Essential Role for Neutrophil Recruitment to the Liver in Concanavalin A-Induced Hepatitis

Bonder, Claudine S.; Ajuebor, Maureen N.; Zbytnuik, Lori; Kubes, Paul; Swain, Mark G.

doi:10.4049/jimmunol.172.1.45

Cited by 175 publications

(181 citation statements)

References 54 publications

(47 reference statements)

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“…Because these cells are instrumental to the liver damage caused by Con A, this effect is likely to play an important role in the protective effect we observed in response to FXR activation (6). In addition, because of the essential role OPN plays in recruiting PMN into the liver in this model, inhibition of OPN synthesis by the FXR agonist is also likely to contribute to the protective effect we measured on the number of liver-infiltrating PMN, another cell type that contributes to liver injury in this model (12,62).…”

Section: Discussionmentioning

confidence: 85%

“…However, it is intriguingly that in contrast to the cleaved form (that is mostly acting through integrin receptors), the intact isoform of OPN binds to CD44 (60). Because CD44 directly activates NKT cells with a different mechanism in comparison to conventional T cells (61,62), this interaction could further strengthen the pathogenic role of the OPN-NKT cell pathway in the model of Con A-induced liver injury.…”

Section: Discussionmentioning

confidence: 99%

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The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

Mencarelli

Renga²,

Migliorati³

et al. 2009

The Journal of Immunology

136

103

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Immune-mediated liver diseases including autoimmune and viral hepatitis are a major health problem worldwide. In this study, we report that activation of the farnesoid X receptor (FXR), a member of the ligand-activated nuclear receptor superfamily and bile sensor highly expressed in the liver, attenuates liver injury in a model of autoimmune hepatitis induced by Con A. We found that FXR gene ablation results in a time-dependent increase of liver expression (up to 20-fold in a 9-mo-old mouse) of osteopontin, a NKT cell-derived extracellular matrix protein and immunoregulatory cytokine. In comparison to wild-type, FXR−/− mice are more susceptible to Con A-induced hepatitis and react to Con A administration by an unregulated production of osteopontin. Administering wild-type mice with a synthetic FXR agonist attenuated Con A-induced liver damage and liver expression of the osteopontin gene. By in vitro studies, we found that FXR is expressed by primarily isolated NKT cells and its ablation favors ostepontin production in response to Con A. Chromatin immunoprecipitation assay and coimmunoprecipitation experiments demonstrate that the short heterodimer partner (SHP), a nuclear receptor and FXR target, was expressed by NKT cell hybridomas and increased in response to FXR activation. FXR activates SHP that interacts with and inhibits c-Jun binding to the osteopontin promoter. These data indicate that in NKT cells, FXR activation causes a SHP-mediated inhibition of osteopontin production. These data support the notion that the bile acid sensor FXR regulates the activation of liver NKT cells.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

Mencarelli

Renga²,

Migliorati³

et al. 2009

The Journal of Immunology

136

103

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“…Hepatic neutrophil infiltration was determined via esterase staining of liver sections and the number of neutrophils counted as previously described. 26 Enrichment of Splenic CD4 ؉ T Cells. Spleen cells were isolated using routine methods.…”

Section: Methodsmentioning

confidence: 99%

CD154-CD40 interactions drive hepatocyte apoptosis in murine fulminant hepatitis

Zhou¹,

Ajuebor²,

Beck³

et al. 2005

Hepatology

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The CD154 -CD40 interaction is a critical costimulatory pathway modulating the cellular immune response. Moreover, fulminant hepatitis of various etiologies is characterized by a hepatic influx of CD154-expressing T cells and an upregulation of CD40 expression on Kupffer cells and hepatocytes, implicating this pathway in the pathogenesis of fulminant hepatitis. In this study, we used a murine model of fulminant hepatitis induced by concanavalin A (con A) and documented a significant influx of CD154-expressing T cells into the livers of mice treated with con A, in association with markedly increased expression of CD40 restricted mainly to hepatocytes in damaged areas of the liver. Furthermore, con A hepatitis in CD154-deficient mice was significantly attenuated compared with that in wildtype controls and was associated with a decrease in hepatic tumor necrosis factor ␣ (TNF-␣) levels and hepatocyte death.

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“…36,44 Previous experiments using rat IgG2b isotype control for RB6-8C5 have shown that neutrophil numbers and function remain unchanged. 37,44 In mice thus treated, leukocyte adhesion in the livers of inflamed mice was abolished (Figs. 4a, 4b).…”

Section: Leukocyte-tumor Cell Interactions Contribute To the Increasementioning

confidence: 99%

“…Some animals received 300 lg of RB6-8C5 (anti-Gr1 Ab; Cedarlane, Hornby, Ontario) ip 24 hr before LPS administration, a procedure previously shown to deplete over 97% of circulation neutrophils without affecting other cells in the circulation. 36,37 Immunohistochemistry…”

Section: Induction Of Systemic Inflammationmentioning

confidence: 99%

Systemic inflammation increases cancer cell adhesion to hepatic sinusoids by neutrophil mediated mechanisms

McDonald

Spicer

Giannais

et al. 2009

Intl Journal of Cancer

197

161

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Interactions between endothelial selectins and selectin ligands expressed on tumor cells have been implicated in the binding of circulating metastatic cancer cells to the vascular endothelium during extravasation. Moreover, there is mounting evidence that inflammatory environments can accelerate the progression of metastasis by neutrophil mediated mechanisms. In this study, a physiologically relevant in vivo model of early metastasis coupled with intravital microscopy was used to visualize the trafficking of tumor cells within the liver vasculature in real time. Using GFPlabeled Lewis lung carcinoma subline H-59 cells, we show here that disrupting the interactions between endothelial selectins and tumor cell selectin ligands diminished tumor cell recruitment to the liver. Furthermore, systemic inflammation induced by intravenous injection of lipopolysaccharide significantly enhanced the metastatic potential of these lung carcinoma cells by increasing their propensity to adhere to the liver sinusoidal endothelium. Confocal microscopy revealed frequent colocalization of cancer cells with neutrophils and neutrophil depletion in vivo significantly attenuated the lipopolysaccharide-induced increase in H-59 cell adhesion. Although direct selectin-selectin ligand interactions contributed significantly to tumor cell adhesion to sinusoidal endothelial cells, we show here that in addition, interactions between adherent neutrophils within the inflamed sinusoids and circulating tumor cells may further increase tumor cell arrest in the liver. ' 2009 UICC Key words: cancer; metastasis; lung; rodent; adhesion molecules; e-selectin; neutrophil; sialyl Lewis X Lung cancer is the leading cause of cancer-related deaths worldwide. 1 A high proportion of patients harbor metastasis to regional lymph nodes upon presentation, and over half of all patients who undergo curative intent surgical resection of the lung will develop metastatic recurrence. 2 The liver is a common site of metastasis for lung cancer, with autopsy studies showing hepatic metastases in over 50% of lung cancer patients. 3 The hematogenous dissemination of cancer cells from a primary tumor to distant organs involves a cascade of sequential steps (reviewed in Refs. 4,5). The adhesion of circulating tumor cells to the vascular endothelium of distant organs is a key step in the metastatic cascade that may determine the organ tropism and extent of metastasis. Interactions between endothelial selectins and tumor cell selectin ligands have been implicated in the metastatic process. [5][6][7][8] Selectins are a family of transmembrane glycoproteins possessing an extracellular lectin domain that binds to carbohydrate moieties present on their ligands. 9 The three known selectins that function as cell adhesion molecules are expressed on the surface of endothelial cells (E-selectin and P-selectin), platelets (P-selectin) and leukocytes (L-selectin). E-selectin has been shown to contribute to the metastatic spread of multiple cancers, including lung and colon carcinoma, and m...

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Essential Role for Neutrophil Recruitment to the Liver in Concanavalin A-Induced Hepatitis

Cited by 175 publications

References 54 publications

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

CD154-CD40 interactions drive hepatocyte apoptosis in murine fulminant hepatitis

Systemic inflammation increases cancer cell adhesion to hepatic sinusoids by neutrophil mediated mechanisms

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