Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis

Krenkel, Oliver; Puengel, Tobias; Govaere, Olivier; Abdallah, Ali T.; Mossanen, Jana C.; Kohlhepp, Marlene; Liepelt, Anke; Lefebvre, E.; Luedde, Tom; Hellerbrand, Claus; Weiskirchen, Ralf; Longerich, Thomas; Costa, Ivan G.; Anstee, Quentin M.; Trautwein, Christian; Tacke, Frank

doi:10.1002/hep.29544

Cited by 398 publications

(360 citation statements)

References 49 publications

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“…Furthermore, CCR2 null mice are protected from NASH . More recently, the CCR2/CCR5 dual antagonist, cenicriviroc, has prevented and reversed NASH in several experimental NASH models and has shown reduction in fibrosis in NASH in the clinic . Recruited macrophages have also been reported to influence the resident Kupffer cells into inflammatory activation …”

Section: Discussionmentioning

confidence: 99%

Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis

Handa¹,

Thomas

Morgan-Stevenson³

et al. 2019

Journal of Leukocyte Biology

123

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We have previously demonstrated that iron overload in hepatic reticuloendothelial system cells (RES) is associated with severe nonalcoholic steatohepatitis (NASH) and advanced fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Recruited myeloid‐derived macrophages have gained a pivotal position as drivers of NASH progression and fibrosis. In this study, we used bone marrow‐derived macrophages (BMDM) from C57Bl6 mice as surrogates for recruited macrophages and examined the effect of iron on macrophage polarization. Treatment with iron (ferric ammonium citrate, FAC) led to increased expression levels of M1 markers: CCL2, CD14, iNOS, IL‐1β, IL‐6, and TNF‐α; it also increased protein levels of CD68, TNF‐α, IL‐1β, and IL‐6 by flow cytometry. This effect could be reversed by desferrioxamine, an iron chelator. Furthermore, iron loading of macrophages in the presence of IL‐4 led to the down‐regulation of M2 markers: arginase‐1, Mgl‐1, and M2‐specific transcriptional regulator, KLF4. Iron loading of macrophages with IL‐4 also resulted in reduced phosphorylation of STAT6, another transcriptional regulator of M2 activation. Dietary iron overload of C57Bl6 mice led to hepatic macrophage M1 activation. Iron overload also stimulated hepatic fibrogenesis. Histologic analysis revealed that iron overload resulted in steatohepatitis. Furthermore, NAFLD patients with hepatic RES iron deposition had increased hepatic gene expression levels of M1 markers, IL‐6, IL‐1β, and CD40 and reduced gene expression of an M2 marker, TGM2, relative to patients with hepatocellular iron deposition pattern. We conclude that iron disrupts the balance between M1/M2 macrophage polarization and leads to macrophage‐driven inflammation and fibrogenesis in NAFLD.

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Section: Discussionmentioning

confidence: 99%

Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis

Handa¹,

Thomas

Morgan-Stevenson³

et al. 2019

Journal of Leukocyte Biology

123

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“…The contribution of this axis to NAFLD pathogenesis is supported by the finding that NAFLD patients exhibited increased hepatic and serum CCL2 concentrations, the latter of which was associated with increased severity of hepatic inflammation [6 ▪ ]. Furthermore, in mouse models of diet-induced steatohepatitis, pharmacological inhibition of CCR2 decreased hepatic accumulation of monocytes [6 ▪ ] and monocyte-derived macrophages [7]. Lipotoxic hepatocytes have also been shown to release extracellular vesicles containing the macrophage chemokine CXCL10, in a JNK-dependent and mixed lineage kinase 3 (MLK3)-dependent manner, thereby inducing macrophage chemotaxis [8].…”

Section: Hepatic Macrophages and Kupffer Cellsmentioning

confidence: 99%

Non-parenchymal hepatic cell lipotoxicity and the coordinated progression of non-alcoholic fatty liver disease and atherosclerosis

Peters¹,

Wilson²,

Borradaile³

2018

Current Opinion in Lipidology

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Purpose of reviewNon-alcoholic fatty liver disease (NAFLD) appears to be independently associated with the development of atherosclerosis. The biological mechanisms underlying this association are complex, and likely involve liver-resident cell types other than hepatocytes. Thus, we review recent evidence that non-parenchymal hepatic cell responses to lipid excess contribute to the pathogenesis of both NAFLD and atherosclerosis.Recent findingsSignificant independent associations between NAFLD and atherosclerosis have been identified through cross-sectional studies and meta-analyses. Mechanistic studies in cell cultures and in rodent models suggest that liver-resident macrophages, activated hepatic stellate cells (HSC) and liver sinusoidal endothelial cells (LSEC) mount lipotoxic responses under NAFLD conditions which can contribute to the progression of both NAFLD and atherosclerosis.SummaryNon-parenchymal hepatic cell types exhibit some similarity in their responses to lipid excess, and in their pathogenic mechanisms, which likely contribute to the coordinated progression of NAFLD and atherosclerosis. In response to lipotoxic conditions, macrophages, Kupffer cells and HSC initiate robust inflammatory responses, whereas LSEC generate excess reactive oxygen species (ROS). The extent to which inflammatory cytokines and ROS produced by non-parenchymal cells contribute to the progression of both NAFLD and atherosclerosis warrants further investigation.

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“…Kupffer cells are the first defensive barrier in the liver and play an important role in the innate immunity of the liver via Toll-like receptor (TLR) signaling [18]. Activated Kupffer cells can participate in the pathogenesis of NAFLD through a variety of pathways [19][20][21][22]. First, activated Kupffer cells interact with other liver cells, including hepatocytes, and release various bioactive substances such as cytokines, chemoattractants, proteolytic enzymes, and reactive oxygen species (ROS) to induce biochemical attacks [5,23].…”

Section: Introductionmentioning

confidence: 99%

Cangju Qinggan Jiangzhi Decoction Reduces the Development of NonAlcoholic Steatohepatitis and Activation of Kupffer Cells

Cheng

Chen

Jian

et al. 2018

Cell Physiol Biochem

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Background/Aims: Nonalcoholic steatohepatitis (NASH) is defined as lipid accumulation with hepatic injury, inflammation and early to moderate fibrosis. Kupffer cells play a crucial role in promoting hepatic inflammation, which further facilitates the development of NASH. Here we investigated the effects of Cangju Qinggan Jiangzhi decoction (CQJD) on high fat diet (HFD) and methionine-choline deficient (MCD) induced mouse NASH pathogenesis. Methods: Mouse NASH models were developed by HFD and MCD diet. The treated mice were divided into three groups: the control group (n = 10), the low-dose CQJD treatment group (n = 10) and the high-dose CQJD treatment group (n = 10). The hepatic injury, inflammation, and apoptotic molecules were evaluated by H&E staining, immunohistochemistry and real-time PCR. Kupffer cells were isolated from control mice and CQJD-treated mice after stimulation by lipopolysaccharide (LPS) and/or palmitic acid. The level of the inflammatory cytokines TNFα, IL1β, and CCL2 was measured by ELISA. Results: The HFD-fed mice displayed significant metabolic, inflammatory, and oxidative stress-related alterations due to hepatic lipid accumulation. CQJD treatment largely normalized the hepatic injury, lowered the ALT/AST level, and reduced the severity of liver inflammation, as revealed by the decreased inflammatory cytokines levels. In vitro, CQJD blocked the activation of LPS- or palmitic acid-primed Kupffer cells in a dose-dependent manner. In the MCD diet-induced NASH mice, similar therapeutic effects of CQJD were also observed. Conclusion: CQJD ameliorates mouse nonalcoholic steatohepatitis. The reduction in liver injury and inflammation induced by CQJD is associated with reduced activation of Kupffer cells. Our results suggest that CQJD is a promising therapeutic strategy in clinical steatohepatitis.

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Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis

Abstract: Pharmacological inhibition of CCR2 monocyte recruitment efficiently ameliorates insulin resistance, hepatic inflammation, and fibrosis, corroborating the therapeutic potential of CVC in patients with NASH. (Hepatology 2018;67:1270-1283).

Cited by 398 publications

References 49 publications

Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis

Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis

Non-parenchymal hepatic cell lipotoxicity and the coordinated progression of non-alcoholic fatty liver disease and atherosclerosis

Cangju Qinggan Jiangzhi Decoction Reduces the Development of NonAlcoholic Steatohepatitis and Activation of Kupffer Cells

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