenuate the accumulation of lipids in macrophages. Moreover, this study is the first occasion to report the interesting link between VitD3 signaling and PTPN6/SHP-1 (protein tyrosine phosphatase non-receptor type 6) in macrophages. VitD3-induced autophagy was abrogated in the presence of the PTPN6/Ptpn6 shRNA or inhibitor. VDR along with RXRA (retinoid X receptor alpha), and NCOA1 (nuclear receptor coactivator 1), are recruited to a specific response element located on the gene promoter and induce PTPN6 expression. PTPN6 contributes to VitD3-mediated autophagy by regulating autophagy-related genes via activation of MAPK1 (mitogen-activated protein kinase 1) and CEBPB (CCAAT enhancer binding protein beta). Furthermore, expression of PTPN6 is also crucial for VitD3-mediated inhibition of macrophage foam cell formation through autophagy. Thus, VitD3-VDR-PTPN6 axis-regulated autophagy attenuates foam cell formation in macrophages.

TGF-ß induced chemoresistance in liver cancer is modulated by xenobiotic nuclear receptor PXR.

Hepatocellular carcinoma appears as an extremely angiogenic solid tumor marked by apoptosis evasion, dysregulated cell cycle and low sensitivity to chemotherapy. TGF-ß, a multifunctional cytokine, plays a pleiotropic role in the tumor microenvironment and has implications in cancer drug resistance. The current study provides novel evidence that TGF-ß signaling contributes to drug resistance in liver cancer cells by inducing the expression of xenobiotic nuclear receptor PXR. We observed that PXR increases the expression of drug efflux transporters; therefore, accounting for exacerbated drug resistance. Additionally, anti-apoptotic nature of PXR contributes to TGF-ß mediated chemoresistance as seen by procaspase-3 and Mcl-1 cellular levels. TGF-ß binding to the TGF-ß receptor triggers a complex downstream signaling cascade through a non-canonical SMAD-independent ERK pathway that leads to increased PXR expression. Activated ERK activates ETS1 transcription factor which is a critical regulator of endogenous PXR expression in hepatic cells. Loss of function of ETS1 abrogates the TGF-ß induced PXR expression. Together these findings indicate that PXR modulates TGF-ß induced resistance to chemotherapy in liver cancer cells. This underscores the need for combinatorial approaches with focus on PXR antagonism to improve drug effectiveness in hepatocellular carcinoma.Abbreviations: HCC: Hepatocellular Carcinoma; FDA: Food and Drug Administration; TGF-ß: Transforming growth factor-ß; PXR: Pregnane X receptor; CAR: Constitutive androstane receptor; P-gp/ABCB1: P-glycoproteins/ATP-binding cassette transporter subfamily B member 1; MRP1/ABCC1 and MRP2/ABCC2: Multidrug-resistance associated proteins; BCRP/ABCG2: Breast cancer resistant protein; DMEs: Drug-metabolizing enzymes; CFDA: 5,6-carboxyfluorescein diacetate; ETS1: Transcription factor E26 transformation specific sequence 1.

An Accord of Nuclear Receptor Expression in CD4+ T Cells in Rheumatoid Arthritis.

Chronically activated CD4+ T cells drive uncontrolled inflammation, leading to tissue damage in various autoimmune disorders, such as rheumatoid arthritis (RA). Investigation of the molecular mechanisms involved in RA and recent analysis of transcriptomic profiles has implicated members of the nuclear receptor (NR) superfamily in RA. NRs are required for the development, differentiation, and effector function of CD4+ T cells; therefore, it is thought that NRs are important in shaping the CD4+ T cell repertoire and associated inflammation in RA. Despite their relevance, the full potential of the NR superfamily in RA, either as biomarkers or disease targets, has not been harnessed. To gain insight on the NR members that are closely associated with RA disease activity, we generated an expression atlas for the NR superfamily in CD4+ T cells isolated either in a steady state or over the course of collagen-induced arthritis mouse model of RA. We observed discrete expression patterns among the NR superfamily during the disease stages. NRs that instigate anti-inflammatory programs underwent major downregulation during disease onset; however, during the fully developed disease stage we noticed that NRs that induce proinflammatory programs had reduced transcript levels. These animal findings corroborated well with the expression patterns of NRs in clinical samples obtained from RA patients. Furthermore, we observed that targeting NRs using synthetic ligands alleviates the progression of collagen-induced arthritis. Overall, our data demonstrates the potential of the NR superfamily as novel therapeutic targets for the treatment of autoimmune disorders.