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Current Biology : CB Aug 2003
Review
Topics: Animals; Annexin A1; Apoptosis; Humans; Jumonji Domain-Containing Histone Demethylases; Models, Biological; Phagocytes; Phagocytosis; Phosphatidylserines; Receptors, Cell Surface
PubMed: 12932346
DOI: 10.1016/s0960-9822(03)00575-x -
Proceedings of the National Academy of... Nov 2017Functional regeneration after axonal injury requires transected axons to regrow and reestablish connection with their original target tissue. The spontaneous...
Functional regeneration after axonal injury requires transected axons to regrow and reestablish connection with their original target tissue. The spontaneous regenerative mechanism known as axonal fusion provides a highly efficient means of achieving targeted reconnection, as a regrowing axon is able to recognize and fuse with its own detached axon segment, thereby rapidly reestablishing the original axonal tract. Here, we use behavioral assays and fluorescent reporters to show that axonal fusion enables full recovery of function after axotomy of mechanosensory neurons. Furthermore, we reveal that the phospholipid phosphatidylserine, which becomes exposed on the damaged axon to function as a "save-me" signal, defines the level of axonal fusion. We also show that successful axonal fusion correlates with the regrowth potential and branching of the proximal fragment and with the retraction length and degeneration of the separated segment. Finally, we identify discrete axonal domains that vary in their propensity to regrow through fusion and show that the level of axonal fusion can be genetically modulated. Taken together, our results reveal that axonal fusion restores full function to injured neurons, is dependent on exposure of phospholipid signals, and is achieved through the balance between regenerative potential and level of degeneration.
Topics: Animals; Axons; Axotomy; Caenorhabditis elegans; Cell Membrane; Hermaphroditic Organisms; Male; Mechanoreceptors; Nerve Regeneration; Phosphatidylserines; Recovery of Function
PubMed: 29109263
DOI: 10.1073/pnas.1703807114 -
Surgery Nov 2019Phosphatidylserine is usually an intracellularly oriented cell membrane phospholipid. Externalized phosphatidylserine on activated cells is a signal for phagocytosis. In...
BACKGROUND
Phosphatidylserine is usually an intracellularly oriented cell membrane phospholipid. Externalized phosphatidylserine on activated cells is a signal for phagocytosis. In sepsis, persistent phosphatidylserine exposure is also a signal for activation of the coagulation and inflammatory cascades. As such, phosphatidylserine may be a key molecule in sepsis induced cellular and organ injury. We hypothesize that phosphatidylserine blockade provides a protective effect in sepsis induced organ dysfunction.
METHODS
Sepsis was induced in adult female rats using an endotoxin model. Diannexin, a homodimer of annexin A5, was administered for phosphatidylserine blockade. Rats were allocated to control (n = 5), sepsis (n = 6), or sepsis and phosphatidylserine blockade (n = 9) groups. Gut, pulmonary, renal, and hematologic dysfunctions were evaluated by mesenteric microvascular fluid leak, partial pressure of oxygen, serum creatinine, activated clotting time, and glomerular fibrin deposition, respectively.
RESULTS
Rats in the sepsis group demonstrated gut, renal, and hematologic dysfunction. Phosphatidylserine blockade reversed signs of gut dysfunction and mesenteric microvascular leak (P < .01). In addition, phosphatidylserine blockade corrected systemic coagulopathy, as measured by activated clotting time (P = .03) and glomerular fibrin deposition (P = .008). There was no difference in renal dysfunction (P = .1) or pulmonary dysfunction in any of the groups (P = .6).
CONCLUSION
In sepsis, phosphatidylserine blockade had a protective effect on gut dysfunction and coagulopathy. Increased phosphatidylserine exposure may be a key mediator of organ dysfunction and coagulopathy during sepsis. These data may provide insights into novel treatment options for septic patients.
Topics: Animals; Annexin A5; Disease Models, Animal; Female; Humans; Infusions, Intravenous; Lipopolysaccharides; Multiple Organ Failure; Phosphatidylserines; Rats; Sepsis; Treatment Outcome
PubMed: 31285044
DOI: 10.1016/j.surg.2019.05.020 -
Developmental Cell Dec 2007Phagocytes recognize apoptotic cells using cell surface receptors, and subsequently engulf these cells. In a recent issue of Nature, two papers reported the... (Review)
Review
Phagocytes recognize apoptotic cells using cell surface receptors, and subsequently engulf these cells. In a recent issue of Nature, two papers reported the identification of novel phagocytic receptors that directly interact with apoptotic cell surface phosphatidylserine (PS). The studies provide new insights into the apoptotic cell clearance process and implicate PS receptors in additional signaling events.
Topics: Animals; Apoptosis; Humans; Macrophages; Phagocytosis; Phosphatidylserines; Receptors, Cell Surface
PubMed: 18061557
DOI: 10.1016/j.devcel.2007.11.009 -
PLoS Pathogens Mar 2022Regulated microneme secretion governs motility, host cell invasion and egress in the obligate intracellular apicomplexans. Intracellular calcium oscillations and...
Regulated microneme secretion governs motility, host cell invasion and egress in the obligate intracellular apicomplexans. Intracellular calcium oscillations and phospholipid dynamics critically regulate microneme exocytosis. Despite its importance for the lytic cycle of these parasites, molecular mechanistic details about exocytosis are still missing. Some members of the P4-ATPases act as flippases, changing the phospholipid distribution by translocation from the outer to the inner leaflet of the membrane. Here, the localization and function of the repertoire of P4-ATPases was investigated across the lytic cycle of Toxoplasma gondii. Of relevance, ATP2B and the non-catalytic subunit cell division control protein 50.4 (CDC50.4) form a stable heterocomplex at the parasite plasma membrane, essential for microneme exocytosis. This complex is responsible for flipping phosphatidylserine, which presumably acts as a lipid mediator for organelle fusion with the plasma membrane. Overall, this study points toward the importance of phosphatidylserine asymmetric distribution at the plasma membrane for microneme exocytosis.
Topics: Cell Membrane; Exocytosis; Microneme; Phosphatidylserines; Protozoan Proteins; Toxoplasma
PubMed: 35325010
DOI: 10.1371/journal.ppat.1010438 -
Lupus Science & Medicine Mar 2022Extracellular vesicles (EVs) released by blood cells have proinflammation and procoagulant action. Patients with systemic lupus erythematosus (SLE) present high vascular...
BACKGROUND
Extracellular vesicles (EVs) released by blood cells have proinflammation and procoagulant action. Patients with systemic lupus erythematosus (SLE) present high vascular inflammation and are prone to develop cardiovascular diseases. Therefore, we postulated that the EV populations found in blood, including platelet EVs (PEVs) and red blood cell EVs (REVs), are associated with SLE disease activity and SLE-associated cardiovascular accidents.
METHOD
We assessed autotaxin (ATX) plasma levels by ELISA, the platelet activation markers PAC1 and CD62P, ATX bound to platelets and the amounts of plasma PEVs and REVs by flow cytometry in a cohort of 102 patients with SLE, including 29 incident cases of SLE and 30 controls. Correlation analyses explored the associations with the clinical parameters.
RESULT
Platelet activation markers were increased in patients with SLE compared with healthy control, with the marker CD62P associated with the SLE disease activity index (SLEDAI). The incident cases show additional associations between platelet markers (CD62P/ATX and PAC1/CD62P) and the SLEDAI. Compared with controls, patients with SLE presented higher levels of PEVs, phosphatidylserine positive (PS) PEVs, REVs and PS REVs, but there is no association with disease activity. When stratified according to the plasma level of PS REVs, the group of patients with SLE with a high level of PS REVs presented a higher number of past thrombosis events and higher ATX levels.
CONCLUSION
Incident and prevalent forms of SLE cases present similar levels of platelet activation markers, with CD62P correlating with disease activity. Though EVs are not associated with disease activity, the incidence of past thrombotic events is higher in patients with a high level of PS REVs.
Topics: Biomarkers; Erythrocytes; Extracellular Vesicles; Humans; Lupus Erythematosus, Systemic; Phosphatidylserines; Thrombosis
PubMed: 35260475
DOI: 10.1136/lupus-2021-000605 -
Nature Chemical Biology Feb 2019Reactive oxygen species (ROS) are transient, highly reactive intermediates or byproducts produced during oxygen metabolism. However, when innate mechanisms are unable to...
Reactive oxygen species (ROS) are transient, highly reactive intermediates or byproducts produced during oxygen metabolism. However, when innate mechanisms are unable to cope with sequestration of surplus ROS, oxidative stress results, in which excess ROS damage biomolecules. Oxidized phosphatidylserine (PS), a proapoptotic 'eat me' signal, is produced in response to elevated ROS, yet little is known regarding its chemical composition and metabolism. Here, we report a small molecule that generates ROS in different mammalian cells. We used this molecule to detect, characterize and study oxidized PS in mammalian cells. We developed a chemical-genetic screen to identify enzymes that regulate oxidized PS in mammalian cells and found that the lipase ABHD12 hydrolyzes oxidized PS. We validated these findings in different physiological settings including primary peritoneal macrophages and brains from Abhd12 mice under inflammatory stress, and in the process, we functionally annotated an enzyme regulating oxidized PS in vivo.
Topics: Animals; Cell Line; Humans; Lipase; Macrophages, Peritoneal; Mice; Monoacylglycerol Lipases; Oxidation-Reduction; Oxidative Stress; Phosphatidylserines; RAW 264.7 Cells; Reactive Oxygen Species
PubMed: 30643283
DOI: 10.1038/s41589-018-0195-0 -
The EMBO Journal Aug 2020Developmental synaptic remodeling is important for the formation of precise neural circuitry, and its disruption has been linked to neurodevelopmental disorders such as...
Developmental synaptic remodeling is important for the formation of precise neural circuitry, and its disruption has been linked to neurodevelopmental disorders such as autism and schizophrenia. Microglia prune synapses, but integration of this synapse pruning with overlapping and concurrent neurodevelopmental processes, remains elusive. Adhesion G protein-coupled receptor ADGRG1/GPR56 controls multiple aspects of brain development in a cell type-specific manner: In neural progenitor cells, GPR56 regulates cortical lamination, whereas in oligodendrocyte progenitor cells, GPR56 controls developmental myelination and myelin repair. Here, we show that microglial GPR56 maintains appropriate synaptic numbers in several brain regions in a time- and circuit-dependent fashion. Phosphatidylserine (PS) on presynaptic elements binds GPR56 in a domain-specific manner, and microglia-specific deletion of Gpr56 leads to increased synapses as a result of reduced microglial engulfment of PS presynaptic inputs. Remarkably, a particular alternatively spliced isoform of GPR56 is selectively required for microglia-mediated synaptic pruning. Our present data provide a ligand- and isoform-specific mechanism underlying microglial GPR56-mediated synapse pruning in the context of complex neurodevelopmental processes.
Topics: Alternative Splicing; Animals; Mice; Mice, Transgenic; Microglia; Phosphatidylserines; Protein Binding; Protein Isoforms; Receptors, G-Protein-Coupled; Synapses
PubMed: 32452062
DOI: 10.15252/embj.2019104136 -
Nature Communications Jan 2020Annexins are abundant cytoplasmic proteins, which bind to membranes that expose negatively charged phospholipids in a Ca-dependent manner. During cell injuries, the...
Annexins are abundant cytoplasmic proteins, which bind to membranes that expose negatively charged phospholipids in a Ca-dependent manner. During cell injuries, the entry of extracellular Ca activates the annexin membrane-binding ability, subsequently initiating membrane repair processes. However, the mechanistic action of annexins in membrane repair remains largely unknown. Here, we use high-speed atomic force microscopy (HS-AFM), fluorescence recovery after photobleaching (FRAP), confocal laser scanning microscopy (CLSM) and molecular dynamics simulations (MDSs) to analyze how annexin-V (A5) binds to phosphatidylserine (PS)-rich membranes leading to high Ca-concentrations at membrane, and then to changes in the dynamics and organization of lipids, eventually to a membrane phase transition. A5 self-assembly into lattices further stabilizes and likely structures the membrane into a gel phase. Our findings are compatible with the patch resealing through vesicle fusion mechanism in membrane repair and indicate that A5 retains negatively charged lipids in the inner leaflet in an injured cell.
Topics: Annexin A5; Calcium; Fluorescence Recovery After Photobleaching; Lipid Bilayers; Membrane Fusion; Microscopy, Atomic Force; Microscopy, Confocal; Molecular Dynamics Simulation; Phase Transition; Phosphatidylserines; Protein Aggregates
PubMed: 31932647
DOI: 10.1038/s41467-019-14045-w -
The Journal of Cell Biology Nov 2001Several receptors are implicated in apoptotic cell (AC) uptake by phagocytic cells; however, their relative dominance in mammalian systems remains to be established. New... (Review)
Review
Several receptors are implicated in apoptotic cell (AC) uptake by phagocytic cells; however, their relative dominance in mammalian systems remains to be established. New studies shed light on the role of the phosphatidyl serine (PS) receptor (PSR). Ligation of PSR by PS on AC surfaces is considered essential for signaling uptake of ACs that are tethered to phagocytes via other receptors.
Topics: Animals; Apoptosis; Humans; Jumonji Domain-Containing Histone Demethylases; Phagocytosis; Phosphatidylserines; Receptors, Cell Surface; Signal Transduction
PubMed: 11706046
DOI: 10.1083/jcb.200110066