Macrophage recognition of externalized phosphatidylserine and phagocytosis of apoptotic Jurkat cells—existence of a threshold

Borisenko, Grigory G.; Matsura, Tatsuya; Liu, Shangxi; Tyurin, Vladimir A.; Jiang, Jianing; Serinkan, F. Behice; Kagan, Valerian E.

doi:10.1016/s0003-9861(03)00083-3

Cited by 115 publications

(101 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…An equal amount of cell lysate was separated by 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis, followed by immunoblotting on Hybond-P membranes (Amersham Pharmacia Biotech, Buckinghamshire, UK). Proteins were visualized using the enhanced chemiluminescence detection system (Amersham Pharmacia Biotech) after incubation overnight at 41C with the following antibodies: anti-rabbit polyclonal ANXA1 antibody, 15 anti-mouse monoclonal ANXA1 antibody (Santa Cruz Biotechnology, Santa Cruz, CA, USA), and anti-procaspase-3 and anti-cleaved caspase-3 antibodies (Cell Signaling Technology, Beverly, MA, USA). Anti-b-actin (Abcam, Cambridge, MA, USA) blots were run in parallel as loading controls.…”

Section: Dna-chipmentioning

confidence: 99%

“…Depending on the cell system, it is implicated in apoptosis induction, 10 caspase-3 activation, 11,12 cell growth inhibition, 13,14 and phagocytosis. 15 Further, downregulation of ANXA1 expression has been reported to correlate with tumor progression in head and neck cancer. 10 In this study, we discovered that FK228 induced histone acetylation, induction of ANXA1 gene expression and C/EBPa binding in ANXA1 promoter specifically in AML1/ ETO-expressing AML cells, and these effects contributed to apoptotic cell death and the engulfment of apoptotic cells by macrophages.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Novel role of HDAC inhibitors in AML1/ETO AML cells: activation of apoptosis and phagocytosis through induction of annexin A1

et al. 2007

View full text Add to dashboard Cite

The chimeric fusion protein AML1-ETO, created by the t(8;21) translocation, recruits histone deacetylase (HDAC) to AML1-dependent promoters, resulting in transcriptional repression of the target genes. We analyzed the transcriptional changes in t(8;21) Kasumi-1 AML cells in response to the HDAC inhibitors, depsipeptide (FK228) and suberoylanilide hydroxamic acid (SAHA), which induced marked growth inhibition and apoptosis. Using cDNA array, annexin A1 (ANXA1) was identified as one of the FK228-induced genes. Induction of ANXA1 mRNA was associated with histone acetylation in ANXA1 promoter and reversal of the HDAC-dependent suppression of C/EBPa by AML1-ETO with direct recruitment of C/EBPa to ANXA1 promoter. This led to increase in the N-terminal cleaved isoform of ANXA1 protein and accumulation of ANXA1 on cell membrane. Neutralization with anti-ANXA1 antibody or gene silencing with ANXA1 siRNA inhibited FK228-induced apoptosis, suggesting that the upregulation of endogenous ANXA1 promotes cell death. FK228-induced ANXA1 expression was associated with massive increase in cell attachment and engulfment of Kasumi-1 cells by human THP-1-derived macrophages, which was completely abrogated with ANXA1 knockdown via siRNA transfection or ANXA1 neutralization. These findings identify a novel mechanism of action of HDAC inhibitors, which induce the expression and externalization of ANXA1 in leukemic cells, which in turn mediates the phagocytic clearance of apoptotic cells by macrophages.

show abstract

Section: Dna-chipmentioning

confidence: 99%

mentioning

confidence: 99%

Novel role of HDAC inhibitors in AML1/ETO AML cells: activation of apoptosis and phagocytosis through induction of annexin A1

et al. 2007

View full text Add to dashboard Cite

show abstract

“…12,13 Another paradox with the concept that PS is the universal 'eat-me' signal comes from observations that, during normal physiologic activation, several cell types including macrophages, lymphocytes and endothelial cells externalize PS at levels sufficient for detection, yet escape engulfment. 14 Furthermore, although both apoptotic and necrotic cells expose PS to varying degrees, 15 consequences of their engulfment are starkly different. 2 This raises the question as to whether cell surface appearance of PS is the single universal harbinger of phagocytosis or there are other ligands that have equally important roles as co-activators of engulfment.…”

mentioning

confidence: 99%

Oxidatively modified phosphatidylserines on the surface of apoptotic cells are essential phagocytic ‘eat-me’ signals: cleavage and inhibition of phagocytosis by Lp-PLA2

et al. 2014

View full text Add to dashboard Cite

Diversified anionic phospholipids, phosphatidylserines (PS), externalized to the surface of apoptotic cells are universal phagocytic signals. However, the role of major PS metabolites, such as peroxidized species of PS (PSox) and lyso-PS, in the clearance of apoptotic cells has not been rigorously evaluated. Here, we demonstrate that H 2 O 2 was equally effective in inducing apoptosis and externalization of PS in naive HL60 cells and in cells enriched with oxidizable polyunsaturated species of PS (supplemented with linoleic acid (LA)). Despite this, the uptake of LA-supplemented cells by RAW264.7 and THP-1 macrophages was more than an order of magnitude more effective than that of naive cells. A similar stimulation of phagocytosis was observed with LA-enriched HL60 cells and Jurkat cells triggered to apoptosis with staurosporine. This was due to the presence of PSox on the surface of apoptotic LA-supplemented cells (but not of naive cells). This enhanced phagocytosis was dependent on activation of the intrinsic apoptotic pathway, as no stimulation of phagocytosis occurred in LA-enriched cells challenged with Fas antibody. Incubation of apoptotic cells with lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ), a secreted enzyme with high specificity towards PSox, hydrolyzed peroxidized PS species in LA-supplemented cells resulting in the suppression of phagocytosis to the levels observed for naive cells. This suppression of phagocytosis by Lp-PLA 2 was blocked by a selective inhibitor of Lp-PLA 2 , SB-435495. Screening of possible receptor candidates revealed the ability of several PS receptors and bridging proteins to recognize both PS and PSox, albeit with diverse selectivity. We conclude that PSox is an effective phagocytic 'eat-me' signal that participates in the engulfment of cells undergoing intrinsic apoptosis.

show abstract

“…In contrast, upon induction by apoptosis by anti-fas or camptothecin, the PtdSer on the outer leaflet of membrane goes up to>240 picomoles/million cells [46]. These differences in the amount of eat me signal between live and apoptotic cell make the phagocyte to recognize the apoptotic cell.…”

Section: Masking "Don't Eat Me" Signal By "Eat Me Signal"mentioning

confidence: 97%

“…Their existence is dominated by the presence of don't eat me signal (CD47) [45,46]. Moreover the natural existence of PtdSer ((Phosphatidylserine) on the live cell is very low<0.9 picomoles/million cells [46], which is not sufficient to engulf a nonapoptotic cell.…”

Section: Masking "Don't Eat Me" Signal By "Eat Me Signal"mentioning

confidence: 99%

Masking Anti-Phagocytic Signal of Tumor by Pro-Phagocytic Signal-a Key to Immurement of Cancer Cell

Mickymaray

Gurusamy

Natarajan

2016

Int J Pharm Pharm Sci

View full text Add to dashboard Cite

Immune surveillance is a mechanism where cells and tissues are watched constantly by ever alerted immune system. Most incipient cancer cells are recognized and eliminated by the immune surveillance mechanism, but still tumors have the ability to evade immune surveillance and immunological killing. One greater arm that tumor use to evade immune surveillance, is by expressing anti-phagocytic signal (CD47). Here we present a provocative hypothesis where cancer cells are removed alive by phagocytic cell (DC). That in turn will elicit effective and higher immunogenic condition. All this could be possible by addition pro-phagocytic signal (PtdSer) over cancer cell surface (Breast Cancer), that mask the presence of anti-phagocytic signal (CD47). In other words, adding eat me signal (PtdSer) over the breast cancer cell surface that mask the presence of don't eat me signal or anti-phagocytic signal present in breast cancer cell surface. This could be possible by using bi-specific antibody, conjugated to PEG-modified liposomes, which carry (PtdSer) pro-phagocytic signal (or) eat me signal, which target both CD47 and EGFRVIII on breast carcinoma. The simultaneous masking of anti-phagocytic signal, and adding of pro-phagocytic signal over cancer cell, will enhance the phagocytic clearance of live tumor cell and elicit immunological killing.

show abstract

Macrophage recognition of externalized phosphatidylserine and phagocytosis of apoptotic Jurkat cells—existence of a threshold

Cited by 115 publications

References 40 publications

Novel role of HDAC inhibitors in AML1/ETO AML cells: activation of apoptosis and phagocytosis through induction of annexin A1

Novel role of HDAC inhibitors in AML1/ETO AML cells: activation of apoptosis and phagocytosis through induction of annexin A1

Oxidatively modified phosphatidylserines on the surface of apoptotic cells are essential phagocytic ‘eat-me’ signals: cleavage and inhibition of phagocytosis by Lp-PLA2

Masking Anti-Phagocytic Signal of Tumor by Pro-Phagocytic Signal-a Key to Immurement of Cancer Cell

Contact Info

Product

Resources

About