Loss of Cell Viability Dramatically Elevates Cell Surface Plasminogen Binding and Activation

O'Mullane, Matthew J.; Baker, Mark S.

doi:10.1006/excr.1998.4067

Cited by 37 publications

(46 citation statements)

References 47 publications

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“…The question that arises is how plasminogen exerts its effect on corpse clearance. Previous reports have described an enhanced binding of plasminogen to the surface of apoptotic cells, suggesting that it might function as an opsonin (14)(15)(16)(17). In the current study, however, we did not observe enhanced surface binding of plasminogen to apoptotic cells.…”

Section: Discussioncontrasting

confidence: 93%

“…Instead of acting as an opsonin, we show that plasminogen enhances efferocytosis under crucial contribution of its proteolytic activity, which is acquired after interaction with apoptotic cells. Our data are in line with studies from other groups that have attributed this activation of plasminogen to an increased expression of urokinase-type plasminogen activator, which was specifically detected on the surface of apoptotic, but not necrotic cells (15)(16)(17). Notably, plasmin(ogen)-mediated enhancement of dying cell engulfment was observed in a phase of apoptosis, in which the maximum level of PS externalization had already been reached and the integrity of the plasma membrane was still intact, suggesting that the exposure of "eat-me" signals is a prerequisite for plasmin(ogen)-dependent phagocytosis promotion.…”

Section: Discussionsupporting

confidence: 92%

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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: Discussioncontrasting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

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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“…72 Using flow cytometric analysis, the binding of FITC-plasminogen to nonviable cells (5%-10% of the cell population) was 100-fold greater than viable cells. Moreover, the binding of FITCplasminogen to viable cells was neither lysine dependent nor inhibited by excess plasminogen, whereas the binding of FITCplasminogen to nonviable cells was lysine dependent and blocked by unlabeled plasminogen.…”

Section: Discussionmentioning

confidence: 98%

Plasminogen-mediated matrix invasion and degradation by macrophages is dependent on surface expression of annexin II

Falcone

Borth

Khan

et al. 2001

Blood

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“…This is in accordance with existing data on involvement of the enzyme in the upregulation of plasminogen activation on the surface of damaged cells. 9 There is good reason to propose that intracellular proteolytic machinery is also active, along with the extracellular plasminogen activation, since the plasmin inhibitor aprotinin did not halt decomposition, a finding based on LDH activity (data not shown). Thus, the execution part of the necrosis is gradually enhanced by a self-driven proteolytic mechanism.…”

Section: Discussionmentioning

confidence: 99%

Cell–cell contacts trigger programmed necrosis and induce cyclooxygenase-2 expression

et al. 2003

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Necrosis was induced by cell-cell contacts of human dermal fibroblasts in three-dimensional culture. Dramatic induction of cyclooxygenase-2 (COX-2) expression was found throughout these necrotizing cell clusters, whereas no increase in expression of apoptosis markers was seen. The cells were rapidly committed to necrosis, and the process could not be reversed by allowing them to spread and adhere on a solid substrate. Induction of COX-2 expression was accompanied by greatly enhanced production of the prostaglandins E 2 , I 2 , and F 2a . When applied exogenously on necrotizing clusters, these prostaglandins delayed cell clustering and further enhanced COX-2 expression. Abolishing prostaglandin production by NS-398 or indomethacin reduced cell membrane damage (as measured by lactate dehydrogenase release into the culture medium). We also identified aenolase-mediated plasminogen activation as the major extracellular proteolytic executor of necrotic cell death. In contrast to inhibition of COX-2, inhibition of plasminogen activation failed to inhibit membrane damage associated with necrosis. Intracellular proteolysis, by caspases, was shown to take part in COX-2 induction. Taken together, our results indicate that cell-cell contacts induce an actively programmed necrotic process that functionally involves COX-2, a known hallmark of inflammation and cancer.

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Loss of Cell Viability Dramatically Elevates Cell Surface Plasminogen Binding and Activation

Cited by 37 publications

References 47 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

Plasminogen-mediated matrix invasion and degradation by macrophages is dependent on surface expression of annexin II

Cell–cell contacts trigger programmed necrosis and induce cyclooxygenase-2 expression

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