Involvement of the TNF and FasL Produced by CD11b Kupffer Cells/Macrophages in CCl4-Induced Acute Hepatic Injury

Sato, Atsushi; Nakashima, Hiroyuki; Nakashima, Masahiro; Ikarashi, Masami; Nishiyama, Kiyoshi; Kinoshita, Manabu; Seki, Shu

doi:10.1371/journal.pone.0092515

Cited by 68 publications

(68 citation statements)

References 35 publications

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“…As previously reported, F4/80+CD11b+ cells produced TNF-α [26]. The mRNA expression of TNF-α in hepatic tissue was significantly higher in IDO-KO mice than WT mice 24 h after single CCl 4 administration (Fig 3).…”

Section: Resultssupporting

confidence: 81%

The Deficiency of Indoleamine 2,3-Dioxygenase Aggravates the CCl4-Induced Liver Fibrosis in Mice

et al. 2016

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In the present study, we examined the role of indoleamine 2,3-dioxygenase (IDO) in the development of CCl4-induced hepatic fibrosis. The liver fibrosis induced by repetitive administration with CCl4 was aggravated in IDO-KO mice compared to WT mice. In IDO-KO mice treated with CCl4, the number of several inflammatory cells and the expression of pro-inflammatory cytokines increased in the liver. In the results, activated hepatic stellate cells (HSCs) and fibrogenic factors on HSCs increased after repetitive CCl4 administration in IDO-KO mice compared to WT mice. Moreover, the treatment with l-tryptophan aggravated the CCl4-induced hepatic fibrosis in WT mice. Our findings demonstrated that the IDO deficiency enhanced the inflammation in the liver and aggravated liver fibrosis in repetitive CCl4-treated mice.

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Section: Resultssupporting

confidence: 81%

The Deficiency of Indoleamine 2,3-Dioxygenase Aggravates the CCl4-Induced Liver Fibrosis in Mice

et al. 2016

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“…The hepatic injury was driven by macrophage-derived TNFα and Fas-Ligand (FasL), as inhibition of TNFα and FasL dampened the hepatic injury induced by a single CCl 4 injection. Interestingly, CD1d-deficient mice lacking both type I and II NKT cells, did not show significant differences in the progression of acute liver injury compared with control mice in this study [44]. However, this study was conducted in Balb/c mice.…”

Section: Discussionmentioning

confidence: 58%

Pharmacological Inhibition of the Chemokine CXCL16 Diminishes Liver Macrophage Infiltration and Steatohepatitis in Chronic Hepatic Injury

et al. 2014

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Non-alcoholic fatty liver disease (NAFLD) is a major cause of morbidity and mortality in developed countries, resulting in steatohepatitis (NASH), fibrosis and eventually cirrhosis. Modulating inflammatory mediators such as chemokines may represent a novel therapeutic strategy for NAFLD. We recently demonstrated that the chemokine receptor CXCR6 promotes hepatic NKT cell accumulation, thereby controlling inflammation in experimental NAFLD. In this study, we first investigated human biopsies (n = 20), confirming that accumulation of inflammatory cells such as macrophages is a hallmark of progressive NAFLD. Moreover, CXCR6 gene expression correlated with the inflammatory activity (ALT levels) in human NAFLD. We then tested the hypothesis that pharmacological inhibition of CXCL16 might hold therapeutic potential in NAFLD, using mouse models of acute carbon tetrachloride (CCl4)- and chronic methionine-choline-deficient (MCD) diet-induced hepatic injury. Neutralizing CXCL16 by i.p. injection of anti-CXCL16 antibody inhibited the early intrahepatic NKT cell accumulation upon acute toxic injury in vivo. Weekly therapeutic anti-CXCL16 administrations during the last 3 weeks of 6 weeks MCD diet significantly decreased the infiltration of inflammatory macrophages into the liver and intrahepatic levels of inflammatory cytokines like TNF or MCP-1. Importantly, anti-CXCL16 treatment significantly reduced fatty liver degeneration upon MCD diet, as assessed by hepatic triglyceride levels, histological steatosis scoring and quantification of lipid droplets. Moreover, injured hepatocytes up-regulated CXCL16 expression, indicating that scavenging functions of CXCL16 might be additionally involved in the pathogenesis of NAFLD. Targeting CXCL16 might therefore represent a promising novel therapeutic approach for liver inflammation and steatohepatitis.

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“…Therefore, Fas expression by CD8 + T cells could engage FasL on tumor-associated Mϕs to induce their activation. Although Fas/FasL interactions have traditionally been considered pro-apoptotic, accumulating evidence indicates that Fas/FasL interactions induce Mϕ activation (31, 32) (33, 34) without apoptosis induction which supports this model.…”

Section: Discussionmentioning

confidence: 67%

Splenectomy Promotes Indirect Elimination of Intraocular Tumors by CD8+ T Cells That Is Associated with IFNγ- and Fas/FasL-Dependent Activation of Intratumoral Macrophages

Miller

Mandell

Beatty

et al. 2014

Cancer Immunology Research

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Ocular immune privilege (IP) limits immune surveillance of intraocular tumors as certain immunogenic tumor cell lines (P815, E.G7-OVA) that are rejected when transplanted in the skin grow progressively when placed in the anterior chamber (a.c.) of the eye. As splenectomy (SPLNX) is known to terminate ocular IP, we characterized immune mechanisms responsible for rejection of intraocular tumors in SPLNX mice as a first step toward identifying how to restore tumoricidal activity within the eye. CD8+ T cells, IFNγ, and FasL, but not perforin, or TNFα were required for elimination of intraocular E.G7-OVA tumors that culminated in destruction of the eye (ocular phthisis). IFNγ and FasL did not target tumor cells directly as the majority of SPLNX IFNγR1−/− mice and Fas defective lpr mice failed to eliminate intraocular E.G7-OVA tumors that expressed Fas and IFNγR1. Bone marrow chimeras revealed that IFNγR1 and Fas expression on immune cells was most critical for rejection and SPLNX increased the frequency of activated macrophages (Mϕ) within intraocular tumors in an IFNγ-and-Fas/FasL-dependent manner suggesting an immune cell target of IFNγ and Fas. As depletion of Mϕs limited CD8 T cell-mediated rejection of intraocular tumors in SPLNX mice, our data support a model in which IFNγ-and-Fas/FasL-dependent activation of intratumoral Mϕs by CD8+ T cells promotes severe intraocular inflammation that indirectly eliminates intraocular tumors by inducing phthisis, and suggests that immunosuppressive mechanisms which maintain ocular IP interfere with the interaction between CD8+ T cells and Mϕs to limit immunosurveillance of intraocular tumors.

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Involvement of the TNF and FasL Produced by CD11b Kupffer Cells/Macrophages in CCl4-Induced Acute Hepatic Injury

Cited by 68 publications

References 35 publications

The Deficiency of Indoleamine 2,3-Dioxygenase Aggravates the CCl4-Induced Liver Fibrosis in Mice

The Deficiency of Indoleamine 2,3-Dioxygenase Aggravates the CCl4-Induced Liver Fibrosis in Mice

Pharmacological Inhibition of the Chemokine CXCL16 Diminishes Liver Macrophage Infiltration and Steatohepatitis in Chronic Hepatic Injury

Splenectomy Promotes Indirect Elimination of Intraocular Tumors by CD8+ T Cells That Is Associated with IFNγ- and Fas/FasL-Dependent Activation of Intratumoral Macrophages

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