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Frontiers in Immunology 2021Rheumatoid arthritis (RA) is a chronic immune-mediated disease managed by conventional synthetic drugs, such as methotrexate (MTX), and targeted drugs including... (Review)
Review
Rheumatoid arthritis (RA) is a chronic immune-mediated disease managed by conventional synthetic drugs, such as methotrexate (MTX), and targeted drugs including biological agents. Cell-based therapeutic approaches are currently developed in RA, mainly mesenchymal stroma cell-based approaches. Early-stage apoptotic cells possess direct and indirect anti-inflammatory properties. During the elimination of dying cells (a process called efferocytosis), specific mechanisms operate to control immune responses. There are compelling evidences in experimental models of arthritis indicating that apoptotic cell administration may benefit joint inflammation, and may even have therapeutic effects on arthritis. Additionally, it has been demonstrated that apoptotic cells could be administered with standard treatments of RA, such as MTX or TNF inhibitors (TNFi), given even a synergistic response with TNFi. Interestingly, apoptotic cell infusion has been successfully experienced to prevent acute graft-vs.-host disease after hematopoietic cell transplantation in patients with hematologic malignancies, with a good safety profile. In this mini-review, the apoptotic cell-based therapy development in arthritis is discussed, as well as its transfer in the short-term to an innovative treatment for patients with RA. The use of apoptotic cell-derived factors, including secretome or phosphatidylserine-containing liposomes, in RA are also discussed.
Topics: Animals; Anti-Inflammatory Agents; Antirheumatic Agents; Apoptosis; Arthritis, Rheumatoid; Cell- and Tissue-Based Therapy; Humans; Immunomodulation; Inflammation; Liposomes; Phosphatidylserines; Tumor Necrosis Factor Inhibitors
PubMed: 33717160
DOI: 10.3389/fimmu.2021.630170 -
Journal of Thrombosis and Haemostasis :... Mar 2022Cellular trauma or activation exposes phosphatidylserine (PS) and the substantially more abundant phospholipid, phosphatidylethanolamine (PE), on the outer layer of the...
BACKGROUND
Cellular trauma or activation exposes phosphatidylserine (PS) and the substantially more abundant phospholipid, phosphatidylethanolamine (PE), on the outer layer of the plasma membrane, thereby allowing binding of many blood clotting proteins. We previously proposed the Anything But Choline (ABC) hypothesis to explain how PS and PE synergize to support binding of clotting proteins with gamma-carboxyglutamate (Gla)-rich domains, which posited that each Gla domain binds to a limited number of PS molecules and multiple PE molecules. However, the minimal number of PS molecules required to stably bind a Gla-domain-containing blood clotting protein in the presence of excess PE was unknown.
OBJECTIVE
To test the ABC hypothesis for factor X by determining the threshold binding requirement of PS molecules under conditions of PS-PE synergy.
METHODS
We used surface plasmon resonance to investigate the stoichiometry of factor X binding to nanoscale membrane bilayers (Nanodiscs) of varying phospholipid composition.
RESULTS AND CONCLUSIONS
We quantified 1.05 ± 0.2 PS molecules per bound factor X molecule in Nanodiscs containing a mixture of 10% PS, 60% PE, and 30% phosphatidylcholine. Hence, there appears to be one truly PS-specific binding site per Gla domain, while the remaining membrane binding interactions can be satisfied by PE.
Topics: Binding Sites; Cell Membrane; Factor X; Humans; Phosphatidylserines; Phospholipids; Protein Binding
PubMed: 34894064
DOI: 10.1111/jth.15620 -
Proceedings of the National Academy of... May 2022The P4-ATPases ATP11A and ATP11C function as flippases at the plasma membrane to translocate phosphatidylserine from the outer to the inner leaflet. We herein...
The P4-ATPases ATP11A and ATP11C function as flippases at the plasma membrane to translocate phosphatidylserine from the outer to the inner leaflet. We herein demonstrated that Atp11a-deficient mouse embryos died at approximately E14.5 with thin-walled heart ventricles. However, the cardiomyocyte- or epiblast-specific Atp11a deletion did not affect mouse development or mortality. ATP11C may have compensated for the function of ATP11A in most of the cell types in the embryo. On the other hand, Atp11a, but not Atp11c, was expressed in the mouse placenta, and the Atp11a-null mutation caused poor development of the labyrinthine layer with an increased number of TUNEL-positive foci. Immunohistochemistry and electron microscopy revealed a disorganized labyrinthine layer with unfused trophoblasts in the Atp11a-null placenta. Human placenta-derived choriocarcinoma BeWo cells expressed the ATP11A and ATP11C genes. A lack of ATP11A and ATP11C eliminated the ability of BeWo cells to flip phosphatidylserine and fuse when treated with forskolin. These results indicate that flippases at the plasma membrane play an important role in the formation of syncytiotrophoblasts in placental development.
Topics: ATP Binding Cassette Transporter 1; Adenosine Triphosphatases; Animals; Cell Membrane; Female; Mice; Phosphatidylserines; Placenta; Pregnancy; Trophoblasts
PubMed: 35476530
DOI: 10.1073/pnas.2200582119 -
Cellular and Molecular Life Sciences :... Jun 1997Annexin V belongs to a family of phospholipid binding proteins, the Annexins. It binds in the presence of Ca(2+)-ions with high affinity to negatively charged... (Review)
Review
Annexin V belongs to a family of phospholipid binding proteins, the Annexins. It binds in the presence of Ca(2+)-ions with high affinity to negatively charged phospholipids like phosphatidylserine (PS). On the basis of its protein structure and biological activity Annexin V is considered as a protein exhibiting its hitherto unknown function within the intracellular environment. One argument comes from the understanding that PS is predominantly located in membrane leaflets, which face the cytosol. However, recent findings show that each cell type has the molecular machinery to expose PS at its cell surface. This machinery is activated during the execution of apoptosis. Once PS is exposed at the cell surface it exhibits procoagulant and proinflammatory activities. Annexin V will bind to the PS-exposing apoptotic cell and can inhibit thereby the procoagulant and pro-inflammatory activities of the dying cell. These findings together with the presence of Annexin V in the extracellular space depict a novel (patho)Physiological significance for Annexin V in vivo.
Topics: Animals; Annexin A5; Apoptosis; Blood Coagulation; Humans; Inflammation; Membranes, Artificial; Phosphatidylserines
PubMed: 9230931
DOI: 10.1007/s000180050067 -
Biochimica Et Biophysica Acta.... Feb 2021It is accepted that the cytotoxicity of beta-amyloid is mediated by its oligomers. Amyloid peptides can form ion channels in cell membranes and allow calcium and other...
It is accepted that the cytotoxicity of beta-amyloid is mediated by its oligomers. Amyloid peptides can form ion channels in cell membranes and allow calcium and other ions to enter cells. In this project, we developed a technique to quantify the appearance of calcium in liposomes and applied this technique to study the effect of amyloid peptides on the permeability of membranes. Calcium influx was monitored in liposomes made of phosphatidylcholine (PC) or phosphatidylserine (PS) with an addition of a lipid-soluble dye DiD and containing fluorescent calcium-sensitive probe Fluo-3. The intensity of fluorescence of individual liposomes was measured using a flow cytometer. Calcium ionophore ionomycin served as a positive control. The addition of micromolar concentrations of short fragments of amyloid-beta (Aβ) permeabilized a significant number of PS liposomes. This effect was not observed in PC liposomes. Our data supports the hypothesis that the ion channel formation by amyloid peptide is dependent on electrostatic interactions. High concentrations of Aβ (above 20 μM) increased signal intensity in a recording channel corresponding to the calcium-sensing probe. However, this phenomenon was also observed in Ca-free conditions and even in liposomes without Fluo-3, so we interpreted it as an artifact. Using the described technique, we were not able to detect the formation of calcium channels by several other amyloid peptides. Considering that liposomes appeared resistant to reasonable concentrations of solvents, we expect that described flowmetric technique can be used in high-throughput screening applications.
Topics: Amyloid beta-Peptides; Flow Cytometry; Humans; Ion Channels; Liposomes; Peptide Fragments; Phosphatidylcholines; Phosphatidylserines
PubMed: 33171157
DOI: 10.1016/j.bbamem.2020.183506 -
Archivum Immunologiae Et Therapiae... Jun 2011Phosphatidylserine (PS), which is normally located on the inner leaflet of the plasma membrane, translocates to the outer leaflet at the early stage of apoptosis. The PS... (Review)
Review
Phosphatidylserine-containing liposomes: potential pharmacological interventions against inflammatory and immune diseases through the production of prostaglandin E(2) after uptake by myeloid derived phagocytes.
Phosphatidylserine (PS), which is normally located on the inner leaflet of the plasma membrane, translocates to the outer leaflet at the early stage of apoptosis. The PS externalization provides a signal for phagocytes to initiate uptake of apoptotic cells. After phagocytosis of apoptotic cells, phagocytes induce the secretion of anti-inflammatory mediators including prostaglandin E(2) (PGE(2)). PS-containing liposomes (PSLs) can mimic the effects of apoptotic cells on phagocytes to induce the secretion of PGE(2). PSLs induce the PGE(2) secretion from microglia without induction of either cyclooxygenase (COX)-2 or microsomal prostaglandin E synthase (mPGES)-1. PSLs are found to rather utilize COX-1/mPGES-2 system to produce PGE(2) secretion and then shift microglia and macrophages from pro- to anti-inflammatory phenotype by an autocrine action of PGE(2). Moreover, PSLs inhibit the maturation of dendritic cells and osteoclast precursors. Therefore, PSLs will be potential pharmacological interventions for inflammatory and immune diseases through feedback mechanism utilizing PGE(2).
Topics: Animals; Autocrine Communication; Cell Differentiation; Dinoprostone; Humans; Immune System Diseases; Immunity; Liposomes; Myeloid Cells; Phagocytes; Phosphatidylserines
PubMed: 21479802
DOI: 10.1007/s00005-011-0123-4 -
Clinical Interventions in Aging 2013To evaluate the efficacy and safety of soybean-derived phosphatidylserine (SB-PS) (300 mg/day) in improving cognitive performance in elderly with memory complaints,...
OBJECTIVE
To evaluate the efficacy and safety of soybean-derived phosphatidylserine (SB-PS) (300 mg/day) in improving cognitive performance in elderly with memory complaints, following a short duration of 12 weeks' SB-PS administration.
METHODS
SB-PS was administered daily for 12 weeks to 30 elderly volunteers with memory complaints (age range 50-90 years). Cognitive performance was determined by a computerized test battery and by the Rey Auditory Verbal Learning Test (Rey-AVLT). Physical examination and blood safety parameters were part of the extensive safety analysis of PS that was performed.
RESULTS
The computerized test results showed that SB-PS supplementation significantly increased the following cognitive parameters: memory recognition (P = 0.004), memory recall (P = 0.006), executive functions (P = 0.004), and mental flexibility (P = 0.01). The Rey-AVLT indicated that, following SB-PS administration, total learning and immediate recall improved significantly (P = 0.013 and P = 0.007, respectively). Unexpected results from the safety tests suggested that SB-PS significantly reduces both systolic (P = 0.043) and diastolic (P = 0.003) blood pressure. SB-PS consumption was well tolerated and no serious adverse events were reported during the study.
CONCLUSION
This exploratory study demonstrates that SB-PS may have favorable effects on cognitive function in elderly with memory complaints. In addition, the study suggests that SB-PS is safe for human consumption and may serve as a safe alternative to phosphatidylserine extracted from bovine cortex. These results encourage further extended studies in order to establish the safety and efficacy of SB-PS treatment.
Topics: Aged; Aged, 80 and over; Analysis of Variance; Female; Geriatric Assessment; Humans; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Phosphatidylserines; Pilot Projects; Glycine max; Statistics, Nonparametric; Treatment Outcome
PubMed: 23723695
DOI: 10.2147/CIA.S40348 -
Electrogenic reaction step and phospholipid translocation pathway of the mammalian P4-ATPase ATP8A2.FEBS Letters Feb 2023ATP8A2 is a mammalian P4-ATPase (flippase) that translocates the negatively charged lipid substrate phosphatidylserine from the exoplasmic leaflet to the cytoplasmic...
ATP8A2 is a mammalian P4-ATPase (flippase) that translocates the negatively charged lipid substrate phosphatidylserine from the exoplasmic leaflet to the cytoplasmic leaflet of cellular membranes. Using an electrophysiological method based on solid supported membranes, we investigated the electrogenicity of specific reaction steps of ATP8A2 and explored a potential phospholipid translocation pathway involving residues with positively charged side chains. Changes to the current signals caused by mutations show that the main electrogenic event occurs in connection with the release of the bound phosphatidylserine to the cytoplasmic leaflet and support the hypothesis that the phospholipid interacts with specific lysine and arginine residues near the cytoplasmic border of the lipid bilayer during the translocation and reorientation required for insertion into the cytoplasmic leaflet.
Topics: Animals; Phosphatidylserines; Adenosine Triphosphatases; Phospholipid Transfer Proteins; Biological Transport; Phospholipids; Cell Membrane; Mammals
PubMed: 35945663
DOI: 10.1002/1873-3468.14459 -
Cell Communication and Signaling : CCS Jan 2020The establishment of parasitic infection is dependent on the development of efficient strategies to evade the host defense mechanisms. Phosphatidylserine (PS) molecules... (Review)
Review
The establishment of parasitic infection is dependent on the development of efficient strategies to evade the host defense mechanisms. Phosphatidylserine (PS) molecules are pivotal for apoptotic cell recognition and clearance by professional phagocytes. Moreover, PS receptors are able to trigger anti-inflammatory and immunosuppressive responses by phagocytes, either by coupled enzymes or through the induction of regulatory cytokine secretion. These PS-dependent events are exploited by parasites in a mechanism called apoptotic mimicry. Generally, apoptotic mimicry refers to the effects of PS recognition for the initiation and maintenance of pathogenic infections. However, in this context, PS molecules can be recognized on the surface of the infectious agent or in the surface of apoptotic host debris, leading to the respective denomination of classical and non-classical apoptotic mimicry. In this review, we discuss the role of PS in the pathogenesis of several human infections caused by protozoan parasites. Video Abstract.
Topics: Animals; Apoptosis; Host-Parasite Interactions; Humans; Parasites; Parasitic Diseases; Phosphatidylserines
PubMed: 31941500
DOI: 10.1186/s12964-019-0482-8 -
Cell Reports Aug 2018Phagocytic clearance of degenerating dendrites or axons is critical for maintaining tissue homeostasis and preventing neuroinflammation. Externalized phosphatidylserine...
Phagocytic clearance of degenerating dendrites or axons is critical for maintaining tissue homeostasis and preventing neuroinflammation. Externalized phosphatidylserine (PS) has been postulated to be an "eat-me" signal allowing recognition of degenerating neurites by phagocytes. Here we show that in Drosophila, PS is dynamically exposed on degenerating dendrites during developmental pruning and after physical injury, but PS exposure is suppressed when dendrite degeneration is genetically blocked. Ectopic PS exposure via phospholipid flippase knockout and scramblase overexpression induced PS exposure preferentially at distal dendrites and caused distinct modes of neurite loss that differ in larval sensory dendrites and in adult olfactory axons. Surprisingly, extracellular lactadherin that lacks the integrin-interaction domain induced phagocyte-dependent degeneration of PS-exposing dendrites, revealing an unidentified bridging function that potentiates phagocytes. Our findings establish a direct causal relationship between PS exposure and neurite degeneration in vivo.
Topics: Animals; Drosophila; Drosophila Proteins; Nerve Degeneration; Neurites; Phosphatidylserines
PubMed: 30157423
DOI: 10.1016/j.celrep.2018.07.095