Suppression of macrophage infiltration inhibits activation of hepatic stellate cells and liver fibrogenesis in rats

Imamura, Michio; Ogawa, Tadashi; Sasaguri, Yasuyuki; Chayama, Kazuaki; Ueno, Hikaru

doi:10.1053/j.gastro.2004.10.005

Cited by 163 publications

(139 citation statements)

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“…Monocytes could be recruited from the blood during acute liver injury and proliferate extensively in the liver [19][20][21]. In order to determine whether secreted IL-1α could enhance the proliferation of CD11b + Gr1 + myeloid cells during acute liver injury, we injected the mice i.p.…”

Section: Secreted Il-1α Promotes the Proliferation Of Cd11b + Gr1 + Mmentioning

confidence: 99%

“…On the other hand, increasing evidences showed that hepatic macrophages (kupffer cells) are important players in the propagation of acute liver damage. During acute liver injury the intrahepatic macrophages massively expanded because of the influx of peripheral monocytes rather than the proliferation of the tissue-resident macrophages [19][20][21]. Most of these infiltrating monocytes may differentiate to M1 macrophages contributing to liver inflammation [21,22].…”

mentioning

confidence: 99%

“…The depletion of CD11b + Gr1 + myeloid cells dramatically aggravated the acute liver injury comparing with secreted IL-1α expression alone, suggesting that the CD11b + Gr1 + myeloid cells play a protective role during acute liver injury and may be a negative feedback induced by secreted IL-1α. Monocytes could be recruited from the blood during acute liver injury and proliferate extensively in the liver [19][20][21]. In order to determine whether secreted IL-1α could enhance the proliferation of CD11b + Gr1 + myeloid cells during acute liver injury, we injected the mice i.p.…”

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confidence: 99%

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Secreted IL‐1α promotes T‐cell activation and expansion of CD11b⁺Gr1⁺ cells in carbon tetrachloride‐induced liver injury in mice

et al. 2015

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Interleukin-1α is mainly expressed on the cell membrane, but can also be secreted during inflammation. The roles of secreted and membrane IL-1α in acute liver inflammation are still not known. Here, we examined the functions of secreted and membrane IL-1α in a mouse model of carbon tetrachloride-induced acute liver injury. We show that secreted IL-1α aggravates liver damage and membrane IL-1α slightly protects mice from liver injury. Further studies showed that secreted IL-1α promotes T-cell activation. It also increased the expansion of CD11b + Gr1 + myeloid cells, which may serve as a negative regulator of acute liver inflammation. Moreover, secreted IL-1α induced IL-6 production from hepatocytes. IL-6 neutralization reduced the proliferation of CD11b + Gr1 + myeloid cells in vivo. CCL2 and CXCL5 expression was increased by secreted IL-1α in vitro and in vivo. Antagonists of the chemokine receptors for CCL2 and CXCL5 significantly reduced the migration of CD11b + Gr1 + myeloid cells. These results demonstrate that secreted and membrane IL-1α play different roles in acute liver injury. Secreted IL-1α could promote Tcell activation and the recruitment and expansion of CD11b + Gr1 + myeloid cells through induction of CCL2, CXCL5, and IL-6. The controlled release of IL-1α could be a critical regulator during acute liver inflammation.Keywords: Acute liver injury r CD11b + Gr1 + myeloid cells r Membrane IL-1α r Secreted IL-1α r T-cell activation Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Haiyan Liu e-mail: hliu@suda.edu.cn IntroductionThe liver plays a central role in metabolic homeostasis [1]. Liver injury is mainly caused by various insults such as drug, chemical agents, viral hepatitis (hepatitis B or C viruses), alcohol, and C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 2084-2098 Molecular immunology 2085 autoimmune attack of hepatocytes [2]. Liver damage by proinflammatory cytokines induced by these causes is a relevant mechanism for liver cell death [3]. Acute liver injury remains one of the most challenging problems in liver diseases, and new therapeutic options for treatment of acute liver injury are urgently needed [4]. Carbon tetrachloride (CCl 4 ) is widely used as a chemical inducer of acute or chronic liver injury in rodents depending on the dosage and administration frequency [5]. ROS and oxidative stress are then generated and inflammatory cells are recruited, which leads to hepatocyte degeneration and necrosis [6,7]. Parenchymal cells could regenerate that involves a complex regulated response after CCl 4 -induced acute liver injury [8]. Therefore, anti-oxidative and anti-inflammatory therapies are thought to be the effective ways to prevent and attenuate CCl 4 -induced liver damage. IL-1 is a pleiotropic cytokine and affects inflammatory immune responses. The IL-1 family includes two important agonistic proteins, IL-1α and IL-1β, which play an important role in ...

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Section: Secreted Il-1α Promotes the Proliferation Of Cd11b + Gr1 + Mmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Secreted IL‐1α promotes T‐cell activation and expansion of CD11b⁺Gr1⁺ cells in carbon tetrachloride‐induced liver injury in mice

et al. 2015

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“…For example, the gene-based dominatenegative form of MCP-1 has been shown to suppress activated HSC and reduce liver fibrosis in rats. 4 In this report, we showed that DPIM treatment significantly suppressed the recruitment of macrophages and/or the proliferation of Kupffer cells into the portal areas (Figures 4a and 7c), which could be fueled by the inflammatory chemokine MCP-1 (Figures 4b and c) expressed and secreted by multiple cell types in the pathological foci. Consequently, a reduction in inflammatory response could result in an inhibition of cellular proliferation around the bile duct area (Supplementary Figure 4).…”

Section: Discussionmentioning

confidence: 55%

“…3 In contrast, suppressing macrophage infiltration resulted in an inhibition of HSC activation, as triggered by liver injury, which in turn could ultimately improve the recovery outcome. 4 Intriguingly, the inflammatory MCP-1 was found to induce the production of fibrogenic collagen in portal fibroblasts, 5 which prominently contribute to the fibrogenesis in cholestatic injuries. 6 In parallel, pathological changes in ECMs, as consequences of an alteration in the delicate balance between the matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs), also significantly contribute to fibrogenesis, and to a great extent dictate the recovery outcomes.…”

mentioning

confidence: 99%

An orally available small imidazolium salt ameliorates inflammation and fibrosis in a murine model of cholestasis

Ding

Kng

Yang

et al. 2011

Laboratory Investigation

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Hepatic fibrosis is the result of chronic liver injuries underlined by diverse etiologies. The massive accumulation of extracellular matrix (ECM) proteins during fibrogenesis leads to structural distortion and functional disruption of the liver. There is currently no effective standard treatment for liver fibrosis. We previously identified a class of imidazolium salts (IMSs) with anti-fibrotic properties in a cell-based screen. In this report, we investigated the anti-fibrotic efficacy and mechanisms of a small IMS, 1,3-diisopropylimidazolium tetrafluoroborate (DPIM), in a hepatic fibrosis model induced by bile duct ligation (BDL) in mice. The orally available DPIM was administered to BDL mice via drinking water at three concentrations (0.5, 0.75, and 1 g/l) for 4 weeks. We observed a significant reduction in inflammation and collagen deposition in the liver, which could be mediated by a reduction in the expression of monocyte chemoattractant protein-1 (MCP-1) and by an enhancement in the matrix metalloproteinase-mediated ECM remodeling. The current findings highlight the importance for simultaneously targeting multiple pathways to more effectively attenuate and resolve liver fibrosis and warrant further studies on this compound in additional models of hepatic fibrosis.

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Monocyte infiltration into obese and fibrilized tissues is regulated by PILRα

et al. 2016

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Paired immunoglobulin-like type 2 receptor α (PILRα) is an inhibitory receptor that is mainly expressed on myeloid cells, and negatively regulates neutrophil infiltration during inflammation. However, PILRα role on monocyte has not been described. Under both steady-state and inflammatory conditions, monocytes migrate into tissues and differentiate into macrophages. Macrophages in adipose and liver tissues play important roles in tissue homeostasis and pathogenesis of metabolic diseases. Here, we found that PILRα controls monocyte mobility through regulating integrin signaling and inhibiting CD99-CD99 binding. Moreover, we found that Pilra −/− mice developed obesity and hepatomegaly with fibrosis, and the numbers of macrophages in adipose and liver tissues are significantly increased in Pilra −/− mice. These data suggest that immune inhibitory receptor, PILRα, plays an important role in the prevention of obesity and liver fibrosis.

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Suppression of macrophage infiltration inhibits activation of hepatic stellate cells and liver fibrogenesis in rats

Cited by 163 publications

References 31 publications

Secreted IL‐1α promotes T‐cell activation and expansion of CD11b⁺Gr1⁺ cells in carbon tetrachloride‐induced liver injury in mice

Secreted IL‐1α promotes T‐cell activation and expansion of CD11b⁺Gr1⁺ cells in carbon tetrachloride‐induced liver injury in mice

An orally available small imidazolium salt ameliorates inflammation and fibrosis in a murine model of cholestasis

Monocyte infiltration into obese and fibrilized tissues is regulated by PILRα

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Suppression of macrophage infiltration inhibits activation of hepatic stellate cells and liver fibrogenesis in rats

Cited by 163 publications

References 31 publications

Secreted IL‐1α promotes T‐cell activation and expansion of CD11b+Gr1+ cells in carbon tetrachloride‐induced liver injury in mice

Secreted IL‐1α promotes T‐cell activation and expansion of CD11b+Gr1+ cells in carbon tetrachloride‐induced liver injury in mice

An orally available small imidazolium salt ameliorates inflammation and fibrosis in a murine model of cholestasis

Monocyte infiltration into obese and fibrilized tissues is regulated by PILRα

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Secreted IL‐1α promotes T‐cell activation and expansion of CD11b⁺Gr1⁺ cells in carbon tetrachloride‐induced liver injury in mice

Secreted IL‐1α promotes T‐cell activation and expansion of CD11b⁺Gr1⁺ cells in carbon tetrachloride‐induced liver injury in mice