scholarly journals Liver X Receptors Regulate Cholesterol Metabolism and Immunity in Hepatic Nonparenchymal Cells

2019 ◽  
Vol 20 (20) ◽  
pp. 5045 ◽  
Author(s):  
Kaori Endo-Umeda ◽  
Makoto Makishima
Keyword(s):  
Kupffer Cells ◽  
Immune Cell ◽  
Cholesterol Metabolism ◽  
Dietary Cholesterol ◽  
Cell Types ◽  
Hepatic Inflammation ◽  
Cholesterol Accumulation ◽  
Transport Pathway ◽  
Nonalcoholic Fatty Liver ◽  
Nonparenchymal Cells

Excess dietary cholesterol intake and the dysregulation of cholesterol metabolism are associated with the pathogenesis and progression of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and fibrosis. Hepatic accumulation of free cholesterol induces activation of nonparenchymal cells, including Kupffer cells, macrophages, and hepatic stellate cells, which leads to persistent inflammation and fibrosis. The nuclear receptors liver X receptor α (LXRα) and LXRβ act as negative regulators of cholesterol metabolism through the induction of hepatocyte cholesterol catabolism, excretion, and the reverse cholesterol transport pathway. Additionally, LXRs exert an anti-inflammatory effect in immune cell types, such as macrophages. LXR activation suppresses acute hepatic inflammation that is mediated by Kupffer cells/macrophages. Acute liver injury, diet-induced steatohepatitis, and fibrosis are exacerbated by significant hepatic cholesterol accumulation and inflammation in LXR-deficient mice. Therefore, LXRs regulate hepatic lipid metabolism and immunity and they are potential therapeutic targets in the treatment of hepatic inflammation that is associated with cholesterol accumulation.

Implications of microRNAs in the pathogenesis of atherosclerosis and prospects for therapy

2021 ◽  
Vol 22 ◽  
Author(s):  
Armita Mahdavi Gorabi ◽  
Mohsen Ghanbari ◽  
Thozhukat Sathyapalan ◽  
Tannaz Jamialahmadi ◽  
Amirhossein Sahebkar
Keyword(s):  
Immune Cell ◽  
Cholesterol Metabolism ◽  
Current Knowledge ◽  
Inflammatory Cells ◽  
Cell Types ◽  
Fine Tuning ◽  
Lipid Uptake ◽  
Atherosclerosis Development ◽  
Signaling Receptors ◽  
Different Cell Types

MicroRNAs (miRNAs) are non-coding RNAs containing around 22 nucleotides, which are expressed in vertebrates and plants. They act as posttranscriptional gene expression regulators, fine-tuning various biological processes in different cell types. There is emerging evidence on their role in different stages of atherosclerosis. In addition to regulating the inflammatory cells involved in atherosclerosis, miRNAs play fundamental roles in the pathophysiology of atherosclerosis such as endothelial cell (EC) dysfunction, the aberrant function of the vascular smooth muscle cell (VSMC) and cholesterol metabolism. Moreover, miRNAs participate in several pathogenic pathways of atherosclerotic plaque development, including their effects on immune cell signaling receptors and lipid uptake. In this study, we review our current knowledge of the regulatory role of miRNAs in various pathogenic pathways underlying atherosclerosis development and also outline potential clinical applications of miRNAs in atherosclerosis.

scholarly journals Pathogenesis of Nonalcoholic Steatohepatitis: Interactions between Liver Parenchymal and Nonparenchymal Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Nancy Magee ◽  
An Zou ◽  
Yuxia Zhang
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Steatohepatitis ◽  
Fatty Liver Disease ◽  
Immune Cell ◽  
Health Concern ◽  
Nonalcoholic Fatty Liver ◽  
Liver Parenchymal ◽  
Nonparenchymal Cells ◽  
The Metabolic Syndrome

Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in the Western countries, affecting up to 25% of the general population and becoming a major health concern in both adults and children. NAFLD encompasses the entire spectrum of fatty liver disease in individuals without significant alcohol consumption, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is a manifestation of the metabolic syndrome and hepatic disorders with the presence of steatosis, hepatocyte injury (ballooning), inflammation, and, in some patients, progressive fibrosis leading to cirrhosis. The pathogenesis of NASH is a complex process and implicates cell interactions between liver parenchymal and nonparenchymal cells as well as crosstalk between various immune cell populations in liver. Lipotoxicity appears to be the central driver of hepatic cellular injury via oxidative stress and endoplasmic reticulum (ER) stress. This review focuses on the contributions of hepatocytes and nonparenchymal cells to NASH, assessing their potential applications to the development of novel therapeutic agents. Currently, there are limited pharmacological treatments for NASH; therefore, an increased understanding of NASH pathogenesis is pertinent to improve disease interventions in the future.

scholarly journals Immunological mechanisms and therapeutic targets of fatty liver diseases

2020 ◽  
Vol 18 (1) ◽  
pp. 73-91 ◽  
Author(s):  
Hua Wang ◽  
Wajahat Mehal ◽  
Laura E. Nagy ◽  
Yaron Rotman
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Liver Diseases ◽  
Bacterial Infections ◽  
Immune Cell ◽  
Therapeutic Targets ◽  
Cell Types ◽  
Nonalcoholic Fatty Liver ◽  
Immunological Mechanisms

AbstractAlcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the two major types of chronic liver disease worldwide. Inflammatory processes play key roles in the pathogeneses of fatty liver diseases, and continuous inflammation promotes the progression of alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH). Although both ALD and NAFLD are closely related to inflammation, their respective developmental mechanisms differ to some extent. Here, we review the roles of multiple immunological mechanisms and therapeutic targets related to the inflammation associated with fatty liver diseases and the differences in the progression of ASH and NASH. Multiple cell types in the liver, including macrophages, neutrophils, other immune cell types and hepatocytes, are involved in fatty liver disease inflammation. In addition, microRNAs (miRNAs), extracellular vesicles (EVs), and complement also contribute to the inflammatory process, as does intertissue crosstalk between the liver and the intestine, adipose tissue, and the nervous system. We point out that inflammation also plays important roles in promoting liver repair and controlling bacterial infections. Understanding the complex regulatory process of disrupted homeostasis during the development of fatty liver diseases may lead to the development of improved targeted therapeutic intervention strategies.

scholarly journals The therapeutic potential of C-C chemokine receptor antagonists in nonalcoholic steatohepatitis

2020 ◽  
Vol 1 (4) ◽  
pp. 170-183
Author(s):  
Michael Doulberis ◽  
Kasiani Papadimitriou ◽  
Apostolis Papaefthymiou ◽  
Jannis Kountouras ◽  
Stergios A. Polyzos
Keyword(s):  
Kupffer Cells ◽  
Chemokine Receptor ◽  
Nonalcoholic Steatohepatitis ◽  
Therapeutic Potential ◽  
Hepatic Inflammation ◽  
Dual Inhibitor ◽  
Nonalcoholic Fatty Liver ◽  
Pooled Prevalence ◽  
Immunodeficiency Virus ◽  
Monocytes And Macrophages

Pooled prevalence of nonalcoholic fatty liver disease (NAFLD) globally is about 25%. Nonalcoholic steatohepatitis (NASH) with advanced fibrosis has been linked with substantial morbidity and mortality, without having to-date any licensed treatment. C-C chemokine receptor (CCR) antagonists have been investigated as candidates for the treatment of NASH. Inhibition of CCR2 is expected to mitigate hepatic inflammation, through reducing the activation of Kupffer cells, as well as the infiltration of monocytes and macrophages into the liver. Inhibition of CCR5 is expected to mitigate hepatic fibrogenesis, through impairing the activation of hepatic stellate cells, as well as to mitigate hepatic inflammation, through impairing the activation of Kupffer cells and macrophages. Cenicriviroc (CVC) is the first in class, dual inhibitor of CCR2 and CCR5. After exhibiting favorable results in animal models, CVC was shown to be beneficial in NASH patients with more severe fibrosis at a phase 2b trial (CENTAUR) and is currently at a phase 3 clinical trial (AURORA). Apart from CVC, other CCR5 mono-antagonists, such as maraviroc, are under evaluation in clinical trials with human immunodeficiency virus patients with NAFLD. The aim of this review was to summarize existing evidence on CVC and other CCR antagonists in NASH patients, primarily focusing on their clinical efficacy and safety.

scholarly journals Cholesterol Metabolism: A Double-Edged Sword in Hepatocellular Carcinoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Fangli Zhou ◽  
Xiaoli Sun
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Cell Types ◽  
Normal Function ◽  
Specific Cell ◽  
Therapeutic Effects ◽  
Nonalcoholic Fatty Liver ◽  
Molecular Events ◽  
Underlying Mechanisms

Hepatocellular carcinoma (HCC) represents a leading cause of cancer-related deaths globally. The rising incidence of metabolic syndrome and its hepatic manifestation, nonalcoholic fatty liver disease (NAFLD), have emerged as the fastest-growing cause of HCC in recent years. Cholesterol, a major lipid component of the cell membrane and lipoprotein particles, is primarily produced and metabolized by the liver. Numerous studies have revealed an increased cholesterol biosynthesis and uptake, reduced cholesterol exportation and excretion in HCC, which all contribute to lipotoxicity, inflammation, and fibrosis, known HCC risk factors. In contrast, some clinical studies have shown that higher cholesterol is associated with a reduced risk of HCC. These contradictory observations imply that the relationship between cholesterol and HCC is far more complex than initially anticipated. Understanding the role of cholesterol and deciphering the underlying molecular events in HCC development is highly relevant to developing new therapies. Here, we discuss the current understanding of cholesterol metabolism in the pathogenesis of NAFLD-associated HCC, and the underlying mechanisms, including the roles of cholesterol in the disruption of normal function of specific cell types and signaling transduction. We also review the clinical progression in evaluating the association of cholesterol with HCC. The therapeutic effects of lowering cholesterol will also be summarized. We also interpret reasons for the contradictory observations from different preclinical and human studies of the roles of cholesterol in HCC, aiming to provide a critical assessment of the potential of cholesterol as a therapeutic target.

Abstract 50: Regulation of Peripheral Tissue Inflammation Links Autoimmunity and Atherosclerosis

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Kristina L Brzoza-Lewis ◽  
Manal Zabalawi ◽  
Ashley J Wilhelm ◽  
John S Owen ◽  
Brian Fulp ◽  
...  
Keyword(s):  
Aortic Root ◽  
Lipid Accumulation ◽  
Immune Cell ◽  
Subcutaneous Fat ◽  
Dietary Cholesterol ◽  
Autoimmune Disorder ◽  
Cell Infiltration ◽  
Plaque Burden ◽  
Immune Cell Infiltration ◽  
Cholesterol Accumulation

Previous publications from our laboratory show that cholesterol-fed LDLr-/-, apoA-I -/- (DKO) mice develop accelerated atherosclerosis, as well as, a severe autoimmune disorder not seen in diet-fed LDLr -/- mice (SKO). This phenotype is characterized by the expansion of cholesterol loaded T cells within lymphoid organs such as skin draining lymph nodes and spleen as well as the manifestation of aberrant T cell responses. In order to examine the link between the progression of atherosclerosis and the onset of autoimmunity we examined the type and amount of immune cell infiltration in both the aorta and the skin of DKO and SKO mice fed an atherogenic diet for 12 weeks. In a subset of mice the immunomodulator, Fingolimod (FTY720), a sphingosine analogue was administered along with the diet. After 12 weeks, plaque burden in the aortic root was measured as both neutral lipid accumulation, and as the type and number of immune cells present. As expected, diet alone increased both lipid and immune cell infiltration in the aortic root, as well as in the skin of DKO compared to SKO mice. Interestingly, FTY-diet DKO mice showed a sharp reduction in both lipid accumulation as well as CD4+ cell infiltration in the aortic root. This decrease in aortic lipid deposition in FTY-diet DKO was well below that of any of the other groups, including diet-only SKO mice, while FTY-diet SKO were not different than diet-only SKO mice. These data suggest that heightened aortic inflammation observed in response to dietary cholesterol in the absence of apoA-I, renders the DKO aorta more susceptible to the immunomodulatory effects of FTY. Quite unexpectedly, the skin of FTY-diet DKO mice continued to show massive cholesterol accumulation and inflammation with a preservation of subcutaneous fat, in light of the dramatic reduction in aortic infiltrates observed. When DKO mice lacking T and B cells (Rag1-/-, LDLr-/-, apoA-I-/-) were studied, massive skin cholesterol accumulation was still observed and TKO mouse dermis showed infiltrates largely composed of neutrophils and monocytes, suggesting that dermal cholesterol imbalance, in the absence of apoA-I, was the basis for disease initiation in the skin. Overall, these studies illustrate the vastly different roles of apoA-I and immunomodulatory drugs in skin versus aorta cholesterol balance.

scholarly journals Interleukin-17 and Th17 Lymphocytes Directly Impair Motoneuron Survival of Wildtype and FUS-ALS Mutant Human iPSCs

2021 ◽  
Vol 22 (15) ◽  
pp. 8042
Author(s):  
Mengmeng Jin ◽  
Katja Akgün ◽  
Tjalf Ziemssen ◽  
Markus Kipp ◽  
Rene Günther ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Th17 Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Positive Control ◽  
Interleukin 17 ◽  
Fused In Sarcoma ◽  
Th17 Lymphocytes ◽  
Human Ipscs ◽  
Als Patients

Amyotrophic lateral sclerosis (ALS) is a progressive disease leading to the degeneration of motor neurons (MNs). Neuroinflammation is involved in the pathogenesis of ALS; however, interactions of specific immune cell types and MNs are not well studied. We recently found a shift toward T helper (Th)1/Th17 cell-mediated, pro-inflammatory immune responses in the peripheral immune system of ALS patients, which positively correlated with disease severity and progression. Whether Th17 cells or their central mediator, Interleukin-17 (IL-17), directly affects human motor neuron survival is currently unknown. Here, we evaluated the contribution of Th17 cells and IL-17 on MN degeneration using the co-culture of iPSC-derived MNs of fused in sarcoma (FUS)-ALS patients and isogenic controls with Th17 lymphocytes derived from ALS patients, healthy controls, and multiple sclerosis (MS) patients (positive control). Only Th17 cells from MS patients induced severe MN degeneration in FUS-ALS as well as in wildtype MNs. Their main effector, IL-17A, yielded in a dose-dependent decline of the viability and neurite length of MNs. Surprisingly, IL-17F did not influence MNs. Importantly, neutralizing IL-17A and anti-IL-17 receptor A treatment reverted all effects of IL-17A. Our results offer compelling evidence that Th17 cells and IL-17A do directly contribute to MN degeneration.

scholarly journals Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Rongqun Guo ◽  
Mengdie Lü ◽  
Fujiao Cao ◽  
Guanghua Wu ◽  
Fengcai Gao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Single Cell ◽  
Myeloid Leukemia ◽  
Immune Cell ◽  
Immune Surveillance ◽  
Cell Types ◽  
Developmental Trajectory ◽  
Significant Difference ◽  
Cell Phenotypes ◽  
Acute Myeloid

Abstract Background Knowledge of immune cell phenotypes, function, and developmental trajectory in acute myeloid leukemia (AML) microenvironment is essential for understanding mechanisms of evading immune surveillance and immunotherapy response of targeting special microenvironment components. Methods Using a single-cell RNA sequencing (scRNA-seq) dataset, we analyzed the immune cell phenotypes, function, and developmental trajectory of bone marrow (BM) samples from 16 AML patients and 4 healthy donors, but not AML blasts. Results We observed a significant difference between normal and AML BM immune cells. Here, we defined the diversity of dendritic cells (DC) and macrophages in different AML patients. We also identified several unique immune cell types including T helper cell 17 (TH17)-like intermediate population, cytotoxic CD4+ T subset, T cell: erythrocyte complexes, activated regulatory T cells (Treg), and CD8+ memory-like subset. Emerging AML cells remodels the BM immune microenvironment powerfully, leads to immunosuppression by accumulating exhausted/dysfunctional immune effectors, expending immune-activated types, and promoting the formation of suppressive subsets. Conclusion Our results provide a comprehensive AML BM immune cell census, which can help to select pinpoint targeted drug and predict efficacy of immunotherapy.

scholarly journals Implications of hematopoietic stem cells heterogeneity for gene therapies

Gene Therapy ◽  
2021 ◽  
Author(s):  
Jeremy Epah ◽  
Richard Schäfer
Keyword(s):  
Immune Cell ◽  
Ex Vivo ◽  
Bone Marrow Failure ◽  
Cell Types ◽  
Blood Disorders ◽  
Hematopoietic Stem ◽  
Therapeutic Concept ◽  
Gene Therapies ◽  
Bone Marrow Failure Syndromes ◽  
Immunodeficiency Syndrome

AbstractHematopoietic stem cell transplantation (HSCT) is the therapeutic concept to cure the blood/immune system of patients suffering from malignancies, immunodeficiencies, red blood cell disorders, and inherited bone marrow failure syndromes. Yet, allogeneic HSCT bear considerable risks for the patient such as non-engraftment, or graft-versus host disease. Transplanting gene modified autologous HSCs is a promising approach not only for inherited blood/immune cell diseases, but also for the acquired immunodeficiency syndrome. However, there is emerging evidence for substantial heterogeneity of HSCs in situ as well as ex vivo that is also observed after HSCT. Thus, HSC gene modification concepts are suggested to consider that different blood disorders affect specific hematopoietic cell types. We will discuss the relevance of HSC heterogeneity for the development and manufacture of gene therapies and in exemplary diseases with a specific emphasis on the key target HSC types myeloid-biased, lymphoid-biased, and balanced HSCs.

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