Non-alcoholic steatohepatitis induces transient changes within the liver macrophage pool

Devisscher, Lindsey; Scott, Charlotte; Lefere, Sander; Raevens, Sarah; Bogaerts, Eliene; Paridaens, Annelies; Verhelst, Xavier; Geerts, Anja; Guilliams, Martin; Vlierberghe, Hans Van

doi:10.1016/j.cellimm.2017.10.006

Cited by 79 publications

(116 citation statements)

References 42 publications

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“…A; Supporting Fig. A‐C) . MCD diet‐fed mice had increased Ang‐2 serum levels and increased hepatic Ang‐2 mRNA expression (Fig.…”

Section: Resultsmentioning

confidence: 83%

“…However, although VEGF and multiple tyrosine kinase inhibitors can successfully counteract angiogenesis in models of chronic liver disease, their clinical use might be limited by their potentially severe side effects, especially in a setting requiring chronic administration. Moreover, vascular alterations resulting from angiogenesis and endothelial dysfunction also promote monocyte infiltration, which in turn fuels NASH progression and stimulates angiogenesis …”

mentioning

confidence: 99%

“…Moreover, vascular alterations resulting from angiogenesis and endothelial dysfunction also promote monocyte infiltration, which in turn fuels NASH progression and stimulates angiogenesis. (12)(13)(14) The angiopoietin/Tie system is a key regulator of angiogenesis and is involved in both endothelial dysfunction and immune cell infiltration. Angiopoietin-1 (Ang-1) is a constitutive activator of the endothelial Tie2 receptor and contributes to the maintenance of vascular stability and quiescence.…”

mentioning

confidence: 99%

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Angiopoietin‐2 Promotes Pathological Angiogenesis and Is a Therapeutic Target in Murine Nonalcoholic Fatty Liver Disease

et al. 2019

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Angiogenesis contributes to the development of nonalcoholic steatohepatitis (NASH) and promotes inflammation, fibrosis, and progression to hepatocellular carcinoma (HCC). Angiopoietin‐2 (Ang‐2) is a key regulator of angiogenesis. We aimed to investigate the role of Ang‐2 and its potential as a therapeutic target in NASH using human samples, in vivo mouse models, and in vitro assays. Serum Ang‐2 levels were determined in 104 obese patients undergoing bariatric surgery and concomitant liver biopsy. The effect of the Ang‐2/Tie2 receptor inhibiting peptibody L1‐10 was evaluated in the methionine‐choline deficient (MCD) and streptozotocin‐western diet nonalcoholic fatty liver disease mouse models, and in vitro on endothelial cells and bone marrow–derived macrophages. The hepatic vasculature was visualized with µCT scans and scanning electron microscopy of vascular casts. Serum Ang‐2 levels were increased in patients with histological NASH compared with patients with simple steatosis and correlated with hepatic CD34 immunoreactivity as a marker of hepatic angiogenesis. Serum and hepatic Ang‐2 levels were similarly increased in mice with steatohepatitis. Both preventive and therapeutic L1‐10 treatment reduced hepatocyte ballooning and fibrosis in MCD diet‐fed mice and was associated with reduced hepatic angiogenesis and normalization of the vascular micro‐architecture. Liver‐isolated endothelial cells and monocytes from MCD‐fed L1‐10–treated mice showed reduced expression of leukocyte adhesion and inflammatory markers, respectively, compared with cells from untreated MCD diet‐fed mice. In the streptozotocin‐western diet model, therapeutic Ang‐2 inhibition was able to reverse NASH and attenuate HCC progression. In vitro, L1‐10 treatment mitigated increased cytokine production in lipopolysaccharide‐stimulated endothelial cells but not in macrophages. Conclusion: Our findings provide evidence for Ang‐2 inhibition as a therapeutic strategy to target pathological angiogenesis in NASH.

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“…A; Supporting Fig. A‐C) . MCD diet‐fed mice had increased Ang‐2 serum levels and increased hepatic Ang‐2 mRNA expression (Fig.…”

Section: Resultsmentioning

confidence: 83%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Angiopoietin‐2 Promotes Pathological Angiogenesis and Is a Therapeutic Target in Murine Nonalcoholic Fatty Liver Disease

et al. 2019

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“…Additionally, in vivo experiments in a rodent model of biliary‐induced fibrosis established that platelet‐derived growth factor b plays a role in HSC activation . A study by Vasina and colleagues also demonstrated that PEVs were implicated in monocyte polarization and thus maturation and may therefore be implicated in the turnover of liver macrophages, particularly in the case of chronic inflammation, such as steatohepatitis, where circulating monocytes are recruited …”

Section: Chronic Liver Diseasesmentioning

confidence: 99%

“…(80) A study by Vasina and colleagues (81) also demonstrated that PEVs were implicated in monocyte polarization and thus maturation and may therefore be implicated in the turnover of liver macrophages, particularly in the case of chronic inflammation, such as steatohepatitis, where circulating monocytes are recruited. (82) The correlation between PEV counts and liver fibrosis is controversial. Some clinical studies demonstrated that PEV blood levels were higher than normal in patients with alcoholic cirrhosis or hepatitis C virus-induced cirrhosis (73) or in patients with Child-Pugh A cirrhosis.…”

Section: Liver Fibrosismentioning

confidence: 99%

Platelets and Platelet‐Derived Extracellular Vesicles in Liver Physiology and Disease

et al. 2019

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Beyond their role in hemostasis, platelets are proposed as key mediators of several physiological and pathophysiological processes of the liver, such as liver regeneration, toxic or viral acute liver injury, liver fibrosis, and carcinogenesis. The effects of platelets on the liver involve interactions with sinusoidal endothelial cells and the release of platelet‐contained molecules following platelet activation. Platelets are the major source of circulating extracellular vesicles, which are suggested to play key roles in platelet interactions with endothelial cells in several clinical disorders. In the present review, we discuss the implications of platelet‐derived extracellular vesicles in physiological and pathophysiological processes of the liver.

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Novel phenotypical and functional sub‐classification of liver macrophages highlights changes in population dynamics in experimental mouse models

Nakashima,

Kearney,

Kato

et al. 2023

Cytometry Pt A

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Liver macrophages are critical components of systemic immune system defense mechanisms. F4/80high Kupffer cells (KCs) are the predominant liver‐resident macrophages and the first immune cells to contact pathogens entering the liver. F4/80low monocyte‐derived macrophages (MoMφs) are essential macrophages that modulate liver immune functions. Here we report a novel method of identifying subpopulations of these two populations using traditional flow cytometry and examine each subpopulation for its putative roles in the pathogenesis of an experimental non‐alcoholic steatohepatitis model. Using male C57BL/6 mice, we isolated and analyzed liver non‐parenchymal cells by flow cytometry. We identified F4/80high and F4/80low macrophage populations and characterized subpopulations using uniform manifold approximation and projection. We identified three subpopulations in F4/80high macrophages: CD163(+) KCs, CD163(−) KCs, and liver capsular macrophages. CD163(+) KCs had higher phagocytic and bactericidal activities and more complex cellular structures than CD163(−) KCs. We also identified four subpopulations of F4/80low MoMφs based on Ly6C and MHC class II expression: infiltrating monocytes, pro‐inflammatory MoMφs, Ly6C(−) monocytes, and conventional dendritic cells. CCR2 knock‐out mice expressed lower levels of these monocyte‐derived cells, and the count varied by subpopulation. In high‐fat‐ and cholesterol‐diet‐fed mice, only one subpopulation, pro‐inflammatory MoMφs, significantly increased in count. This indicates that changes to this subpopulation is the first step in the progression to non‐alcoholic steatohepatitis. The community can use our novel subpopulation and gating strategy to better understand complex immunological mechanisms in various liver disorders through detailed analysis of these subpopulations.

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Non-alcoholic steatohepatitis induces transient changes within the liver macrophage pool

Cited by 79 publications

References 42 publications

Angiopoietin‐2 Promotes Pathological Angiogenesis and Is a Therapeutic Target in Murine Nonalcoholic Fatty Liver Disease

Angiopoietin‐2 Promotes Pathological Angiogenesis and Is a Therapeutic Target in Murine Nonalcoholic Fatty Liver Disease

Platelets and Platelet‐Derived Extracellular Vesicles in Liver Physiology and Disease

Novel phenotypical and functional sub‐classification of liver macrophages highlights changes in population dynamics in experimental mouse models

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