CD11c+ resident macrophages drive hepatocyte death-triggered liver fibrosis in a murine model of nonalcoholic steatohepatitis

Ichii, Michiko; Suganami, Takayoshi; Kato, Hideaki; Kanai, Setsuko; Shirakawa, Ibuki; Sakai, Toshiyasu; Goto, Toshihiro; Asakawa, M; Hidaka, Isao; Sakugawa, Hiroshi; Ohnishi, Koji; Komohara, Yoshihiro; Asano, Kenichi; Sakaida, Isao; Tanaka, Masato; Ogawa, Yoshihiro

doi:10.1172/jci.insight.92902

Cited by 72 publications

(79 citation statements)

References 45 publications

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“…Moreover, in a NASH model using melanocortin-4 receptor-deficient mice fed a Western diet followed by a low-dose carbon tetrachloride injection, the depletion of CD11c þ liver macrophages-shown to develop from resident Kupffer cells and strongly associate with NASH features in this study-prevented NASH fibrosis. 102 These studies suggest that both resident Kupffer cells and bone marrow derived infiltrated macrophages are crucial in developing NASH fibrosis.…”

Section: Liver Macrophages Mediate Liver Fibrosis Progressionmentioning

confidence: 96%

Hepatic Stellate Cell–Macrophage Crosstalk in Liver Fibrosis and Carcinogenesis

2020

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Chronic liver injury due to viral hepatitis, alcohol abuse, and metabolic disorders is a worldwide health concern. Insufficient treatment of chronic liver injury leads to fibrosis, causing liver dysfunction and carcinogenesis. Most cases of hepatocellular carcinoma (HCC) develop in the fibrotic liver. Pathological features of liver fibrosis include extracellular matrix (ECM) accumulation, mesenchymal cell activation, immune deregulation, and angiogenesis, all of which contribute to the precancerous environment, supporting tumor development. Among liver cells, hepatic stellate cells (HSCs) and macrophages play critical roles in fibrosis and HCC. These two cell types interplay and remodel the ECM and immune microenvironment in the fibrotic liver. Once HCC develops, HCC-derived factors influence HSCs and macrophages to switch to protumorigenic cell populations, cancer-associated fibroblasts and tumor-associated macrophages, respectively. This review aims to summarize currently available data on the roles of HSCs and macrophages in liver fibrosis and HCC, with a focus on their interaction.

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Section: Liver Macrophages Mediate Liver Fibrosis Progressionmentioning

confidence: 96%

Hepatic Stellate Cell–Macrophage Crosstalk in Liver Fibrosis and Carcinogenesis

2020

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“…(109) In a nonalcoholic steatohepatitis (NASH) model using melanocortin-4 receptor-deficient mice fed a Western diet followed by a low-dose CCl 4 injection, it was reported that CD11c + liver macrophage depletion prevented fibrogenesis. (110) Similarly, the use of a CCR2/ CCR5 antagonist that prevents MoMF recruitment to the liver in patients with NASH and murine models shows promising results notably by preventing fibrosis. (111) Another good representation of these apparently conflicting macrophage functions is time-controlled macrophage depletion.…”

Section: Multifaceted Roles Of Macrophages During Liver Injury and Rementioning

confidence: 99%

Liver Macrophages: Old Dogmas and New Insights

2019

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Inflammation is a hallmark of virtually all liver diseases, such as liver cancer, fibrosis, nonalcoholic steatohepatitis, alcoholic liver disease, and cholangiopathies. Liver macrophages have been thoroughly studied in human disease and mouse models, unravelling that the hepatic mononuclear phagocyte system is more versatile and complex than previously believed. Liver macrophages mainly consist of liver-resident phagocytes, or Kupffer cells (KCs), and bone marrow-derived recruited monocytes. Although both cell populations in the liver demonstrate principal functions of macrophages, such as phagocytosis, danger signal recognition, cytokine release, antigen processing, and the ability to orchestrate immune responses, KCs and recruited monocytes retain characteristic ontogeny markers and remain remarkably distinct on several functional aspects. While KCs dominate the hepatic macrophage pool in homeostasis ("sentinel function"), monocyte-derived macrophages prevail in acute or chronic injury ("emergency response team"), making them an interesting target for novel therapeutic approaches in liver disease. In addition, recent data acquired by unbiased large-scale techniques, such as single-cell RNA sequencing, unraveled a previously unrecognized complexity of human and murine macrophage polarization abilities, far beyond the old dogma of inflammatory (M1) and anti-inflammatory (M2) macrophages. Despite tremendous progress, numerous challenges remain in deciphering the full spectrum of macrophage activation and its implication in either promoting liver disease progression or repairing injured liver tissue. Being aware of such heterogeneity in cell origin and function is of crucial importance when studying liver diseases, developing novel therapeutic interventions, defining macrophage-based prognostic biomarkers, or designing clinical trials. Growing knowledge in gene expression modulation and emerging technologies in drug delivery may soon allow shaping macrophage populations toward orchestrating beneficial rather than detrimental inflammatory responses. (Hepatology Communications 2019;3:730-743). T he liver is the largest solid organ and exerts vital metabolic functions. Liver diseases leading to liver cirrhosis or cancer are increasingly challenging for public health, the current trend being an augmentation of such diseases mainly caused by changes in alimentation and life habits. (1) Liver diseases are various by nature in terms of etiologies, chronicity, and chances of recovery. However, one constant feature is the presence of liver inflammation, and most remarkably, there is an apparent compulsory association of inflammation with a poor outcome for patients. (2-6) Liver macrophages are included in the mononuclear phagocyte system and are renown cornerstones in most if not all inflammation-related liver disorders due to their ability to respond to a seemingly infinite

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“…57 A recent report suggests that CD11c + resident macrophages play a key role in the progression of simple steatosis to NASH in a murine model. 60 …”

Section: Hepatocyte Lipotoxicity and Liver Inflammationmentioning

confidence: 99%

Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation

Ibrahim

Hirsova

Gores

2018

Gut

219

197

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A subset of patients with non-alcoholic fatty liver disease develop an inflammatory condition, termed nonalcoholic steatohepatitis (NASH). NASH is characterised by hepatocellular injury, innate immune cell-mediated inflammation and progressive liver fibrosis. The mechanisms whereby hepatic inflammation occurs in NASH remain incompletely understood, but appear to be linked to the proinflammatory microenvironment created by toxic lipid-induced hepatocyte injury, termed lipotoxicity. In this review, we discuss the signalling pathways induced by sublethal hepatocyte lipid overload that contribute to the pathogenesis of NASH. Furthermore, we will review the role of proinflammatory, proangiogenic and profibrotic hepatocyte-derived extracellular vesicles as disease biomarkers and pathogenic mediators during lipotoxicity. We also review the potential therapeutic strategies to block the feed-forward loop between sublethal hepatocyte injury and liver inflammation.

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CD11c+ resident macrophages drive hepatocyte death-triggered liver fibrosis in a murine model of nonalcoholic steatohepatitis

Cited by 72 publications

References 45 publications

Hepatic Stellate Cell–Macrophage Crosstalk in Liver Fibrosis and Carcinogenesis

Hepatic Stellate Cell–Macrophage Crosstalk in Liver Fibrosis and Carcinogenesis

Liver Macrophages: Old Dogmas and New Insights

Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation

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