Critical Role of the α4 Integrin/VCAM-1 Pathway in Cerebral Leukocyte Trafficking in Lupus-Prone MRL/<i>fas</i><i>lpr</i>Mice

James, Will G.; Bullard, Daniel C.; Hickey, Michael J.

doi:10.4049/jimmunol.170.1.520

Cited by 44 publications

(50 citation statements)

References 38 publications

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“…Our previous intravital microscopy analyses of P-sel/Fas lpr mice support this hypothesis (28,29). We found that the numbers of rolling leukocytes were reduced, but not completely inhibited, in the skin and brain microvasculature in these mutant mice compared with controls, and significant differences in the numbers of firmly adherent leukocytes were not observed.…”

Section: Discussionsupporting

confidence: 66%

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Deficiency of P-Selectin or P-Selectin Glycoprotein Ligand-1 Leads to Accelerated Development of Glomerulonephritis and Increased Expression of CC Chemokine Ligand 2 in Lupus-Prone Mice

He¹,

Schoeb²,

Panoskaltsis‐Mortari

et al. 2006

The Journal of Immunology

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The selectins and their ligands mediate leukocyte rolling on endothelial cells, the initial step in the emigration cascade leading to leukocyte infiltration of tissue. These adhesion molecules have been shown to be key promoters of acute leukocyte emigration events; however, their roles in the development of long-term inflammatory responses, including those that occur during chronic inflammatory diseases such as systemic lupus erythematosus, are unclear. To assess participation of P-selectin in such disorders, we studied the progression of systemic lupus erythematosus-like disease in P-selectin-deficient and control MRL/MpJ-Faslpr (Faslpr) mice. Surprisingly, we found that P-selectin deficiency resulted in significantly earlier mortality, characterized by a more rapid development of glomerulonephritis and dermatitis. Expression of CCL2 (MCP-1) was increased in the kidneys of P-selectin mutant mice and in supernatants of LPS-stimulated primary renal endothelial cell cultures from these mice. A closely similar phenotype, including elevated renal expression of CCL2, was also observed in Faslpr mice deficient in the major P-selectin ligand, P-selectin glycoprotein ligand-1. These results indicate that P-selectin and P-selectin glycoprotein ligand-1 are not required for leukocyte infiltration and the development of autoimmune disease in Faslpr mice, but rather expression of these adhesion molecules is important for modulating the progression of glomerulonephritis, possibly through down-regulation of endothelial CCL2 expression.

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Section: Discussionsupporting

confidence: 66%

“…suggesting that these adhesion molecules may be functional in promoting inflammatory disease in this mouse model and SLE (28,29). In the present study, we analyzed Fas lpr mice deficient in P-selectin or its major ligand P-selectin glycoprotein ligand-1 (PSGL-1) to determine the roles of these adhesion molecules in IC-mediated SLE-like vascular inflammation.…”

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confidence: 99%

Deficiency of P-Selectin or P-Selectin Glycoprotein Ligand-1 Leads to Accelerated Development of Glomerulonephritis and Increased Expression of CC Chemokine Ligand 2 in Lupus-Prone Mice

He¹,

Schoeb²,

Panoskaltsis‐Mortari

et al. 2006

The Journal of Immunology

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“…Vascular cell adhesion molecule-1 supports the adhesion of the primary leukocyte populations present in atherosclerotic plaques and may contribute to the quantitative predominance of monocytes over lymphocytes (Gerszten et al, 1998). Vascular cell adhesion molecule-1 facilitates transendothelial entry of circulating monocytes through human brain endothelial cells (MacIntyre et al, 2003), and it plays an important role in leukocyte recruitment in brain diseases, as shown in experimental models of systemic lupus erythematosus (James et al, 2003), and in chronic graft-versus-host disease (Sostak et al, 2004). At the bedside, soluble VCAM-1 concentration in plasma is raised in patients with acute stroke (Blann et al, 1999), and a two-fold increase of this parameter was found independently associated to poor outcome after stroke (Chamorro et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Anti-VCAM-1 Antibodies did not Protect against Ischemic Damage Either in Rats Or in Mice

Justicia

Martín

Rojas

et al. 2006

J Cereb Blood Flow Metab

100

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Cerebral ischemia triggers an inflammatory process involving the infiltration of leukocytes to the parenchyma. Circulating leukocytes adhere to the vascular wall through adhesion molecules. Here we quantified the in vivo expression of vascular cell adhesion molecule-1 (VCAM-1) in the brain, heart and lungs from 6 to 48 h after transient middle cerebral artery (MCA) occlusion in rats, by intravenous injection of a tracer radiolabelled anti-VCAM-1 antibody. The vascular localization of VCAM-1 was verified by immunohistochemistry after in vivo injection of the antibody. Vascular cell adhesion molecule-1 was strongly induced (4-fold at 24 h) in the microvasculature of the ischemic area, and, to a lesser extent, in the contralateral hemisphere and in a remote organ, the heart, but not in the lungs, indicating that the inflammatory process propagates beyond the injured brain. We injected intravenously either blocking doses of anti-VCAM-1 antibodies or control antibodies after MCA occlusion in rats and mice. We evaluated the neurological score in rats, and infarct volume at 2 days in rats and at 4 days in mice. Anti-VCAM-1 did not protect against ischemic damage either in rats or in mice. Vascular cell adhesion molecule-1 blockade significantly decreased the number of ED1 (labeling monocytes /macrophages/reactive microglia)-positive cells in the ischemic rat brain. However, it did not reduce the numbers of infiltrating neutrophils and lymphocytes, and total leukocytes (CD45 positive), which showed a trend to increase. The results show vascular upregulation of VCAM-1 after transient focal ischemia, but no benefits of blocking VCAM-1, suggesting that this is not a therapeutical strategy for stroke treatment.

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“…Immunoneutralization of VCAM-1 has also been shown to ameliorate hepatic necrosis and neutrophil infiltration in response to endotoxin (4). Indeed, VCAM-1 appears to be integral to leukocyte recruitment in a variety of tissues, including the brain (10,11), kidney (12), and intestine (13).…”

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confidence: 99%

Unconjugated Bilirubin Inhibits VCAM-1-Mediated Transendothelial Leukocyte Migration

Keshavan

Deem²,

Schwemberger

et al. 2005

The Journal of Immunology

145

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During lymphocyte migration, engagement of VCAM-1 stimulates the generation of endothelial cell-derived reactive oxygen species (ROS) and activation of matrix metalloproteinases, facilitating endothelial retraction. Because bilirubin is a potent antioxidant, we examined the hypothesis that this bile pigment inhibits VCAM-1-dependent cellular events. The migration of isolated murine splenic lymphocytes across monolayers of murine endothelial cell lines (which constitutively express VCAM-1) is significantly inhibited by physiological concentrations of bilirubin, in the absence of an effect on lymphocyte adhesion. Bilirubin administration also suppresses VCAM-1-stimulated ROS generation and reduces endothelial cell matrix metalloproteinase activity. In a murine asthma model characterized by VCAM-1-dependent airway inflammation, treatment of C57BL6/J mice with i.p. bilirubin decreases the total leukocyte count in the lung parenchyma and lavage fluid, through specific inhibition of eosinophil and lymphocyte infiltration. Blood eosinophil counts were increased in bilirubin-treated animals, while VCAM-1 expression in the capillary endothelium and cytokine levels in both lung lavage and supernatants from cultured lymph node lymphocytes were unchanged, suggesting that bilirubin inhibits leukocyte migration. Conclusion: bilirubin blocks VCAM-1-dependent lymphocyte migration in vitro and ameliorates VCAM-1-mediated airway inflammation in vivo, apparently through the suppression of cellular ROS production. These findings support a potential role for bilirubin as an endogenous immunomodulatory agent.

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Critical Role of the α4 Integrin/VCAM-1 Pathway in Cerebral Leukocyte Trafficking in Lupus-Prone MRL/faslprMice

Cited by 44 publications

References 38 publications

Deficiency of P-Selectin or P-Selectin Glycoprotein Ligand-1 Leads to Accelerated Development of Glomerulonephritis and Increased Expression of CC Chemokine Ligand 2 in Lupus-Prone Mice

Deficiency of P-Selectin or P-Selectin Glycoprotein Ligand-1 Leads to Accelerated Development of Glomerulonephritis and Increased Expression of CC Chemokine Ligand 2 in Lupus-Prone Mice

Anti-VCAM-1 Antibodies did not Protect against Ischemic Damage Either in Rats Or in Mice

Unconjugated Bilirubin Inhibits VCAM-1-Mediated Transendothelial Leukocyte Migration

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