bp(MESH:Phagocytosis)
Flow cytometry revealed that Torin1 treatment of TFEB transduced astrocytes increased dye-conjugated pff uptake 63% relative to EGFP transduced controls as shown by median fluorescence in- tensity, while under basal conditions, the TFEB overexpressing astrocytes increased uptake just 18% relative to EGFP expressing controls (Fig. 2 K). Thus, TFEB enhances phagocytic pathways in astrocytes, in particular increasing the uptake of pffs. PubMed:30108137
We focused on macrophage effector functions and found that heme pretreatment (15 min, 3–30 μM unless otherwise indicated) led to a strong, dose-dependent reduction of phagocytosis of E. coli by RAW264.7 macrophages compared with DMSO-treated controls (Fig. 3a,b and Supplementary Fig. 2a). PubMed:27798618
Induction of hemolysis with phenylhydrazine or addition of heme to whole blood at concentrations mimicking the physiological range of plasma heme in hemolytic patients (5–50 μM)6 led to a dose-dependent impairment of E. coli phagocytosis by neutrophils and monocytes, as compared with DMSO controls (Fig. 3g and Supplementary Fig. 2n,o), indicating that our mouse model was reflective of human hemolytic conditions. PubMed:27798618
The top performing drug identified was the antimalarial compound quinine, which fully restored phagocytosis in the presence of heme, without affecting baseline phagocytosis (Fig. 8a and Supplementary Fig. 8b,c). PubMed:27798618
Quinine pretreatment protected RAW264.7 macrophages (Fig. 8b and Supplementary Fig. 8c,d) and human macrophages (Fig. 8c) from heme-induced inhibition of phagocytosis and actin cytoskeleton changes (Supplementary Fig. 8e,f) compared with DMSO-treated cells. PubMed:27798618
The causes for RBC-based toxicant exposures are multifactorial; however, following acute transfusion, the most common occurs during the processes of extravascular hemolysis, which includes macrophage erythrophagocytosis followed by macrophage death [1&&], release of iron, transferrin (Tf) saturation and, finally, accumulation of labile plasma iron (LPI) [2]. PubMed:30281034
We quantified these changes by automatic image analysis and found that heme-induced cytoskeleton rearrangement led to a significant increase in cell area and perimeter, as well as a decrease in circularity (form factor) (Fig. 4d,e and Supplementary Fig. 3b–d), indicating that the heme-induced defective phagocytic response was likely tied to cytoskeleton rearrangements. PubMed:27798618
Together, these data indicate that heme induces extensive actin cytoskeleton alterations, which results in defective phagocytosis and inflammatory cell migration. PubMed:27798618
Our finding that DOCK8 is necessary for the cytoskeleton changes and disruption of bacterial phagocytosis by heme is consistent with recent studies showing that DOCK8 regulates dendritic cell migration via Cdc42 (refs. 37,44). PubMed:27798618
The placenta histology revealed an increased erythrophagocytosis in the starved placebo treated animals compared to controls. A1M-treatment appeared to attenuate phagocytosis (Figure 5). PubMed:24489717
Cdc42 is involved in cell motility and phagocytosis, but is mainly recognized as being a central node in the formation of lamellipodia and filopodia at the leading edge3 PubMed:27798618
The hematoma clearance may be via red blood cell (RBC) lysis or phagocytosis. PubMed:27125525
The hematoma clearance may be via red blood cell (RBC) lysis or phagocytosis. PubMed:27125525
We focused on macrophage effector functions and found that heme pretreatment (15 min, 3–30 μM unless otherwise indicated) led to a strong, dose-dependent reduction of phagocytosis of E. coli by RAW264.7 macrophages compared with DMSO-treated controls (Fig. 3a,b and Supplementary Fig. 2a). PubMed:27798618
Induction of hemolysis with phenylhydrazine or addition of heme to whole blood at concentrations mimicking the physiological range of plasma heme in hemolytic patients (5–50 μM)6 led to a dose-dependent impairment of E. coli phagocytosis by neutrophils and monocytes, as compared with DMSO controls (Fig. 3g and Supplementary Fig. 2n,o), indicating that our mouse model was reflective of human hemolytic conditions. PubMed:27798618
We quantified these changes by automatic image analysis and found that heme-induced cytoskeleton rearrangement led to a significant increase in cell area and perimeter, as well as a decrease in circularity (form factor) (Fig. 4d,e and Supplementary Fig. 3b–d), indicating that the heme-induced defective phagocytic response was likely tied to cytoskeleton rearrangements. PubMed:27798618
Together, these data indicate that heme induces extensive actin cytoskeleton alterations, which results in defective phagocytosis and inflammatory cell migration. PubMed:27798618
Cdc42 is involved in cell motility and phagocytosis, but is mainly recognized as being a central node in the formation of lamellipodia and filopodia at the leading edge3 PubMed:27798618
The top performing drug identified was the antimalarial compound quinine, which fully restored phagocytosis in the presence of heme, without affecting baseline phagocytosis (Fig. 8a and Supplementary Fig. 8b,c). PubMed:27798618
Quinine pretreatment protected RAW264.7 macrophages (Fig. 8b and Supplementary Fig. 8c,d) and human macrophages (Fig. 8c) from heme-induced inhibition of phagocytosis and actin cytoskeleton changes (Supplementary Fig. 8e,f) compared with DMSO-treated cells. PubMed:27798618
Our finding that DOCK8 is necessary for the cytoskeleton changes and disruption of bacterial phagocytosis by heme is consistent with recent studies showing that DOCK8 regulates dendritic cell migration via Cdc42 (refs. 37,44). PubMed:27798618
The causes for RBC-based toxicant exposures are multifactorial; however, following acute transfusion, the most common occurs during the processes of extravascular hemolysis, which includes macrophage erythrophagocytosis followed by macrophage death [1&&], release of iron, transferrin (Tf) saturation and, finally, accumulation of labile plasma iron (LPI) [2]. PubMed:30281034
The causes for RBC-based toxicant exposures are multifactorial; however, following acute transfusion, the most common occurs during the processes of extravascular hemolysis, which includes macrophage erythrophagocytosis followed by macrophage death [1&&], release of iron, transferrin (Tf) saturation and, finally, accumulation of labile plasma iron (LPI) [2]. PubMed:30281034
The causes for RBC-based toxicant exposures are multifactorial; however, following acute transfusion, the most common occurs during the processes of extravascular hemolysis, which includes macrophage erythrophagocytosis followed by macrophage death [1&&], release of iron, transferrin (Tf) saturation and, finally, accumulation of labile plasma iron (LPI) [2]. PubMed:30281034
The causes for RBC-based toxicant exposures are multifactorial; however, following acute transfusion, the most common occurs during the processes of extravascular hemolysis, which includes macrophage erythrophagocytosis followed by macrophage death [1&&], release of iron, transferrin (Tf) saturation and, finally, accumulation of labile plasma iron (LPI) [2]. PubMed:30281034
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.