Macrophage migration inhibitory factor is required for recruitment of scar-associated macrophages during liver fibrosis

Barnes, Mark; McMullen, Megan R.; Roychowdhury, Sukla; Madhun, Nabil Z.; Niese, Kathryn A.; Olman, Mitchell A.; Stavitsky, Abram B.; Bucala, Richard; Nagy, Laura E.

doi:10.1189/jlb.3a0614-280r

Cited by 45 publications

(40 citation statements)

References 50 publications

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“…In contrast, MIF can also have protective effects at specific phases of liver disease. For example, MIF is required for the recruitment of scar-associated macrophages to the liver; these macrophages are critical for the resolution of fibrosis after an injury[28]. This recruitment likely contributes to the protective function of MIF and its receptor CD74 in response to fibrotic insults[29].…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte-derived macrophage migration inhibitory factor mediates alcohol-induced liver injury in mice and patients

Marin

Poulsen²,

Òdena

et al. 2017

Journal of Hepatology

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Background & aims Macrophage migration inhibitory factor (MIF) is a multi-potent cytokine that contributes to the inflammatory response to injury. MIF is expressed by multiple cell types; however, the cellular source and actions of MIF in alcoholic liver disease (ALD) are not well known. Here we tested the hypothesis that non-myeloid cells, specifically hepatocytes, are an important cellular source of MIF in ALD. Methods MIF expression was measured in HuH7 and differentiated THP-1 cells in response to ethanol. Ethanol-induced liver injury was assessed in C57BL/6 (WT) and Mif−/− bone marrow chimeras. MIF was measured in peripheral and suprahepatic serum, as well as visualized by immunohistochemistry in liver biopsies, from patients with alcoholic hepatitis (AH). Results HuH7 hepatocytes, but not THP-1 macrophages, released MIF in response to challenge with ethanol in culture. In chimeric mice expressing MIF in non-myeloid cells (Mif−/− →WT), chronic ethanol feeding increased ALT/AST, hepatic steatosis, and expression of cytokine/chemokine mRNA. In contrast, chimeric mice not expressing MIF in non-myeloid cells (WT→ Mif−/−) were protected from ethanol-induced liver injury. Immunohistochemical staining of liver biopsies from patients with AH revealed a predominant localization of MIF to hepatocytes. Interestingly, the concentration of MIF in suprahepatic serum, but not peripheral serum, was positively correlated with clinical indicators of disease severity and with an increased risk of mortality in patients with AH. Conclusions Taken together, these data provide evidence that hepatocyte-derived MIF is critical to the pathogenesis of ALD in mice and likely contributes to liver injury in patients with AH.

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Section: Discussionmentioning

confidence: 99%

Hepatocyte-derived macrophage migration inhibitory factor mediates alcohol-induced liver injury in mice and patients

Marin

Poulsen²,

Òdena

et al. 2017

Journal of Hepatology

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“…They are recruited by a variety of chemokines, which have salutary as well as detrimental effects. For example, macrophage inhibitor factor (MIF), a pluripotent cytokine and chemokine, recruits peripheral Ly6C+ monocytes to livers of mice during development of chronic ethanol-induced injury and carbon tetrachloride-induced fibrosis 89, 90 . MIF-mediated recruitment of monocytes contributes to inflammation and damage, but protects against fibrosis.…”

Section: Innate Immune Responses To Alcohol and Injured Hepatocytesmentioning

confidence: 99%

Linking Pathogenic Mechanisms of Alcoholic Liver Disease With Clinical Phenotypes

et al. 2016

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Alcoholic liver disease (ALD) develops in approximately 20% of alcoholics, with a higher prevalence in females. ALD progression is marked by fatty liver and hepatocyte necrosis, as well as apoptosis, inflammation, regenerating nodules, fibrosis, and cirrhosis 1. ALD develops via a complex process involving parenchymal and non-parenchymal cells, as well as recruitment of other cell types to the liver in response to damage and inflammation. Hepatocytes are damaged by ethanol, via generation of reactive oxygen species and induction of endoplasmic reticulum stress and mitochondrial dysfunction. Hepatocyte cell death via apoptosis and necrosis are markers of ethanol-induced liver injury. We review the mechanisms by which alcohol injures hepatocytes and the response of hepatic sinusoidal cells to alcohol-induced injury. We also discuss how recent insights into the pathogenesis of ALD will affect treatment and management of patients.

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“…Despite its seemingly contradictory name, MIF is required for restorative macrophage recruitment to liver and fibrosis resolution [109]. Barnes, et al .…”

Section: Introductionmentioning

confidence: 99%

“…These data parallel MIF’s role in macrophage recruitment after CCl 4 shown by Barnes, et al . [109]. Strikingly, the changes in adipose inflammation are associated with improved insulin sensitivity in obese Mif−/− mice assessed by insulin-stimulated 3H-glucose uptake into adipose tissue, ex vivo .…”

Section: Introductionmentioning

confidence: 99%

Identifying Novel Targets for Treatment of Liver Fibrosis: What Can We Learn from Injured Tissues which Heal Without a Scar?

Pritchard

McCracken²

2015

CDT

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The liver is unique in that it is able to regenerate. This regeneration occurs without formation of a scar in the case of non-iterative hepatic injury. However, when the liver is exposed to chronic liver injury, the purely regenerative process fails and excessive extracellular matrix proteins are deposited in place of normal liver parenchyma. While much has been discovered in the past three decades, insights into fibrotic mechanisms have not yet lead to effective therapies; liver transplant remains the only cure for advanced liver disease. In an effort to broaden the collection of possible therapeutic targets, this review will compare and contrast the liver wound healing response to that found in two types of wound healing: scarless wound healing of fetal skin and oral mucosa and scar-forming wound healing found in adult skin. This review will examine wound healing in the liver and the skin in relation to the role of humoral and cellular factors, as well as the extracellular matrix, in this process. While several therapeutic targets are similar between fibrotic liver and adult skin wound healing, others are unique and represent novel areas for hepatic anti-fibrotic research. In particular, investigations into the role of hyaluronan in liver fibrosis and fibrosis resolution are warranted.

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Macrophage migration inhibitory factor is required for recruitment of scar-associated macrophages during liver fibrosis

Cited by 45 publications

References 50 publications

Hepatocyte-derived macrophage migration inhibitory factor mediates alcohol-induced liver injury in mice and patients

Hepatocyte-derived macrophage migration inhibitory factor mediates alcohol-induced liver injury in mice and patients

Linking Pathogenic Mechanisms of Alcoholic Liver Disease With Clinical Phenotypes

Identifying Novel Targets for Treatment of Liver Fibrosis: What Can We Learn from Injured Tissues which Heal Without a Scar?

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