Kupffer Cells Hasten Resolution of Liver Immunopathology in Mouse Models of Viral Hepatitis

Sitia, Giovanni; Iannacone, Matteo; Aiolfi, Roberto; Isogawa, Masanori; Rooijen, Nico van; Scozzesi, Cristina; Bianchi, Marco E.; Andrian, Ulrich H. von; Chisari, Francis V.; Guidotti, Luca G.

doi:10.1371/journal.ppat.1002061

Cited by 101 publications

(88 citation statements)

References 61 publications

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“…The accumulation of virus-nonspecific CD8 + T cells in the liver of chronically infected patients has been linked to signs of active organ damage (6,18,19), and inhibiting the hepatic accumulation of virus-nonspecific CD8 + T cells and other virus-nonspecific inflammatory cells [i.e., CD4 + T cells, neutrophils, dendritic cells, monocytes, natural killer (NK) cells, NKT cells] in mouse models of acute viral hepatitis has been shown to reduce liver disease severity (5,(20)(21)(22)(23). Of note, the recruitment process of virus-nonspecific inflammatory cells into the liver of these animals is different from that of virus-specific CD8 + T cells.…”

Section: Discussionmentioning

confidence: 99%

“…chemokines and damage-associated molecular pattern molecules whose hepatic expression/release follows hepatocellular antigen recognition by the virus-specific CD8 + T cells (5,(20)(21)(22)(23), and the latter significantly depends on platelets. Indeed, using HBV transgenic mice as recipients of HBV-specific CD8 + T cells and mice acutely infected with adenovirus, we recently showed that platelets are detectable within CD8 + T cell-containing hepatic necroinflammatory foci and that their selective depletion profoundly ameliorates the severity of liver disease (7).…”

Section: Discussionmentioning

confidence: 99%

“…Total liver RNA was isolated and analyzed by real-time PCR for the expression of COX-2 and GAPDH as described (23).…”

Section: Methodsmentioning

confidence: 99%

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Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B

Sitia

Aiolfi

Lucia

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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277

283

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Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of hepatocellular carcinoma (HCC). The pathogenesis of HBV-associated HCC involves both viral and host factors. The latter include a functionally inefficient CD8 + T-cell response that fails to clear the infection from the liver but sustains a chronic necroinflammatory process that contributes to the development of HCC. According to this scenario, amelioration of immune-mediated chronic liver injury may prevent HCC. Because platelets facilitate immune-mediated liver injury by promoting the hepatic accumulation of virus-specific CD8 + T cells, we evaluated the long-term consequences of antiplatelet therapy in an HBV transgenic mouse model of chronic immune-mediated necroinflammatory liver disease that progresses to HCC. Treatment with aspirin and clopidogrel during the chronic phase of the disease diminished the number of intrahepatic HBV-specific CD8 + T cells and HBV-nonspecific inflammatory cells, the severity of liver fibrosis, and the development of HCC. Antiplatelet therapy improved overall survival without causing significant side effects. In contrast, the same antiplatelet regimen had no antitumor effect when HCC was induced nonimmunologically by chronic exposure to a hepatotoxic chemical. The unprecedented observation that antiplatelet therapy inhibits or delays immune-mediated hepatocarcinogenesis suggests that platelets may be key players in the pathogenesis of HBV-associated liver cancer and supports the notion that immune-mediated necroinflammatory reactions are an important cause of hepatocellular transformation during chronic hepatitis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B

Sitia

Aiolfi

Lucia

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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277

283

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“…In many models of liver injury, hepatic macrophages themselves are involved in the pathogenesis of the liver damage (31). In other models, macrophages play a role in preventing severe hepatic immunopathology (32) or in limiting the severity of liver immunopathology (33). These particular mechanisms do not appear to play a significant role in our HBV model, as mice lacking macrophages or CXCL13/CXCR5 did not have a significant difference in liver injury, despite developing significantly different immune responses to HBV (Figures 3, 5, and 6).…”

Section: Discussionmentioning

confidence: 99%

Age-dependent hepatic lymphoid organization directs successful immunity to hepatitis B

Publicover¹,

Gaggar²,

Nishimura³

et al. 2013

J. Clin. Invest.

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Hepatitis B virus (HBV) is a major human pathogen that causes immune-mediated hepatitis. Successful immunity to HBV is age dependent: viral clearance occurs in most adults, whereas neonates and young children usually develop chronic infection. Using a mouse model of HBV infection, we sought mechanisms underpinning the age-dependent outcome of HBV and demonstrated that hepatic macrophages facilitate lymphoid organization and immune priming within the adult liver and promote successful immunity. In contrast, lymphoid organization and immune priming was greatly diminished in the livers of young mice, and of macrophage-depleted adult mice, leading to abrogated HBV immunity. Furthermore, we found that CXCL13, which is involved in B lymphocyte trafficking and lymphoid architecture and development, is expressed in an age-dependent manner in both adult mouse and human hepatic macrophages and plays an integral role in facilitating an effective immune response against HBV. Taken together, these results identify some of the immunological mechanisms necessary for effective control of HBV.

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“…To test whether KCs were important for inducing P25 T cell activation, we injected rAAVtreated mice with clodronate liposomes before T cell transfer at an i.v. dose that depletes KCs while sparing hepatic CD11c high DCs (28). This treatment resulted in efficient specific depletion of F4/80 + cells (Fig.…”

Section: Intrahepatic P25 Activation Was Mediated By Liver Phagocyticmentioning

confidence: 92%

Intrahepatic Activation of Naive CD4+ T Cells by Liver-Resident Phagocytic Cells

Tay

Wong

Roediger

et al. 2014

The Journal of Immunology

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Naive T cell activation is normally restricted to the lymphoid organs, in part because of their limited ability to migrate into the parenchyma of peripheral tissues. The liver vasculature is unique, however, and circulating leukocytes within the hepatic sinusoids have direct access to liver-resident cells, which include an abundant population of Kupffer cells. It is well accepted that recognition of cognate Ag within the liver leads to naive CD8+ T cell activation in situ, but it is unclear whether the liver also supports naive CD4+ T cell activation. In this study, we show that naive CD4+ T cells can be activated to proliferate in the liver when cognate Ag expression is induced in hepatocytes by recombinant adeno-associated viral vectors. Ag-specific retention and activation of naive CD4+ T cells within the liver are independent of lymphoid tissues but dependent on a clodronate liposome–sensitive population of liver-resident phagocytic cells. To our knowledge, this study provides the first unequivocal evidence that naive CD4+ T cells can be activated in a nonlymphoid organ. It also gives critical insight into how CD4+ T cells specific for Ag expressed in the liver are recruited to participate in protective or pathological responses during hepatotropic infections and autoimmune liver disease.

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Kupffer Cells Hasten Resolution of Liver Immunopathology in Mouse Models of Viral Hepatitis

Cited by 101 publications

References 61 publications

Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B

Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B

Age-dependent hepatic lymphoid organization directs successful immunity to hepatitis B

Intrahepatic Activation of Naive CD4+ T Cells by Liver-Resident Phagocytic Cells

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