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Dendritic Cell-Mediated Phagocytosis but Not Immune Activation Is Enhanced by Plasmin.

Borg RJ, Samson AL, Au AE, Scholzen A, Fuchsberger M, Kong YY, Freeman R, Mifsud NA, Plebanski M, Medcalf RL - PLoS ONE (2015)

Bottom Line: Plasmin also promoted phagocytosis of protease-resistant microparticles by diverse mouse dendritic cell sub-types both in vitro and in vivo.Together with an increased phagocytic capacity, plasmin-treated dendritic cells maintain an immature phenotype, exhibit reduced migration to lymph nodes, increase their expression/release of the immunosuppressive cytokine TGF-β, and lose their capacity to mount an allogeneic response.Collectively, our findings support a novel role for plasmin formed on dead cells and other phagocytic targets in maintaining tissue homeostasis by increasing the phagocytic function of dendritic cells while simultaneously decreasing their immunostimulatory capacity consistent with producing an immunosuppressive state.

View Article: PubMed Central - PubMed

Affiliation: Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct, Melbourne, 3004, Victoria Australia.

ABSTRACT
Removal of dead cells in the absence of concomitant immune stimulation is essential for tissue homeostasis. We recently identified an injury-induced protein misfolding event that orchestrates the plasmin-dependent proteolytic degradation of necrotic cells. As impaired clearance of dead cells by the innate immune system predisposes to autoimmunity, we determined whether plasmin could influence endocytosis and immune cell stimulation by dendritic cells - a critical cell that links the innate and adaptive immune systems. We find that plasmin generated on the surface of necrotic cells enhances their phagocytic removal by human monocyte-derived dendritic cells. Plasmin also promoted phagocytosis of protease-resistant microparticles by diverse mouse dendritic cell sub-types both in vitro and in vivo. Together with an increased phagocytic capacity, plasmin-treated dendritic cells maintain an immature phenotype, exhibit reduced migration to lymph nodes, increase their expression/release of the immunosuppressive cytokine TGF-β, and lose their capacity to mount an allogeneic response. Collectively, our findings support a novel role for plasmin formed on dead cells and other phagocytic targets in maintaining tissue homeostasis by increasing the phagocytic function of dendritic cells while simultaneously decreasing their immunostimulatory capacity consistent with producing an immunosuppressive state.

No MeSH data available.


Related in: MedlinePlus

Working model for plasmin-mediated clearance of dead cells.Injury to a live cell results in necrosis and widespread aggregation of intracellular proteins via the phenomenon of Nucleocytoplasmic Coagulation (NCC) [7] (in red). Plasma membrane breakdown allows NCC-protein aggregates to bind t-PA and plasminogen and facilitate in situ plasmin formation [8]. Plasmin then proteolytically degrades NCC-aggregated proteins. In addition, an immature dendritic cell comes into physical contact with the necrotic cell. Plasmin directly activates dendritic cells which transduce an immunomodulatory signal to dendritic cells that instructs immunologically discrete clearance by increasing phagocytic capacity, increasing TGF-β expression, maintaining an immature phenotype, and preventing migration to draining lymph nodes. The plasmin-stimulated dendritic cell, because of its immature status and because of high TGF-β levels is unable to effectively trigger lymphocyte proliferation and adaptive immunity.
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pone.0131216.g007: Working model for plasmin-mediated clearance of dead cells.Injury to a live cell results in necrosis and widespread aggregation of intracellular proteins via the phenomenon of Nucleocytoplasmic Coagulation (NCC) [7] (in red). Plasma membrane breakdown allows NCC-protein aggregates to bind t-PA and plasminogen and facilitate in situ plasmin formation [8]. Plasmin then proteolytically degrades NCC-aggregated proteins. In addition, an immature dendritic cell comes into physical contact with the necrotic cell. Plasmin directly activates dendritic cells which transduce an immunomodulatory signal to dendritic cells that instructs immunologically discrete clearance by increasing phagocytic capacity, increasing TGF-β expression, maintaining an immature phenotype, and preventing migration to draining lymph nodes. The plasmin-stimulated dendritic cell, because of its immature status and because of high TGF-β levels is unable to effectively trigger lymphocyte proliferation and adaptive immunity.

Mentions: We have previously shown that t-PA-mediated plasmin generation participates in the degradation of dead cells from injured tissues [7,8]. As the removal of dead cells is classically linked to innate immune response [2], we considered whether plasmin also enhances the clearance of dead cells by modulating the phagocytic function of dendritic cells. Our investigation establishes the proof-of-concept that plasmin not only promotes the phagocytic capacity of dendritic cells, but it does so in a manner that avoids dendritic cell maturation and T cell stimulatory activity. Our observations complement the findings that plasmin modulates macrophage function by increasing efferocytosis [16,31] and uptake of aggregated low-density lipoprotein [32]. Fig 7 outlines our working model for how plasmin influences both the phagocytic and non-phagocytic arms of dead cell removal.


Dendritic Cell-Mediated Phagocytosis but Not Immune Activation Is Enhanced by Plasmin.

Borg RJ, Samson AL, Au AE, Scholzen A, Fuchsberger M, Kong YY, Freeman R, Mifsud NA, Plebanski M, Medcalf RL - PLoS ONE (2015)

Working model for plasmin-mediated clearance of dead cells.Injury to a live cell results in necrosis and widespread aggregation of intracellular proteins via the phenomenon of Nucleocytoplasmic Coagulation (NCC) [7] (in red). Plasma membrane breakdown allows NCC-protein aggregates to bind t-PA and plasminogen and facilitate in situ plasmin formation [8]. Plasmin then proteolytically degrades NCC-aggregated proteins. In addition, an immature dendritic cell comes into physical contact with the necrotic cell. Plasmin directly activates dendritic cells which transduce an immunomodulatory signal to dendritic cells that instructs immunologically discrete clearance by increasing phagocytic capacity, increasing TGF-β expression, maintaining an immature phenotype, and preventing migration to draining lymph nodes. The plasmin-stimulated dendritic cell, because of its immature status and because of high TGF-β levels is unable to effectively trigger lymphocyte proliferation and adaptive immunity.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4488505&req=5

pone.0131216.g007: Working model for plasmin-mediated clearance of dead cells.Injury to a live cell results in necrosis and widespread aggregation of intracellular proteins via the phenomenon of Nucleocytoplasmic Coagulation (NCC) [7] (in red). Plasma membrane breakdown allows NCC-protein aggregates to bind t-PA and plasminogen and facilitate in situ plasmin formation [8]. Plasmin then proteolytically degrades NCC-aggregated proteins. In addition, an immature dendritic cell comes into physical contact with the necrotic cell. Plasmin directly activates dendritic cells which transduce an immunomodulatory signal to dendritic cells that instructs immunologically discrete clearance by increasing phagocytic capacity, increasing TGF-β expression, maintaining an immature phenotype, and preventing migration to draining lymph nodes. The plasmin-stimulated dendritic cell, because of its immature status and because of high TGF-β levels is unable to effectively trigger lymphocyte proliferation and adaptive immunity.
Mentions: We have previously shown that t-PA-mediated plasmin generation participates in the degradation of dead cells from injured tissues [7,8]. As the removal of dead cells is classically linked to innate immune response [2], we considered whether plasmin also enhances the clearance of dead cells by modulating the phagocytic function of dendritic cells. Our investigation establishes the proof-of-concept that plasmin not only promotes the phagocytic capacity of dendritic cells, but it does so in a manner that avoids dendritic cell maturation and T cell stimulatory activity. Our observations complement the findings that plasmin modulates macrophage function by increasing efferocytosis [16,31] and uptake of aggregated low-density lipoprotein [32]. Fig 7 outlines our working model for how plasmin influences both the phagocytic and non-phagocytic arms of dead cell removal.

Bottom Line: Plasmin also promoted phagocytosis of protease-resistant microparticles by diverse mouse dendritic cell sub-types both in vitro and in vivo.Together with an increased phagocytic capacity, plasmin-treated dendritic cells maintain an immature phenotype, exhibit reduced migration to lymph nodes, increase their expression/release of the immunosuppressive cytokine TGF-β, and lose their capacity to mount an allogeneic response.Collectively, our findings support a novel role for plasmin formed on dead cells and other phagocytic targets in maintaining tissue homeostasis by increasing the phagocytic function of dendritic cells while simultaneously decreasing their immunostimulatory capacity consistent with producing an immunosuppressive state.

View Article: PubMed Central - PubMed

Affiliation: Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct, Melbourne, 3004, Victoria Australia.

ABSTRACT
Removal of dead cells in the absence of concomitant immune stimulation is essential for tissue homeostasis. We recently identified an injury-induced protein misfolding event that orchestrates the plasmin-dependent proteolytic degradation of necrotic cells. As impaired clearance of dead cells by the innate immune system predisposes to autoimmunity, we determined whether plasmin could influence endocytosis and immune cell stimulation by dendritic cells - a critical cell that links the innate and adaptive immune systems. We find that plasmin generated on the surface of necrotic cells enhances their phagocytic removal by human monocyte-derived dendritic cells. Plasmin also promoted phagocytosis of protease-resistant microparticles by diverse mouse dendritic cell sub-types both in vitro and in vivo. Together with an increased phagocytic capacity, plasmin-treated dendritic cells maintain an immature phenotype, exhibit reduced migration to lymph nodes, increase their expression/release of the immunosuppressive cytokine TGF-β, and lose their capacity to mount an allogeneic response. Collectively, our findings support a novel role for plasmin formed on dead cells and other phagocytic targets in maintaining tissue homeostasis by increasing the phagocytic function of dendritic cells while simultaneously decreasing their immunostimulatory capacity consistent with producing an immunosuppressive state.

No MeSH data available.


Related in: MedlinePlus