Cytokine-induced meningitis is dramatically attenuated in mice deficient in endothelial selectins.

Tang, Tao; Frenette, Paul S.; Hynes, Richard O.; Wagner, Denisa D.; Mayadas, Tanya N.

doi:10.1172/jci118695

Cited by 130 publications

(77 citation statements)

References 35 publications

(32 reference statements)

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“…This acute surface presentation of P-selectin is not seen on endothelial cells of VWF KO mice that cannot form WPB and show both, strongly reduced cell surface expression of P-selectin and decreased leukocyte recruitment, even though the amount of intracellular P-selectin remains unchanged 25 . The defect in P-selectin cell surface presentation observed in these mice indicates that the rapidly releasable pool of P-selectin originates from WPB and emphasizes the importance of these specialized secretory organelles as P-selectin storage compartments in the control of inflammation [25][26][27] . We observed that anxA8-depleted HUVEC displayed a severe reduction in leukocyte rolling and adhesion upon histamine activation.…”

Section: Discussionmentioning

confidence: 99%

Annexin A8 controls leukocyte recruitment to activated endothelial cells via cell surface delivery of CD63

et al. 2014

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To enable leukocyte adhesion to activated endothelium, the leukocyte receptor P-selectin is released from Weibel-Palade bodies (WPB) to the endothelial cell surface where it is stabilized by CD63. Here we report that loss of annexin A8 (anxA8) in human umbilical vein endothelial cells (HUVEC) strongly decreases cell surface presentation of CD63 and P-selectin, with a concomitant reduction in leukocyte rolling and adhesion. We confirm the compromised leukocyte adhesiveness in inflammatory-activated endothelial venules of anxA8-deficient mice. We find that WPB of anxA8-deficient HUVEC contain less CD63, and that this is caused by improper transport of CD63 from late multivesicular endosomes to WPB, with CD63 being retained in intraluminal vesicles. Consequently, reduced CD63 cell surface levels are seen following WPB exocytosis, resulting in enhanced P-selectin re-internalization. Our data support a model in which anxA8 affects leukocyte recruitment to activated endothelial cells by supplying WPB with sufficient amounts of the P-selectin regulator CD63.

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Section: Discussionmentioning

confidence: 99%

Annexin A8 controls leukocyte recruitment to activated endothelial cells via cell surface delivery of CD63

et al. 2014

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“…Tang and others have shown P-selectin-deficient mice to exhibit partial inhibition of cerebrospinal fluid leucocyte accumulation [24]. However, mice with null mutations in both P-and E-selectin genes exhibited an almost complete inhibition of leucocyte accumulation in models of contact hypersensitivity [12], meningitis [24] and peritonitis [25]. These studies suggest that, at least in contact hypersensitivity, meningeal inflammation and peritonitis, P-and E-selectin contribute cooperatively to leucocyte recruitment [12,24,25].…”

Section: Discussionmentioning

confidence: 99%

P-selectin requirement for neutrophil accumulation and injury in the direct passive Arthus reaction

Santos

Huang

Berndt³

et al. 1998

Clinical and Experimental Immunology

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SUMMARYThe aim of this study was to investigate the role of P-selectin in the accumulation of neutrophils in the direct passive Arthus reaction in rat skin. Direct passive Arthus dermal reaction was induced in male Sprague-Dawley (SD) rats by a single i.v. injection of rat anti-sheep globulin (SG) 1 h before i.d. injection of SG antigen. Anti-P-selectin or irrelevant control antibody was given 1 h before rat anti-SG injection. Complement depletion was also performed in a separate group by pretreatment with cobra venom factor (CVF). In all groups dermal swelling was assessed 4 h after antigen challenge. Four hours after antigen challenge, rats treated with control antibody developed skin swelling (2·29 Ϯ 0·47 mm), prominent complement deposition and neutrophil accumulation. This response was associated with local up-regulation of endothelial P-selectin. Pre-treatment with anti-P-selectin antibody 1 h before passive Arthus induction prevented skin swelling (0·29 Ϯ 0·06 mm, P < 0·05, cf with control antibody treatment), neutrophil accumulation and up-regulation of endothelial P-selectin despite complement deposition. CVF treatment prevented complement deposition, neutrophil accumulation and skin swelling (0·13 Ϯ 0·07 mm, P < 0·05, cf with saline treatment). However, endothelial P-selectin expression was still present. Inhibition of skin swelling and neutrophil accumulation in direct passive Arthus by functional inhibition of P-selectin suggest a pivotal role for this adhesion molecule in this inflammatory process. These results also suggest that multiple steps are involved in the evolution of direct passive Arthus, including both P-selectin expression and complement activation. However, while complement activation is essential for neutrophil accumulation and expression of dermal injury, Pselectin up-regulation initiated by antibody/antigen deposition occurs independently of complement activation.

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“…All mice used in this study were on a mixed background C57BL͞6J͞129Sv, so that comparison with previously published inflammatory models with P-selectin (P Ϫ͞Ϫ) mice (3) would be possible (11,12). The experimental procedures were approved by the Animal Care and Use Committee of the Center for Blood Research.…”

Section: Methodsmentioning

confidence: 99%

“…Meningitis was induced as described (11). Four hours after induction of the meningitis with lumbar injection of human recombinant IL-1␤ (25 pg͞g) and recombinant human tumor necrosis factor ␣ (TNF␣) (80 pg͞g) (Genzyme) the cerebrospinal fluid (CSF) was collected by aspiration with a glass capillary pipette.…”

Section: Methodsmentioning

confidence: 99%

“…Both CSF and plasma samples, prepared from centrifugation of the blood at 2,500 ϫ g for 15 min, were diluted in PBS, and the fluorescence intensity was measured with a fluorometer (Perkin-Elmer) with an excitation wavelength of 497 nm and an emission wavelength of 519 nm. The BBB permeability index was expressed as the ratio of the fluorescence intensity of the CSF sample divided by the fluorescence intensity of the plasma (11,14).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Defect in regulated secretion of P-selectin affects leukocyte recruitment in von Willebrand factor-deficient mice

Denis

André

Saffaripour

et al. 2001

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

156

145

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Stimulation of endothelial cells by various inflammatory mediators leads to release of Weibel-Palade bodies and therefore to exocytosis of both P-selectin (adhesion receptor for leukocytes) and von Willebrand factor (vWf) (platelet ligand). The potential role of vWf in leukocyte recruitment was investigated with the use of vWfdeficient mice. We report a strong reduction of leukocyte rolling in venules of vWf-deficient mice. Similarly, vWf deficiency led to a decrease in neutrophil recruitment in a cytokine-induced meningitis model as well as in early skin wounds. In all instances with an antibody that preferentially recognizes plasma membrane P-selectin, we observed a dramatic reduction in P-selectin expression at the cell surface of vWf-deficient endothelium. With confocal microscopy, we found that the typical rodlike shape of the WeibelPalade body is missing in vWf ؊͞؊ endothelial cells and that part of the P-selectin content in the vWf ؊͞؊ cells colocalized with LAMP-1, a lysosomal marker. However, intracellular P-selectin levels were similar in tumor necrosis factor ␣-and lipopolysaccharide-activated cells of both genotypes. We conclude that the absence of vWf, as found in severe von Willebrand disease, leads to a defect in Weibel-Palade body formation. This defect results in decreased P-selectin translocation to the cell surface and reduced leukocyte recruitment in early phases of inflammation.

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Cytokine-induced meningitis is dramatically attenuated in mice deficient in endothelial selectins.

Cited by 130 publications

References 35 publications

Annexin A8 controls leukocyte recruitment to activated endothelial cells via cell surface delivery of CD63

Annexin A8 controls leukocyte recruitment to activated endothelial cells via cell surface delivery of CD63

P-selectin requirement for neutrophil accumulation and injury in the direct passive Arthus reaction

Defect in regulated secretion of P-selectin affects leukocyte recruitment in von Willebrand factor-deficient mice

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