Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury

Baeck, Christer; Wehr, Alexander; Karlmark, Karlin Raja; Heymann, Felix; Vucur, Mihael; Gaßler, Nikolaus; Huss, Sebastian; Klussmann, Sven; Eulberg, Dirk; Luedde, Tom; Trautwein, Christian; Tacke, Frank

doi:10.1136/gutjnl-2011-300304

Cited by 513 publications

(519 citation statements)

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“…Increased chemotactic cytokines, such as MCP-1, at later time points for some treatment groups suggest an adaptive shift in response to persistent tissue stress/injury that results in recruitment of inflammatory cells to the site of damage (Baeck et al, 2012). Observed differences in the cytokine profiles in TGF-b1-versus compound-treated tissues is likely due to mechanistic differences between the TGF-b1 response (little to no hepatocellular injury) and compound-induced responses to hepatocellular injury and/or the transient nature of cytokine profiles.…”

Section: Discussionmentioning

confidence: 99%

“…Fmsrelated tyrosine kinase-1 (Flt-1), involved in cell proliferation, differentiation, and monocyte activation/recruitment (Motomura et al, 2005), is statistically increased at Tx7 for 25 mM TAA-treated tissues and then returns to vehicle-treated levels by Tx14. Monocyte chemotactic protein-1 (MCP-1), involved in facilitating macrophage/monocyte infiltration to perpetuate an adaptive response to continued insult (Baeck et al, 2012), increases at Tx7 for 1.0 mM MTX and 5.0 mM TAA treatment and continues to increase by Tx14 with the exception of 25 mM TAA. Interestingly, the abundance of eotaxin, a mediator of inflammatory cell infiltration and recruitment, was significantly increased in the culture medium of tissues treated with 10 ng/mL TGF-b1 suggesting a possible direct-acting stimulation of eotaxin expression in the absence of overt hepatocellular injury (Matsukura et al, 2010).…”

Section: Cytokine Profiles Are Indicative Of a Fibrogenic Statementioning

confidence: 99%

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Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

et al. 2016

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Compound-induced liver injury leading to fibrosis remains a challenge for the development of an Adverse Outcome Pathway useful for human risk assessment. Latency to detection and lack of early, systematically detectable biomarkers make it difficult to characterize the dynamic and complex intercellular interactions that occur during progressive liver injury. Here, we demonstrate the utility of bioprinted tissue constructs comprising primary hepatocytes, hepatic stellate cells, and endothelial cells to model methotrexate-and thioacetamide-induced liver injury leading to fibrosis. Repeated, low-concentration exposure to these compounds enabled the detection and differentiation of multiple modes of liver injury, including hepatocellular damage, and progressive fibrogenesis characterized by the deposition and accumulation of fibrillar collagens in patterns analogous to those described in clinical samples obtained from patients with fibrotic liver injury. Transient cytokine production and upregulation of fibrosis-associated genes ACTA2 and COL1A1 mimics hallmark features of a classic wound-healing response. A surge in proinflammatory cytokines (eg, IL-8, IL-1b) during the early culture time period is followed by concentration-and treatment-dependent alterations in immunomodulatory and chemotactic cytokines such as IL-13, IL-6, and MCP-1. These combined data provide strong proof-of-concept that 3D bioprinted liver tissues can recapitulate drug-, chemical-, and TGF-b1-induced fibrogenesis at the cellular, molecular, and histological levels and underscore the value of the model for further exploration of compound-specific fibrogenic responses. This novel system will enable a more comprehensive characterization of key attributes unique to fibrogenic agents during the onset and progression of liver injury as well as mechanistic insights, thus improving compound risk assessment.Key words: liver fibrosis in vitro; 3D bioprinted liver; compound-induced liver injury.Chronic liver injury progressing to fibrosis and liver failure can result from a wide range of insults including drug or chemical exposure, metabolic disease, alcoholism, or viral infection, and is a major health burden worldwide with 2% of all deaths attributable to liver cirrhosis Murray et al., 2012). Whereas the major precipitating factors underlying drug-and chemicalinduced fibrosis have been gleaned from animal models, the key initiating and series of adaptive events that perpetuate this response, especially in humans, are still not well understood. Regardless of etiology, progressive fibrotic liver injury is

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Section: Discussionmentioning

confidence: 99%

Section: Cytokine Profiles Are Indicative Of a Fibrogenic Statementioning

confidence: 99%

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

et al. 2016

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“…and were sacrificed at indicated time points. For induction of liver fibrosis, CCl 4 was injected twice per week for 6 wk, and mice were sacrificed 48 h after the last injection (8). The control population of animals received the same volume of tracer (corn oil) i.p.…”

Section: Mouse Models and Phenotyping Analysesmentioning

confidence: 99%

“…no. 390439; MP Biomedicals, Solon, OH) (8). Biochemical assays and gene and protein expression studies were performed as described previously (8,24,25).…”

Section: Mouse Models and Phenotyping Analysesmentioning

confidence: 99%

“…On a cellular level, the activation of liver-resident macrophages, traditionally called "Kupffer cells," and the vast infiltration of monocytes into the injured liver have been identified as major pathogenic factors (4). Because this pool of hepatic macrophages releases essential proinflammatory cytokines (e.g., TNF), they promote hepatocellular stress responses and lipid accumulation (5)(6)(7)(8). In addition, CD8 T cells endorse liver fibrosis via activating hepatic stellate cells (HSC) (9), whereas NK cells are capable of promoting HSC apoptosis and are thus considered antifibrotic (10,11).…”

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Chemokine Receptor CXCR6-Dependent Hepatic NK T Cell Accumulation Promotes Inflammation and Liver Fibrosis

Wehr

Baeck

Heymann

et al. 2013

The Journal of Immunology

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Chronic liver injury characteristically results in hepatic inflammation, which represents a prerequisite for organ fibrosis. Although NKT cells are abundantly present in liver and involved in hepatic inflammation, molecular mechanisms of their recruitment in liver fibrosis remained elusive. We hypothesized that chemokine receptor CXCR6 and its ligand CXCL16 control NKT cell migration and functionality in liver fibrosis. In patients with chronic liver diseases (n = 58), CXCR6 and CXCL16 expression was intrahepatically upregulated compared with controls. In murine liver, Cxcl16 was strongly expressed by endothelium and macrophages, whereas lymphocyte populations (NKT, NK, CD4 T, CD8 T cells) expressed CXCR6. Intravital two-photon microscopy imaging of Cxcr6+/gfp and Cxcr6gfp/gfp mice and chemotaxis studies in vitro revealed that CXCR6 specifically controls hepatic NKT cell accumulation during the early response upon experimental liver damage. Hepatic invariant NKT cells expressed distinct proinflammatory cytokines including IFN-γ and IL-4 upon injury. CXCR6-deficient mice were protected from liver fibrosis progression in two independent experimental models. Macrophage infiltration and protein levels of inflammatory cytokines IFN-γ, TNF-α, and IL-4 were also reduced in fibrotic livers of Cxcr6−/− mice, corroborating that hepatic NKT cells provide essential cytokine signals perpetuating hepatic inflammation and fibrogenesis. Adoptive transfer of NKT cells, but not CD4 T cells, isolated from wild type livers restored hepatic fibrosis in Cxcr6−/− mice upon experimental steatohepatitis. Our results demonstrate that hepatic NKT cells accumulate CXCR6-dependent early upon injury, thereby accentuating the inflammatory response in the liver and promoting hepatic fibrogenesis. Interfering with CXCR6/CXCL16 might therefore bear therapeutic potential in liver fibrosis.

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Therapeutic Approaches for Nonalcoholic Steatohepatitis (NASH)

Glatthar

Arch

2021

Burger's Medicinal Chemistry and Drug Discovery

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Nonalcoholic fatty liver disease (NAFLD), the most prevalent liver disease worldwide, is the hepatic manifestation of metabolic syndrome, which often also includes obesity, type 2 diabetes, and dyslipidemia. While NAFLD was thought to be nonprogressive, it has been shown in several studies that 12–40% of NAFLD patients develop its progressive form nonalcoholic steatohepatitis (NASH), which is characterized by inflammatory changes that can lead to progressive liver damage, fibrosis, cirrhosis, and hepatocellular carcinoma. There are presently no approved pharmacological agents for the treatment of NAFLD and NASH, but numerous agents are currently being investigated in clinical trials. These innovative therapies include three main approaches: inhibiting or reducing hepatic fat accumulation; ameliorating oxidative stress, inflammation, and apoptosis; and improving hepatic fibrosis by inhibition of fibrogenesis or promoting fibrolysis. This article provides a brief introduction to the underlying disease features and describes the medicinal chemistry and current status of the main low‐molecular‐weight pharmacological agents currently in development for NASH.

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Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury

Cited by 513 publications

References 37 publications

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

Chemokine Receptor CXCR6-Dependent Hepatic NK T Cell Accumulation Promotes Inflammation and Liver Fibrosis

Therapeutic Approaches for Nonalcoholic Steatohepatitis (NASH)

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