Shaping macrophages function and innate immunity by bile acids: Mechanisms and implication in cholestatic liver diseases

Calmus, Yvon; Poupon, Raoul

doi:10.1016/j.clinre.2014.07.007

Cited by 65 publications

(58 citation statements)

References 40 publications

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“…The other subset, M2 macrophages, which are alternatively activated by IL-4 and IL-13, release IL-4, IL-10 and IL-13, have an anti-inflammatory phenotype. However, increasing evidence shows that during liver injury, macrophages are highly plastic as “mixed” macrophage phenotypes are also observed and they can rapidly change from a pro- inflammatory to an anti-inflammatory phenotype in response to changes in the hepatic microenvironment(83, 84). The various populations of hepatic macrophages display different forms of activation and exert diverse functional properties in liver inflammation, including phagocytosis of apoptotic cells and cell debris, initiation of an immune response in other liver cells such as hepatocytes, antigen presentation and immune cell recruiting (85, 86).…”

Section: The Role Of Other Immune Cells In Cholestatic Liver Injurymentioning

confidence: 99%

Mechanisms of bile acid mediated inflammation in the liver

Cai

Boyer

2017

Molecular Aspects of Medicine

207

120

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Bile acids are synthesized in the liver and are the major component in bile. Impaired bile flow leads to cholestasis that is characterized by elevated levels of bile acid in the liver and serum, followed by hepatocyte and biliary injury. Although the causes of cholestasis have been extensively studied, the molecular mechanisms as to how bile acids initiate liver injury remain controversial. In this chapter, we summarize recent advances in the pathogenesis of bile acid induced liver injury. These include bile acid signaling pathways in hepatocytes as well as the response of cholangiocytes and innate immune cells in the liver in both patients with cholestasis and cholestatic animal models. We focus on how bile acids trigger the production of molecular mediators of neutrophil recruitment and the role of the inflammatory response in this pathological process. These advances point to a number of novel targets where drugs might be judged to be effective therapies for cholestatic liver injury.

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Section: The Role Of Other Immune Cells In Cholestatic Liver Injurymentioning

confidence: 99%

Mechanisms of bile acid mediated inflammation in the liver

Cai

Boyer

2017

Molecular Aspects of Medicine

207

120

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“…Gut microbes can also affect bile acid pool composition 151 , by conjugating and deconjugating bile acids. Thus, physiological bile acid pool compositions might have homeostatic antiinflammatory affects, altered in the setting of a dysbiotic intestine, and might exert effects that promote macrophage activation 147,152,153 (FIG. 3).…”

Section: Early Postnatal Factorsmentioning

confidence: 99%

Developmental origins of NAFLD: a womb with a clue

Wesolowski

Kasmi

Jonscher

et al. 2016

Nat Rev Gastroenterol Hepatol

180

167

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Changes in the maternal environment leading to an altered intrauterine milieu can result in subtle insults to the fetus, promoting increased lifetime disease risk and/or disease acceleration in childhood and later in life. Particularly worrisome is that the prevalence of NAFLD is rapidly increasing among children and adults, and is being diagnosed at increasingly younger ages, pointing towards an early-life origin. A wealth of evidence, in humans and non-human primates, suggests that maternal nutrition affects the placenta and fetal tissues, leading to persistent changes in hepatic metabolism, mitochondrial function, the intestinal microbiota, liver macrophage activation and susceptibility to NASH postnatally. Deleterious exposures in utero include fetal hypoxia, increased nutrient supply, inflammation and altered gut microbiota that might produce metabolic clues, including fatty acids, metabolites, endotoxins, bile acids and cytokines, which prime the infant liver for NAFLD in a persistent manner and increase susceptibility to NASH. Mechanistic links to early disease pathways might involve shifts in lipid metabolism, mitochondrial dysfunction, pioneering gut microorganisms, macrophage programming and epigenetic changes that alter the liver microenvironment, favouring liver injury. In this Review, we discuss how maternal, fetal, neonatal and infant exposures provide developmental clues and mechanisms to help explain NAFLD acceleration and increased disease prevalence. Mechanisms identified in clinical and preclinical models suggest important opportunities for prevention and intervention that could slow down the growing epidemic of NAFLD in the next generation.NAFLD is a general term used to describe a broad spectrum of liver abnormalities, ranging from simple, uncomplicated hepatic steatosis to NASH, accompanied by different degrees of Correspondence to J.E.F. jed.friedman@ucdenver.edu. Author contributionsAll authors researched data for the article, provided a substantial contribution to discussion of content, wrote the article, and reviewed and edited the manuscript before submission. Competing interests statementThe authors declare no competing interests. HHS Public AccessAuthor manuscript Nat Rev Gastroenterol Hepatol. Author manuscript; available in PMC 2017 December 12. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript inflammation and fibrosis. NAFLD is increasing in prevalence, especially in adolescents 1 , despite the levellingoff of the obesity epidemic from 2003-2004 to 2013-2014 in children and adolescents aged 2-19 years (REF.2). The most common chronic liver disease worldwide, NAFLD increases the risk of cardiovascular events eightfold and type 2 diabetes mellitus (T2DM) threefold 3 , and is a strong risk factor for hepatocellular carcinoma (HCC) 4 . At the time of paediatric NAFLD diagnosis, 25-50% of children have NASH and 10-25% have advanced fibrosis 5 . For many decades, it was thought that NAFLD was predominantly driven by obesity in the setting of genetic suscep...

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“…It should be noted that AMACR also plays a physiological role in the catabolism of cholesterol to bile acids and AMACR deficiency in mice leads to the accumulation of C27 bile acid precursors [24]. Bile acids have also been shown to alter the phenotype of human macrophages, promoting the generation of an anti-inflammatory phenotype [25]. Consequently, it is possible that some of the effects observed in our study may have been mediated by effects on macrophage regulation of T-cell responses.…”

Section: Discussionmentioning

confidence: 71%

Alpha‐methylacyl‐CoA racemase deletion has mutually counteracting effects on T‐cell responses, associated with unchanged course of EAE

et al. 2016

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Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Altering the metabolism of immune cells is an attractive strategy to modify their activity during autoimmunity in MS.We investigated the effect of modulating fatty acid metabolism in an animal model of MS, EAE. Alpha-methylacyl-CoA racemase (AMACR) converts R-configuration branched fatty acids into the S-configuration, thereby preparing them for β-oxidation. We observed a significant, disease-dependent elevation of AMACR expression in monocytes and T cells from blood, draining lymph nodes and spleen of EAE mice during the preclinical phase. In vitro analysis revealed that the proliferation of T cells was inhibited in AMACR KO mice, but T-cell polarization was switched toward a pathogenic state involving the production of more IFN-γ and IL-17, but less IL-4. These opposing effects appeared to cancel out each other in vivo, because AMACR KO EAE mice showed a marginal increase in the severity of early clinical symptoms. AMACR was not regulated in the white blood cells of MS patients. Our data show that AMACR is regulated in immune cells during EAE, but it is not a suitable target for the treatment of MS due to its opposing effects.Keywords: Alpha-methylacyl-CoA racemase (AMACR) r Cytokines r EAE r Multiple sclerosis r T cells Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMultiple sclerosis (MS) and its prototype animal model, EAE, are induced by autoimmune responses against myelin components Correspondence: Dr. Susanne Schiffmann e-mail: susanne.schiffmann@med.uni-frankfurt.de in the CNS. To initiate CNS inflammation, myelin-specific T cells must be activated in the periphery, gain access to the CNS and then be reactivated by APCs displaying self-antigens [1]. The preferential ability of myelin-specific T cells to infiltrate the CNS implies that these cells are first activated in the draining lymph nodes before entering the CNS [1]. T-cell reactivation triggers the production of soluble mediators by many cell types, which then recruit The energy demands of immune cells are met by metabolic pathways that use substrates such as glucose (glycolysis) or fatty acids (β-oxidation) to produce adenosine triphosphate (ATP) via the citric acid cycle in mitochondria [3]. Short chain fatty acids can diffuse into mitochondria, but long-chain or branched-chain fatty acids must be initially activated to their acyl-CoA esters in peroxisomes. Subsequently, the acyl-CoA esters are transferred by the carnitine shuttle into the mitochondria where they are degraded by β-oxidation to chain-shortened derivatives. The aliphatic chains of branched fatty acids have methyl side-chain substituents, so even short-chain branched fatty acids cannot be metabolized within mitochondria and instead undergo initial activation in peroxisomes. A consequence of the presence of methyl groups on the carbon chain is that many of these fatty acids contain chiral centers [4]. However, o...

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Shaping macrophages function and innate immunity by bile acids: Mechanisms and implication in cholestatic liver diseases

Cited by 65 publications

References 40 publications

Mechanisms of bile acid mediated inflammation in the liver

Mechanisms of bile acid mediated inflammation in the liver

Developmental origins of NAFLD: a womb with a clue

Alpha‐methylacyl‐CoA racemase deletion has mutually counteracting effects on T‐cell responses, associated with unchanged course of EAE

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