PAI-1 inhibits neutrophil efferocytosis

Park, Young-Jun; Liu, Gang; Lorne, Emmanuel; Zhao, Xia; Wang, Jing; Tsuruta, Yuko; Żmijewski, Jaroslaw W.; Abraham, Edward

doi:10.1073/pnas.0801394105

Cited by 103 publications

(112 citation statements)

References 30 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). These studies taken together with our work suggest that dysregulation of the plasminogen system might lead to deranged apoptotic cell clearance.…”

Section: Discussionsupporting

confidence: 51%

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: Discussionsupporting

confidence: 51%

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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“…Although increased levels of PAI-1 and inhibition of plasmin generation are found in the lungs and circulation of critically ill patients with sepsis or ALI (28,40), recent studies have also shown that PAI-1 can affect a broad range of cellular functions independent of its effects on coagulation, including cell adhesion, proliferation, migration, and viability (6,21,36). In particular, PAI-1 can facilitate neutrophil chemotaxis, enhance release of cytokines by Toll-like receptor 4-stimulated neutrophils, and diminish the uptake of apoptotic neutrophils by macrophages (23,26).…”

mentioning

confidence: 99%

Inhibition of neutrophil apoptosis by PAI-1

Żmijewski¹,

Bae

Deshane

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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Increased circulating and tissue levels of plasminogen activator inhibitor 1 (PAI-1) are often present in severe inflammatory states associated with neutrophil activation and accumulation and correlate with poor clinical outcome from many of these conditions. The mechanisms by which PAI-1 contributes to inflammation have not been fully delineated. In the present experiments, we found that addition of PAI-1 to neutrophil cultures diminished the rate of spontaneous and TNF-related apoptosis-inducing ligand-induced apoptotic cell death. The effects of PAI-1 on cell viability were associated with activation of antiapoptotic signaling pathways, including upregulation of PKB/Akt, Mcl-1, and Bcl-xL. Although urokinase-plasminogen activator receptor, lipoprotein receptor-related protein, and vitronectin are primary ligands for PAI-1, these molecules were not involved in mediating its antiapoptotic properties. In contrast, blocking pertussis toxin-sensitive G protein-coupled receptors and selective inhibition of phosphatidylinositide 3-kinase reversed the ability of PAI-1 to extend neutrophil viability. The antiapoptotic effects of PAI-1 were also evident under in vivo conditions during LPS-induced acute lung injury, where enhanced apoptosis was present among neutrophils accumulating in the lungs of PAI-1−/−compared with PAI-1+/+mice. These results demonstrate a novel antiapoptotic role for PAI-1 that may contribute to its participation in neutrophil-associated inflammatory responses.

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“…Of note, diminished neutrophil apoptosis is a well characterized finding during acute lung injury in experimental models and in patients with this condition (39,41,42). Furthermore, in addition to its antiapoptotic effects, vitronectin may also exacerbate the severity of acute lung injury through decreasing the uptake and clearance of apoptotic neutrophils by alveolar and tissue-based macrophages (12), thereby allowing the apoptotic neutrophils to progress to necrotic death with associated release of proinflammatory contents into the pulmonary parenchyma.…”

Section: Discussionmentioning

confidence: 99%

“…The vitronectin SMB domain has been shown to bind plasminogen activator inhibitor (PAI) -1, uPAR, collagen, and thrombin-antithrombin complexes. Previous studies demonstrated that vitronectin and its binding partners, PAI-1 and the uPA, can diminish the phagocytosis of apoptotic cells by macrophages, a process referred to as efferocytosis (11)(12)(13). However, a role for vitronectin in modulating neutrophil apoptosis has not been described.…”

mentioning

confidence: 95%

Vitronectin Inhibits Neutrophil Apoptosis through Activation of Integrin-Associated Signaling Pathways

Bae

Żmijewski²,

Deshane

et al. 2012

Am J Respir Cell Mol Biol

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Vitronectin is present in large concentrations in serum and the extracellular matrix. Although vitronectin is known to modulate neutrophil adhesion and chemotaxis, and to contribute to neutrophil-associated proinflammatory processes, a role in apoptosis has not been demonstrated. In the present studies, we found that neutrophils demonstrated more rapid progression to spontaneous or TNF-related apoptosisinducing ligand-induced apoptosis when incubated under vitronectinfree conditions than when vitronectin was present. The ability of native vitronectin to delay neutrophil apoptosis was not recapitulated by the vitronectin somatomedin B domain. In contrast, inclusion of the cyclo[Arg-Gly-Asp-D-Phe-Val] peptide in cultures containing vitronectin resulted in enhanced neutrophil apoptosis, showing that the vitronectin RGD motif (Arg-Gly-Asp motif) was responsible for the antiapoptotic effects of vitronectin. Addition of antibodies to b 1 , b 3 , or b 5 , but not to b 2 or b 4 integrins, reversed the ability of vitronectin to diminish neutrophil apoptosis. The ability of vitronectin to enhance neutrophil viability was dependent on activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2 kinases, but not on the p38 kinase. Increased numbers of apoptotic neutrophils were present in the lungs of LPS-treated transgenic vitronectin-deficient mice, as compared with control mice. These results demonstrate a novel antiapoptotic function for vitronectin.Keywords: vitronectin; inflammation; neutrophils; apoptosis; lung injury Although neutrophils play a central role in host defense against invading microbes, organ injury can result if neutrophils activated to produce proinflammatory mediators remain in tissues for prolonged periods. The timely progression of neutrophils to apoptotic cell death and subsequent clearance is essential for the successful resolution of neutrophil-associated inflammatory processes (1). Under normal conditions, neutrophils are short lived, but during inflammatory responses, such as acute lung injury, they demonstrate prolonged viability. The importance of diminished neutrophil apoptosis in promoting tissue injury during inflammatory processes has been demonstrated by studies in which pharmacologically induced increase in apoptosis resulted in diminished severity of organ dysfunction, such as lung injury induced by LPS or hemorrhage (2-4).Vitronectin is a glycoprotein present in large concentrations in serum, extracellular matrix, and platelets, and participates in the regulation of coagulation, fibrinolysis, and complement activation (5, 6). Tissue levels of vitronectin markedly increase in pathophysiologic settings associated with acute inflammation, such as severe sepsis, and appear to contribute to organ injury in such conditions (7,8). Vitronectin promotes neutrophil adhesion and migration through interaction with integrins, including a v b 3 , and other ligands, such as the urokinase plasminogen activator (uPA) receptor (uPAR) (9, 10). The first 43 amino acids of N-...

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PAI-1 inhibits neutrophil efferocytosis

Cited by 103 publications

References 30 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

Inhibition of neutrophil apoptosis by PAI-1

Vitronectin Inhibits Neutrophil Apoptosis through Activation of Integrin-Associated Signaling Pathways

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