Participation of the urokinase receptor in neutrophil efferocytosis

Park, Young-Jun; Liu, Gang; Tsuruta, Yuko; Lorne, Emmanuel; Abraham, Edward

doi:10.1182/blood-2008-12-193524

Cited by 58 publications

(66 citation statements)

References 51 publications

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“…Notably, the urokinase plasminogen activator receptor has recently been described as a novel engulfment receptor (20), although its prophagocytic role remains controversial (21). Moreover, Das and Plow (22) have described the histone 2B-dependent recruitment of plasminogen to PS-rich surfaces, and it has been shown that PAI impairs apoptotic cell removal (23).…”

Section: Discussionmentioning

confidence: 99%

Serum-Derived Plasminogen Is Activated by Apoptotic Cells and Promotes Their Phagocytic Clearance

Rosenwald

Koppe

Keppeler

et al. 2012

The Journal of Immunology

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The elimination of apoptotic cells, called efferocytosis, is fundamentally important for tissue homeostasis and prevents the onset of inflammation and autoimmunity. Serum proteins are known to assist in this complex process. In the current study, we performed a multistep chromatographic fractionation of human serum and identified plasminogen, a protein involved in fibrinolysis, wound healing, and tissue remodeling, as a novel serum-derived factor promoting apoptotic cell removal. Even at levels significantly lower than its serum concentration, purified plasminogen strongly enhanced apoptotic prey cell internalization by macrophages. Plasminogen acted mainly on prey cells, whereas on macrophages no enhancement of the engulfment process was observed. We further demonstrate that the efferocytosis-promoting activity essentially required the proteolytic activation of plasminogen and was completely abrogated by the urokinase plasminogen activator inhibitor-1 and serine protease inhibitor aprotinin. Thus, our study assigns a new function to plasminogen and plasmin in apoptotic cell clearance.

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Section: Discussionmentioning

confidence: 99%

Serum-Derived Plasminogen Is Activated by Apoptotic Cells and Promotes Their Phagocytic Clearance

Rosenwald

Koppe

Keppeler

et al. 2012

The Journal of Immunology

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“…Partly in contrast with these results, Park et al demonstrated increased macrophage efferocytosis of apoptotic neutrophils when uPAR was knocked-out, either in the neutrophil or the macrophage, but interestingly not when knocked-out in both cell types [109]. A wide range of integrins were shown to be involved in this unilateral uPAR effect and the increased efferocytosis was reversed when exogenous suPAR was added to the experimental system [109]. The incomplete concordance of these studies can possibly be explained by differences between species as well as the cell types being professional versus non-professional phagocytes.…”

Section: Efferocytosis -The Quiet Elimination Of Dying Cellsmentioning

confidence: 72%

“…In line with these results, there is another study reporting increased uptake of apoptotic T cells in uPAR overexpressing cancer cell lines [108]. Partly in contrast with these results, Park et al demonstrated increased macrophage efferocytosis of apoptotic neutrophils when uPAR was knocked-out, either in the neutrophil or the macrophage, but interestingly not when knocked-out in both cell types [109]. A wide range of integrins were shown to be involved in this unilateral uPAR effect and the increased efferocytosis was reversed when exogenous suPAR was added to the experimental system [109].…”

Section: Efferocytosis -The Quiet Elimination Of Dying Cellsmentioning

confidence: 77%

“…Since a defective clearance of dying cells is central in the SLE pathogenesis it is of interest to note that uPAR expression has been found to regulate efferocytosis [107][108][109][110] Briassouli et al found anti-SSA/Ro60 to up-regulate cardiocyte uPAR expression, and that this resulted in reduced efferocytosis and increased plasminogen activity [117]. Further, the augmentation of plasminogen activity resulted in transforming growth factor beta activation with a scarring phenotype of cardiac fibroblasts as a result [118].…”

Section: Efferocytosis -The Quiet Elimination Of Dying Cellsmentioning

confidence: 99%

Section: Efferocytosis -The Quiet Elimination Of Dying Cellsmentioning

confidence: 99%

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Soluble urokinase plasminogen activator receptor—A valuable biomarker in systemic lupus erythematosus?

Enocsson¹,

Sjöwall²,

Wetterö³

2015

Clinica Chimica Acta

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The expression of uPAR is mainly regulated by growth factors and pro-inflammatory cytokines like basic fibroblast growth factor, epidermal growth factor, tumor necrosis factor, interleukin ( suPAR as a clinical marker of inflammation and organ damagePlasma membrane expression of uPAR as well as the levels of circulating suPAR have been investigated in relation to a broad range of conditions and suPAR has been referred to as a "molecular crystal ball" due to its prognostic value in diseases like tuberculosis, HIV, sepsis and cancer [2,6,13,26,58,59]. Further, it has been reported that it reflects overall immune activation and systemic inflammation [2]. suPAR has also emerged as a potential biomarker of fibrosis in chronic liver diseases of diverse etiology [10,11,[60][61][62].Recently, suPAR attracted significant attention in primary focal segmental glomerulosclerosis (FSGS). data from this pilot study revealed significantly higher suPAR levels among patients with moderately or highly elevated SDI after study inclusion, compared to patients without SDI increase (Figure 2).Furthermore, there were higher death rates among patients in the two groups with SDI increase (Figure 2). However, it is well known that present organ damage predicts further organ damage [17,100], and thus, adjustment for SDI at baseline should be performed to reduce the risk of bias. A stepwise linear multiple regression analysis was therefore performed to evaluate the impact of suPAR on future SDI increase. After adjusting for age, sex and SDI at study inclusion, we found suPAR levels to have a significant impact on future SDI increase (p = 0.005, standardized β = 0.20) whereas SDI at study inclusion was excluded from the model. Since recent studies have revealed an inverse correlation between serum suPAR and glomerular filtration [67,68,96], we also included estimated glomerular filtration (eGFR) (calculated by the 4-variable Modification of Diet in Renal Disease StudyGroup formula [101]) in the analysis, but eGFR was not retained in the model. From these results, we suggest that suPAR can actually predict organ damage independent of present SDI score or eGFR, but that a prospective study examining the association between suPAR levels at the time of diagnosis with future SDI would be preferable.In line with these findings, elevated suPAR levels have previously been demonstrated to associate with the risk of developing cancer, cardiovascular disease and type 2 diabetes later in life in the general population [7]. Importantly, these associations were independent of CRP, which is known for its predictive value in cardiovascular disease [7,102].7 Potential roles of suPAR in SLE pathogenesisAssessment of circulating suPAR levels at the clinical laboratory could possibly become a future way to estimate organ damage in SLE, and suPAR would be an even more appealing biomarker candidate if the levels could be mechanistically linked to the disease. The pathogenesis of SLE is notoriously complex and not fully understood, but includes disturbances in t...

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Acute Lung Injury and Pulmonary Vascular Permeability: Use of Transgenic Models

Parker

2011

Comprehensive Physiology

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Acute lung injury is a general term that describes injurious conditions that can range from mild interstitial edema to massive inflammatory tissue destruction. This review will cover theoretical considerations and quantitative and semi-quantitative methods for assessing edema formation and increased vascular permeability during lung injury. Pulmonary edema can be quantitated directly using gravimetric methods, or indirectly by descriptive microscopy, quantitative morphometric microscopy, altered lung mechanics, high-resolution computed tomography, magnetic resonance imaging, positron emission tomography, or x-ray films. Lung vascular permeability to fluid can be evaluated by measuring the filtration coefficient (Kf) and permeability to solutes evaluated from their blood to lung clearances. Albumin clearances can then be used to calculate specific permeability-surface area products (PS) and reflection coefficients (σ). These methods as applied to a wide variety of transgenic mice subjected to acute lung injury by hyperoxic exposure, sepsis, ischemia-reperfusion, acid aspiration, oleic acid infusion, repeated lung lavage, and bleomycin are reviewed. These commonly used animal models simulate features of the acute respiratory distress syndrome, and the preparation of genetically modified mice and their use for defining specific pathways in these disease models are outlined. Although the initiating events differ widely, many of the subsequent inflammatory processes causing lung injury and increased vascular permeability are surprisingly similar for many etiologies.

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Participation of the urokinase receptor in neutrophil efferocytosis

Abstract: The urokinase receptor (uPAR) plays an important role in regulation of fibronolysis, cell migration, and adhesion. In this study, we examined whether uPAR plays a role in modulating efferocytosis of neutrophils.

Cited by 58 publications

References 51 publications

Serum-Derived Plasminogen Is Activated by Apoptotic Cells and Promotes Their Phagocytic Clearance

Serum-Derived Plasminogen Is Activated by Apoptotic Cells and Promotes Their Phagocytic Clearance

Soluble urokinase plasminogen activator receptor—A valuable biomarker in systemic lupus erythematosus?

Acute Lung Injury and Pulmonary Vascular Permeability: Use of Transgenic Models

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