L-Selectin Facilitates Emigration and Extravascular Locomotion of Leukocytes During Acute Inflammatory Responses In Vivo

CXCR4 plays significant roles in immune and inflammatory responses and is important for selective recruitment of leukocytes. We previously showed that CXCR4 surface expression of human lymphocytes was affected by sulfatide, an in vivo ligand for L-selectin. Increased CXCR4 expression was shown to promote biologically relevant functions such as integrin-dependent adhesion and transmigration. Here, we show that sulfatide-induced CXCR4 up-regulation also occurs on other leukocyte subsets in humans and mice. B cells and CD4 + CD25 + T cells had the highest CXCR4 up-regulation after sulfatide stimulation. Transfection of L-selectin was sufficient for K562 cells to acquire sulfatide-induced CXCR4 up-regulation, while analysis of L-selectin knockout mice revealed that this response was critically L-selectin dependent only for CD4 + T cells, suggesting an alternative pathway in CD8 + T cells and B cells. Sulfatide triggered several intracellular signaling events in CD4 + T cells, but only tyrosine kinase activation, including members of the Src family, were essential for L-selectin to CXCR4 signaling. CXCR4 up-regulation was rapid, enhanced CXCL12-induced signaling and increased chemotaxis toward CXCL12, and therefore has potentially important roles in vivo. Thus, the response to CXCL12 depends in part on tissue expression of sulfatide and, specifically in CD4 + T cells, also depends on the surface level of L-selectin.

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“…5D). L-Sel -/-CD4 + T cells had impaired migration independently of stimulation, as reported previously [30].…”

Section: Sulfatide-induced Cxcr4 Up-regulation May Affect Migration Osupporting

confidence: 87%

Up‐regulation of leukocyte CXCR4 expression by sulfatide: An L‐selectin‐dependent pathway on CD4⁺ T cells

et al. 2007

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“…30,31 First, the kinetics of LPS-induced leukocyte recruitment within the hepatic vasculature was measured by intravital microscopy as others and we previously described. 40,42,43 Leukocyte adhesion in sinusoids and postsinusoidal venules increased by 8-and 17.5-fold, respectively, relative to untreated controls (Figs. 4a, 4b).…”

Section: Leukocyte-tumor Cell Interactions Contribute To the Increasementioning

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

201

163

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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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“…The function of the abluminal L-selectin ligand is not presently known. In recent studies, it has been proposed that L-selectin may be involved in postextravasation migration events in tissues (45,46). Further analysis of GlcNAc6ST-1 null mice will help to clarify the role of the abluminal L-selectin ligand, especially in PP.…”

Section: Altered Expression Pattern Of Meca-79 Epitope In Hev Ofmentioning

confidence: 99%

N-Acetylglucosamine 6-O-Sulfotransferase-1 Regulates Expression of L-Selectin Ligands and Lymphocyte Homing

Uchimura

Kadomatsu

El-Fasakhany

et al. 2004

Journal of Biological Chemistry

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Lymphocyte homing is initiated by the binding of Lselectin on lymphocytes to its ligands on high endothelial venules (HEV). Sialyl 6-sulfo Lewis X is a major capping group of L-selectin ligands. N-Acetylglucosamine (GlcNAc) 6-sulfation is essential for the ligand activity, and is catalyzed by GlcNAc 6-O-sulfotransferases (GlcNAc6STs) of which GlcNAc6ST-1 and GlcNAc6ST-2 are expressed in HEV. Here, we report that mice deficient in GlcNAc6ST-1 were impaired in the elaboration of sialyl 6-sulfo Lewis X in HEV and that an epitope of L-selectin ligands recognized by the MECA-79 antibody was greatly reduced or abolished in the abluminal aspect of HEV. Lymphocyte homing to peripheral lymph nodes, mesenteric lymph nodes, and Peyer's patches was significantly reduced in GlcNAc6ST-1 null mice. These results demonstrate that GlcNAc6ST-1 is involved in lymphocyte homing in vivo, and indicate that GlcNAc6ST-1 and -2 play complementary roles. The importance of GlcNAc6ST-1 is particularly highlighted by its involvement in lymphocyte homing to Peyer's patches where GlcNAc6ST-2 expression is undetectable.

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L-Selectin Facilitates Emigration and Extravascular Locomotion of Leukocytes During Acute Inflammatory Responses In Vivo

Cited by 105 publications

References 44 publications

Up‐regulation of leukocyte CXCR4 expression by sulfatide: An L‐selectin‐dependent pathway on CD4⁺ T cells

Up‐regulation of leukocyte CXCR4 expression by sulfatide: An L‐selectin‐dependent pathway on CD4⁺ T cells

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

N-Acetylglucosamine 6-O-Sulfotransferase-1 Regulates Expression of L-Selectin Ligands and Lymphocyte Homing

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L-Selectin Facilitates Emigration and Extravascular Locomotion of Leukocytes During Acute Inflammatory Responses In Vivo

Cited by 105 publications

References 44 publications

Up‐regulation of leukocyte CXCR4 expression by sulfatide: An L‐selectin‐dependent pathway on CD4+ T cells

Up‐regulation of leukocyte CXCR4 expression by sulfatide: An L‐selectin‐dependent pathway on CD4+ T cells

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

N-Acetylglucosamine 6-O-Sulfotransferase-1 Regulates Expression of L-Selectin Ligands and Lymphocyte Homing

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Up‐regulation of leukocyte CXCR4 expression by sulfatide: An L‐selectin‐dependent pathway on CD4⁺ T cells

Up‐regulation of leukocyte CXCR4 expression by sulfatide: An L‐selectin‐dependent pathway on CD4⁺ T cells