L-selectin-deficient mice have impaired leukocyte recruitment into inflammatory sites.

Tedder, Thomas F.; Steeber, Douglas A.; Pizcueta, P.

doi:10.1084/jem.181.6.2259

Cited by 419 publications

(270 citation statements)

References 28 publications

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“…Moreover, PS exposure is associated with increased cellular adhesion to endothelia and might promote the extravasation of T cells. CD62L is the major homing receptor for lymph nodes, and cells lacking CD62L show impaired migration to peripheral lymph nodes (63)(64)(65). Metalloprotease-mediated shedding of CD62L is triggered also upon activation of T cells by engagement of the TCR or by mitogenic stimulation (66,67).…”

Section: Discussionmentioning

confidence: 99%

NAD+ and ATP Released from Injured Cells Induce P2X7-Dependent Shedding of CD62L and Externalization of Phosphatidylserine by Murine T Cells

Scheuplein

Schwarz²,

Adriouch

et al. 2009

The Journal of Immunology

114

136

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Extracellular NAD+ and ATP trigger the shedding of CD62L and the externalization of phosphatidylserine on murine T cells. These events depend on the P2X7 ion channel. Although ATP acts as a soluble ligand to activate P2X7, gating of P2X7 by NAD+ requires ecto-ADP-ribosyltransferase ART2.2-catalyzed transfer of the ADP-ribose moiety from NAD+ onto Arg125 of P2X7. Steady-state concentrations of NAD+ and ATP in extracellular compartments are highly regulated and usually are well below the threshold required for activating P2X7. The goal of this study was to identify possible endogenous sources of these nucleotides. We show that lysis of erythrocytes releases sufficient levels of NAD+ and ATP to induce activation of P2X7. Dilution of erythrocyte lysates or incubation of lysates at 37°C revealed that signaling by ATP fades more rapidly than that by NAD+. We further show that the routine preparation of primary lymph node and spleen cells induces the release of NAD+ in sufficient concentrations for ART2.2 to ADP-ribosylate P2X7, even at 4°C. Gating of P2X7 occurs when T cells are returned to 37°C, rapidly inducing CD62L-shedding and PS-externalization by a substantial fraction of the cells. The “spontaneous” activation of P2X7 during preparation of primary T cells could be prevented by i.v. injection of either the surrogate ART substrate etheno-NAD or ART2.2-inhibitory single domain Abs 10 min before sacrificing mice.

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Section: Discussionmentioning

confidence: 99%

NAD+ and ATP Released from Injured Cells Induce P2X7-Dependent Shedding of CD62L and Externalization of Phosphatidylserine by Murine T Cells

Scheuplein

Schwarz²,

Adriouch

et al. 2009

The Journal of Immunology

114

136

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“…Since the FucTVII Ϫ/Ϫ mice lack functional E-, P-, and L-selectin ligands, this difference points toward a role of L-selectin ligands, especially in lymphocyte extravasation into the skin. The importance of Lselectin in mediating leukocyte migration into the skin has been demonstrated using models of contact hypersensitivity and allogeneic skin transplantation (39,40). The specificity of the defect for skin homing could be explained by the recent finding, that the CLA displayed on PSGL-1 on leukocytes is a predominant L-selectin ligand (41).…”

Section: Discussionmentioning

confidence: 99%

Fucosyltransferase VII-Deficient Mice with Defective E-, P-, and L-Selectin Ligands Show Impaired CD4+ and CD8+ T Cell Migration into the Skin, but Normal Extravasation into Visceral Organs

Erdmann¹,

Scheidegger²,

Koch³

et al. 2002

The Journal of Immunology

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The first step of leukocyte extravasation, leukocyte rolling, is mediated by E-, P-, and L-selectins. Mice deficient for α-1,3-fucosyltransferase VII (FucTVII)−/− are characterized by deficiency of E-, P-, and L-selectin ligand activity. This model system was used to evaluate the role of the interactions of selectins with their ligands in T and B cell responses. In the present study, FucTVII−/− mice showed reduced CD4+ T cell-mediated contact hypersensitivity reactions of the ears to FITC as well as reduced CD8+ T cell-mediated delayed-type hypersensitivity reactions of the footpads against lymphocytic choriomeningitis virus infection. As Langerhans cell migration to local lymph nodes as well as CD4+ and CD8+ T cell induction were found to be normal, the afferent arm of these reactions was not impaired. The reduced inflammatory reactions of the skin were due to inefficient lymphocyte extravasation into the skin. In contrast, extravasation of CD4+ and CD8+ T cells into visceral organs, such as the ovaries or the brain, was not impaired in FucTVII−/− mice. Elimination of vaccinia virus and of lymphocytic choriomeningitis virus from ovaries and brain, as well as elimination of tumor cells from several visceral organs was normal. Thus, interactions of selectins with their ligands are important for lymphocyte homing into the skin, but not for lymphocyte extravasation into visceral organs.

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“…Murine CD62L, CD128a/ CXCR1, and CD128b/CXCR2 are also susceptible to proteolytic removal by bromelain. Mice deficient in CD62L/L-selection molecules that mediate leukocyte rolling have markedly impaired migration into the inflamed peritoneal cavity (28). Removal of CD128a/CXCR1, and CD128b/CXCR2 molecules might also be predicted to decrease leukocyte migration, by preventing IL-8-induced changes in integrin affinity that allow firm adhesion.…”

Section: Bromelain Treatment Primarily Affects Firm Adhesion Of Leukomentioning

confidence: 99%

Bromelain treatment decreases neutrophil migration to sites of inflammation

Fitzhugh

Shan

Dewhirst

et al. 2008

Clinical Immunology

114

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Bromelain, a mixture of proteases derived from pineapple stem, has been reported to have therapeutic benefits in a variety of inflammatory diseases, including murine inflammatory bowel disease. The purpose of this work was to understand potential mechanisms for this anti-inflammatory activity. Exposure to bromelain in vitro has been shown to remove a number of cell surface molecules that are vital to leukocyte trafficking, including CD128a/CXCR1 and CD128b/CXCR2 that serve as receptors for the neutrophil chemoattractant IL-8 and its murine homologues. We hypothesized that specific proteolytic removal of CD128 molecules by bromelain would inhibit neutrophil migration to IL-8 and thus decrease acute responses to inflammatory stimuli. Using an in vitro chemotaxis assay, we demonstrated a 40% reduction in migration of bromelain-vs. sham-treated human neutrophils in response to rhIL-8. Migration to the bacterial peptide analog fMLP was unaffected, indicating that bromelain does not induce a global defect in leukocyte migration. In vivo bromelain treatment generated a 50 -85% reduction in neutrophil migration in 3 different murine models of leukocyte migration into the inflamed peritoneal cavity. Intravital microscopy demonstrated that although in vivo bromelain treatment transiently decreased leukocyte rolling, its primary long-term effect was abrogation of firm adhesion of leukocytes to blood vessels at the site of inflammation. These changes in adhesion were correlated with rapid re-expression of the bromelain-sensitive CD62L/L-selectin molecules that mediate rolling following in vivo bromelain treatment and minimal re-expression of CD128 over the time period studied. Taken together, these studies demonstrate that bromelain can effectively decrease neutrophil migration to sites of acute inflammation and support the specific removal of the CD128 chemokine receptor as a potential mechanism of action.

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L-selectin-deficient mice have impaired leukocyte recruitment into inflammatory sites.

Cited by 419 publications

References 28 publications

NAD+ and ATP Released from Injured Cells Induce P2X7-Dependent Shedding of CD62L and Externalization of Phosphatidylserine by Murine T Cells

NAD+ and ATP Released from Injured Cells Induce P2X7-Dependent Shedding of CD62L and Externalization of Phosphatidylserine by Murine T Cells

Fucosyltransferase VII-Deficient Mice with Defective E-, P-, and L-Selectin Ligands Show Impaired CD4+ and CD8+ T Cell Migration into the Skin, but Normal Extravasation into Visceral Organs

Bromelain treatment decreases neutrophil migration to sites of inflammation

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