Limited endothelial E‐ and P‐selectin expression in MRL/lpr lupus‐prone mice

Harari, Olivier; Marshall, Diane; McHale, Julie F.; Ahmed, S. I.; Haskard, Dorian O.

doi:10.1093/rheumatology/40.8.889

Cited by 21 publications

(13 citation statements)

References 31 publications

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“…However, the aforementioned molecular and cellular pathomechanisms of autoimmune lung injury differ, at least in part, from those of lupus nephritis because Icam-1 -deficiency as well as TNF-α antagonism protects MRL lpr mice from lung but not from kidney disease [39], [41]. Furthermore, P-selectin is only induced in lungs but not in kidneys upon immune stimulation with LPS [38] or, as we found here, in experimental SLE. The latter finding is of particular interest because PTX3 was recently identified as an endogenous P-selectin inhibitor that limits leukocyte recruitment to the lung [27].…”

Section: Discussionmentioning

confidence: 53%

“…Kidney disease in autoimmune mice (and lupus patients) mainly develops from immune complex disease and depends on glomerular complement activation and macrophage recruitment [36]. By contrast, lung disease in MRL lpr mice involves the recruitment of CXCR3 positive T cells via local secretion of CXCL10 [37], and the endothelial expression of selectins [38] and intercellular adhesion molecule (ICAM)-1 [39]. In addition, TNF-α is a crucial mediator of lung injury in experimental lupus [40], [41].…”

Section: Discussionmentioning

confidence: 99%

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Lack of the Long Pentraxin PTX3 Promotes Autoimmune Lung Disease but not Glomerulonephritis in Murine Systemic Lupus Erythematosus

Lech¹,

Römmele²,

Kulkarni³

et al. 2011

PLoS ONE

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The long pentraxin PTX3 has multiple roles in innate immunity. For example, PTX3 regulates C1q binding to pathogens and dead cells and regulates their uptake by phagocytes. It also inhibits P-selectin-mediated recruitment of leukocytes. Both of these mechanisms are known to be involved in autoimmunity and autoimmune tissue injury, e.g. in systemic lupus erythematosus, but a contribution of PTX3 is hypothetical. To evaluate a potential immunoregulatory role of PTX3 in autoimmunity we crossed Ptx3-deficient mice with Fas-deficient (lpr) C57BL/6 (B6) mice with mild lupus-like autoimmunity. PTX3 was found to be increasingly expressed in kidneys and lungs of B6lpr along disease progression. Lack of PTX3 impaired the phagocytic uptake of apoptotic T cells into peritoneal macrophages and selectively expanded CD4/CD8 double negative T cells while other immune cell subsets and lupus autoantibody production remained unaffected. Lack of PTX3 also aggravated autoimmune lung disease, i.e. peribronchial and perivascular CD3+ T cell and macrophage infiltrates of B6lpr mice. In contrast, histomorphological and functional parameters of lupus nephritis remained unaffected by the Ptx3 genotype. Together, PTX3 specifically suppresses autoimmune lung disease that is associated with systemic lupus erythematosus. Vice versa, loss-of-function mutations in the Ptx3 gene might represent a genetic risk factor for pulmonary (but not renal) manifestations of systemic lupus or other autoimmune diseases.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Lack of the Long Pentraxin PTX3 Promotes Autoimmune Lung Disease but not Glomerulonephritis in Murine Systemic Lupus Erythematosus

Lech¹,

Römmele²,

Kulkarni³

et al. 2011

PLoS ONE

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“…Alternatively, the level of P-selectin expression in the brains of MRL/fas lpr mice may not be elevated to the same extent as has been demonstrated in several of these models, including the TNF-␣, LPS, and experimental autoimmune encephalomyelitis studies (15,35,36). It is noteworthy that measurement of P-selectin expression in various organs of MRL/fas lpr mice has shown no increase from basal levels, despite the presence of ongoing inflammation in these animals (37). This suggests that the chronic inflammatory conditions present in these mice are not conducive to increased expression of P-selectin.…”

Section: Discussionmentioning

confidence: 89%

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

James

Bullard

Hickey

2003

The Journal of Immunology

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MRL/faslpr mice are affected by a systemic autoimmune disease that results in leukocyte recruitment to a wide range of vascular beds, including the cerebral microvasculature. The mechanisms responsible for the leukocyte trafficking to the brain in these animals are not known. Therefore, the aim of this study was to directly examine the cerebral microvasculature in MRL/faslpr mice and determine the molecular mechanisms responsible for this leukocyte recruitment. Intravital microscopy was used to assess leukocyte-endothelial cell interactions (rolling, adhesion) in the pial microcirculation of MRL+/+ (control) and MRL/faslpr mice at 8, 12, and 16 wk of age. Leukocyte rolling and adhesion were rarely observed in MRL+/+ mice of any age. MRL/faslpr mice displayed similar results at 8 and 12 wk. However, at 16 wk, significant increases in leukocyte rolling and adhesion were observed in these mice. Histological analysis revealed that the interacting cells were exclusively mononuclear. Leukocyte rolling was reduced, but not eliminated in P-selectin−/−-MRL/faslpr mice. However, leukocyte adhesion was not reduced in these mice, indicating that P-selectin-dependent rolling was not required for leukocyte recruitment to the cerebral vasculature in this model of systemic inflammation. E-selectin blockade also had no effect on leukocyte rolling. In contrast, blockade of either the α4 integrin or VCAM-1 eliminated P-selectin-independent leukocyte rolling. α4 Integrin blockade also significantly inhibited leukocyte adhesion. These studies demonstrate that the systemic inflammatory response that affects MRL/faslpr mice results in leukocyte rolling and adhesion in the cerebral microcirculation, and that the α4 integrin/VCAM-1 pathway plays a central role in mediating these interactions.

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“…Studies in SLE mouse models have shown limited vascular expression of P-selectin and E-selectin in mice at different stages of disease development, which may indicate a minor role for these adhesion molecules (27). However, it is clear from our previous work that these molecules are expressed at sufficient levels to support leukocyte rolling events in the dermal and cerebral microvasculatures in lupus-prone MRL/MpJ-Fas lpr (Fas lpr ) mice,…”

mentioning

confidence: 87%

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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Limited endothelial E‐ and P‐selectin expression in MRL/lpr lupus‐prone mice

Cited by 21 publications

References 31 publications

Lack of the Long Pentraxin PTX3 Promotes Autoimmune Lung Disease but not Glomerulonephritis in Murine Systemic Lupus Erythematosus

Lack of the Long Pentraxin PTX3 Promotes Autoimmune Lung Disease but not Glomerulonephritis in Murine Systemic Lupus Erythematosus

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

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

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