Liver X receptors in immune cell function in humans

2015 ◽  
Vol 43 (4) ◽  
pp. 752-757 ◽  
Author(s):  
Kirsty E. Waddington ◽  
Elizabeth C. Jury ◽  
Inés Pineda-Torra
Keyword(s):  
Lipid Metabolism ◽  
Immune Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Cholesterol Homeostasis ◽  
Liver X Receptors ◽  
Inflammatory Stimuli ◽  
X Receptors ◽  
Species Specific

The liver X receptors (LXRs), LXRα and LXRβ, are transcription factors with well-established roles in the regulation of lipid metabolism and cholesterol homeostasis. In addition, LXRs influence innate and adaptive immunity, including responses to inflammatory stimuli, proliferation and differentiation, migration, apoptosis and survival. However, the majority of work describing the role of LXRs in immune cells has been carried out in mouse models, and there are a number of known species-specific differences concerning LXR function. Here we review what is known about the role of LXRs in human immune cells, demonstrating the importance of these receptors in the integration of lipid metabolism and immune function, but also highlighting the need for a better understanding of the species, isoform, and cell-type specific effects of LXR activation.

scholarly journals Inflammation Triggers Liver X Receptor-Dependent Lipogenesis

2019 ◽  
Vol 40 (2) ◽  
Author(s):  
Sophie R. Liebergall ◽  
Jerry Angdisen ◽  
Shun Hang Chan ◽  
YingJu Chang ◽  
Timothy F. Osborne ◽  
...  
Keyword(s):  
Cell Function ◽  
Immune Cell ◽  
Acid Synthesis ◽  
Liver X Receptor ◽  
Cholesterol Homeostasis ◽  
Type I Interferons ◽  
Type I ◽  
Liver X Receptors ◽  
Inflammatory Signals ◽  
X Receptors

ABSTRACT Immune cell function can be modulated by changes in lipid metabolism. Our studies indicate that cholesterol and fatty acid synthesis increases in macrophages between 12 and 18 h after the activation of Toll-like receptors with proinflammatory stimuli and that the upregulation of lipogenesis may contribute to the resolution of inflammation. The inflammation-dependent increase in lipogenesis requires the induction of the liver X receptors, members of the nuclear receptor superfamily of transcription factors, by type I interferons in response to inflammatory signals. Instead of the well-established role for liver X receptors in stimulating cholesterol efflux, we demonstrate that liver X receptors are necessary for the proper resumption of cholesterol synthesis in response to inflammatory signals. Thus, liver X receptors function as bidirectional regulators of cholesterol homeostasis, driving efflux when cholesterol levels are high and facilitating synthesis in response to inflammatory signals. Liver X receptor activity is also required for the proper shutdown of a subset of type I interferon-stimulated genes as inflammation subsides, placing the receptors in a negative-feedback loop that may contribute to the resolution of the inflammatory response.

scholarly journals Regulation of Cholesterol Homeostasis and Lipid Metabolism in Skeletal Muscle by Liver X Receptors

2002 ◽  
Vol 277 (43) ◽  
pp. 40722-40728 ◽  
Author(s):  
George E. O. Muscat ◽  
Brandee L. Wagner ◽  
Jinzhao Hou ◽  
Rajendra K. Tangirala ◽  
Eric D. Bischoff ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Cholesterol Homeostasis ◽  
Liver X Receptors ◽  
X Receptors

Lipid metabolism as a mechanism of immunomodulation in macrophages: the role of liver X receptors

2020 ◽  
Vol 53 ◽  
pp. 18-26 ◽  
Author(s):  
Sophia Leussink ◽  
Irene Aranda-Pardos ◽  
Noelia A-Gonzalez
Keyword(s):  
Lipid Metabolism ◽  
Liver X Receptors ◽  
X Receptors

Liver X receptors and immune regulation

2010 ◽  
Vol 1 (5-6) ◽  
pp. 381-387
Author(s):  
Satoshi Nunomura ◽  
Makoto Makishima ◽  
Chisei Ra
Keyword(s):  
Lipid Metabolism ◽  
Immune Cells ◽  
Immune Regulation ◽  
Cholesterol Synthesis ◽  
Inflammatory Responses ◽  
Liver X Receptors ◽  
Immunoglobulin Production ◽  
Intracellular Cholesterol ◽  
X Receptors ◽  
Derivatives Of

AbstractRecent studies suggest that homeostasis of lipid metabolism is crucial for the function of various immune cells. Oxygenated derivatives of cholesterol (oxysterols) are well-known regulators of lipid metabolism and have diverse functions, such as inhibition of cholesterol synthesis, efflux of intracellular cholesterol, synthesis of cholesterol esters, and activation of liver X receptors (LXRs). In this review, we introduce novel roles of the oxysterol receptors LXRs in the immune system, including regulation of inflammatory responses, T cell expansion, immunoglobulin production, and antitumor responses. We also discuss lipid-mediated signaling as a potential target for treatment of immune diseases.

scholarly journals Altered Ca2+ Homeostasis in Immune Cells during Aging: Role of Ion Channels

2020 ◽  
Vol 22 (1) ◽  
pp. 110
Author(s):  
Dorina Zöphel ◽  
Chantal Hof ◽  
Annette Lis
Keyword(s):  
Immune Cells ◽  
Irreversible Process ◽  
Cell Function ◽  
Immune Cell ◽  
Compensatory Mechanisms ◽  
Cellular Environment ◽  
Age Related ◽  
Dependent Processes ◽  
Equal Density

Aging is an unstoppable process and begins shortly after birth. Each cell of the organism is affected by the irreversible process, not only with equal density but also at varying ages and with different speed. Therefore, aging can also be understood as an adaptation to a continually changing cellular environment. One of these very prominent changes in age affects Ca2+ signaling. Especially immune cells highly rely on Ca2+-dependent processes and a strictly regulated Ca2+ homeostasis. The intricate patterns of impaired immune cell function may represent a deficit or compensatory mechanisms. Besides, altered immune function through Ca2+ signaling can profoundly affect the development of age-related disease. This review attempts to summarize changes in Ca2+ signaling due to channels and receptors in T cells and beyond in the context of aging.

scholarly journals Immunotherapies and Metastatic Cancers: Understanding Utility and Predictivity of Human Immune Cell Engrafted Mice in Preclinical Drug Development

2020 ◽  
Author(s):  
Tiina E. Kähkönen ◽  
Jussi M. Halleen ◽  
Jenni Bernoulli
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Efficacy And Safety ◽  
Human Immune System ◽  
Oncology Research ◽  
Preclinical Drug Development ◽  
Metastatic Process ◽  
Human Immune ◽  
Species Specific

Metastases cause high mortality in several cancers and immunotherapies are expected to be effective in the prevention and treatment of metastatic disease. However, only a minority of patients benefit from immunotherapies. This creates a need for novel therapies that are efficacious regardless of the cancer types and metastatic environments they are growing in. Preclinical immuno-oncology models for studying metastases have long been limited to syngeneic or carcinogenesis-inducible models that have murine cancer and immune cells. However, the translational power of these models has been questioned. Interactions between tumor and immune cells are often species-specific and regulated by different cytokines in mice and humans. For increased translational power, mice engrafted with functional parts of human immune system have been developed. These humanized mice are utilized to advance understanding the role of immune cells in the metastatic process, but increasingly also to study the efficacy and safety of novel immunotherapies. From these aspects, this review will discuss the role of immune cells in the metastatic process and the utility of humanized mouse models in immuno-oncology research for metastatic cancers, covering several models from the perspective of efficacy and safety of immunotherapies.

scholarly journals STAT3, a Master Regulator of Anti-Tumor Immune Response

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1280 ◽  
Author(s):  
Rébé ◽  
Ghiringhelli
Keyword(s):  
Cancer Progression ◽  
Immune Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Cancer Growth ◽  
Signal Transducer ◽  
Immune Cell Function ◽  
Transcription 3

Immune cells in the tumor microenvironment regulate cancer growth. Thus cancer progression is dependent on the activation or repression of transcription programs involved in the proliferation/activation of lymphoid and myeloid cells. One of the main transcription factors involved in many of these pathways is the signal transducer and activator of transcription 3 (STAT3). In this review we will focus on the role of STAT3 and its regulation, e.g. by phosphorylation or acetylation in immune cells and how it might impact immune cell function and tumor progression. Moreover, we will review the ability of STAT3 to regulate checkpoint inhibitors.

scholarly journals Small molecule AZD4635 inhibitor of A2AR signaling rescues immune cell function including CD103+ dendritic cells enhancing anti-tumor immunity

2020 ◽  
Vol 8 (2) ◽  
pp. e000417 ◽  
Author(s):  
Alexandra Borodovsky ◽  
Christine M Barbon ◽  
Yanjun Wang ◽  
Minwei Ye ◽  
Laura Prickett ◽  
...  
Keyword(s):  
T Cell ◽  
Antigen Presentation ◽  
Small Molecule ◽  
Immune Cells ◽  
Antitumor Immunity ◽  
Cell Function ◽  
Immune Cell ◽  
T Cell Function ◽  
Adenosine Signaling

Accumulation of extracellular adenosine within the microenvironment is a strategy exploited by tumors to escape detection by the immune system. Adenosine signaling through the adenosine 2A receptor (A2AR) on immune cells elicits a range of immunosuppressive effects which promote tumor growth and limit the efficacy of immune checkpoint inhibitors. Preclinical data with A2AR inhibitors have demonstrated tumor regressions in mouse models by rescuing T cell function; however, the mechanism and role on other immune cells has not been fully elucidated.MethodsWe report here the development of a small molecule A2AR inhibitor including characterization of binding and inhibition of A2AR function with varying amounts of a stable version of adenosine. Functional activity was tested in both mouse and human T cells and dendritic cells (DCs) in in vitro assays to understand the intrinsic role on each cell type. The role of adenosine and A2AR inhibition was tested in DC differentiation assays as well as co-culture assays to access the cross-priming function of DCs. Syngeneic models were used to assess tumor growth alone and in combination with alphaprogrammed death-ligand 1 (αPD-L1). Immunophenotyping by flow cytometry was performed to examine global immune cell changes upon A2AR inhibition.ResultsWe provide the first report of AZD4635, a novel small molecule A2AR antagonist which inhibits downstream signaling and increases T cell function as well as a novel mechanism of enhancing antigen presentation by CD103+ DCs. The role of antigen presentation by DCs, particularly CD103+ DCs, is critical to drive antitumor immunity providing rational to combine a priming agent AZD4635 with check point blockade. We find adenosine impairs the maturation and antigen presentation function of CD103+ DCs. We show in multiple syngeneic mouse tumor models that treatment of AZD4635 alone and in combination with αPD-L1 led to decreased tumor volume correlating with enhanced CD103+ function and T cell response. We extend these studies into human DCs to show that adenosine promotes a tolerogenic phenotype that can be reversed with AZD4635 restoring antigen-specific T cell activation. Our results support the novel role of adenosine signaling as an intrinsic negative regulator of CD103+ DCs maturation and priming. We show that potent inhibition of A2AR with AZD4635 reduces tumor burden and enhances antitumor immunity. This unique mechanism of action in CD103+ DCs may contribute to clinical responses as AZD4635 is being evaluated in clinical trials with IMFINZI (durvalumab, αPD-L1) in patients with solid malignancies.ConclusionWe provide evidence implicating suppression of adaptive and innate immunity by adenosine as a mechanism for immune evasion by tumors. Inhibition of adenosine signaling through selective small molecule inhibition of A2AR using AZD4635 restores T cell function via an internal mechanism as well as tumor antigen cross-presentation by CD103+ DCs resulting in antitumor immunity.

scholarly journals Liver X receptors alpha and beta promote myelination and remyelination in the cerebellum

2015 ◽  
Vol 112 (24) ◽  
pp. 7587-7592 ◽  
Author(s):  
Delphine Meffre ◽  
Ghjuvan’Ghjacumu Shackleford ◽  
Mehdi Hichor ◽  
Victor Gorgievski ◽  
Eleni T. Tzavara ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Control ◽  
Motor Coordination ◽  
Cholesterol Homeostasis ◽  
Liver X Receptors ◽  
Protein Levels ◽  
Myelin Sheaths ◽  
X Receptors ◽  
Myelin Gene

The identification of new pathways governing myelination provides innovative avenues for remyelination. Liver X receptors (LXRs) α and β are nuclear receptors activated by oxysterols that originated from the oxidation of cholesterol. They are crucial for cholesterol homeostasis, a major lipid constituent of myelin sheaths that are formed by oligodendrocytes. However, the role of LXRs in myelin generation and maintenance is poorly understood. Here, we show that LXRs are involved in myelination and remyelination processes. LXRs and their ligands are present in oligodendrocytes. We found that mice invalidated for LXRs exhibit altered motor coordination and spatial learning, thinner myelin sheaths, and reduced myelin gene expression. Conversely, activation of LXRs by either 25-hydroxycholesterol or synthetic TO901317 stimulates myelin gene expression at the promoter, mRNA, and protein levels, directly implicating LXRα/β in the transcriptional control of myelin gene expression. Interestingly, activation of LXRs also promotes oligodendroglial cell maturation and remyelination after lysolecithin-induced demyelination of organotypic cerebellar slice cultures. Together, our findings represent a conceptual advance in the transcriptional control of myelin gene expression and strongly support a new role of LXRs as positive modulators in central (re)myelination processes.

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