Phosphatidylserine, a death knell

Schlegel, Robert; Williamson, Patrick

doi:10.1038/sj.cdd.4400817

Cited by 327 publications

(260 citation statements)

References 163 publications

(136 reference statements)

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“…Recently, a similar domain in a homologous molecule Stabilin-2 has been shown to play a key role in the clearance of aged and apoptotic cells through recognition of the exposed phosphatidyl serine (PS) on the cell surface [21]. Since externalization of PS can also occur during many other cellular processes, like platelet activation and T-cell migration [22,23] and the phenomenon has been observed on human tumor cells also [24], it can be hypothesized that the 3-372 Ab inhibits the interaction between these EGF-like domains of Clever-1/Stabilin-1 on the endothelium and externalized PS of the transmigrating cell. The recycling nature of Clever-1/Stabilin-1 also fits well to this idea, especially when the cells are transmigrating via the transcellular route.…”

Section: Discussionmentioning

confidence: 99%

Clever‐1/Stabilin‐1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation

et al. 2009

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Clever-1/Stabilin-1 is a scavenger receptor present on lymphatic and sinusoidal endothelium as well as on a subset of type II macrophages. It is also induced on vasculature at sites of inflammation. However, its in vivo function has remained practically unknown and this work addresses those unknown aspects. We demonstrate using in vivo models that Clever-1/Stabilin-1 mediates migration of T and B lymphocytes to the draining lymph nodes in vivo and identify the adhesive epitope of the Clever-1/Stabilin-1 molecule responsible for the interaction between lymphocytes and lymphatic endothelium. Moreover, we demonstrate that Ab blocking of Clever-1/Stabilin-1 efficiently inhibits peritonitis in mice by decreasing the entrance of granulocytes by 50%, while migration of monocytes and lymphocytes into the inflamed peritoneum is prevented almost completely. Despite efficient anti-inflammatory activity the Ab therapy does not dramatically dampen immune responses against the bacterial and foreign protein Ag tested and bacterial clearance. These results indicate that anti-Clever-1/Stabilin-1 treatment can target two different arms of the vasculature -traffic via lymphatics and inflamed blood vessels. IntroductionImmune cell trafficking between blood and lymphoid organs is an essential element in the proper functioning of the immune system. The mechanisms mediating lymphocyte entrance from the blood into the lymphoid organs and leukocyte trafficking to sites of inflammation are well known [1][2][3]. In contrast, mechanisms involved in lymphocyte migration from the periphery via the afferent lymphatics into the draining lymph nodes and their exit from the lymph nodes are poorly known. Besides lymphocytes, many tumors also use lymphatics for dissemination to distant sites of the body [4]. Eur. J. Immunol. 2009. 39: 3477-3487 DOI 10.1002 Innate immunity 3477Clever-1/Stabilin-1, also known as Feel-1, is a multifunctional molecule possessing scavenging ability on a subset of type II macrophages [5,6]. It is also present both on afferent and efferent lymphatic endothelial cells and sinusoidal endothelial cells in the liver and spleen [7][8][9][10]. In man, it is brightly expressed on high endothelial venules (HEV), which are the specific vessels within organized lymphatic tissues mediating lymphocyte entrance into the tissues, and on sinusoidal macrophages. Moreover, at sites of inflammation its expression is induced in flat-walled vessels. On lymphatic vasculature it is able to bind lymphocytes and certain tumor cells and on inflamed blood vessel endothelium it can mediate adhesion of lymphocytes, granulocytes and monocytes [8,11]. In vitro analyses have indicated it to be important in the transmigration step during the leukocyte extravasation process [12].Clever-1/Stabilin-1 is involved in two intracellular trafficking pathways, namely in receptor mediated endocytosis and recycling as well as in shuttling between endosomal compartment and trans-Golgi network. These complex mechanisms require interactions with several molecules ...

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Section: Discussionmentioning

confidence: 99%

Clever‐1/Stabilin‐1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation

et al. 2009

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“…For instance, apoptosis-induced PS exposure occurs over a much longer time scale (hours) than the Ca 2 þ -induced scrambling process in platelets (minutes). 11 Contortions of the plasma membrane, commonly referred to as blebbing, are a characteristic feature of apoptosis, and occur downstream of caspase-dependent activation of the ROCK kinase. 1 PS externalization can, in some cases, be divorced from membrane blebbing; however, macrophage engulfment of PS-positive cell corpses appears to be less efficient when blebbing is prevented (unpublished findings).…”

Section: Ps Signaling Is Required For Programmed Cell Clearancementioning

confidence: 99%

“…14 Furthermore, developing myotubes, as well as megakaryocytes and megakaryoblasts, exhibit PS externalization, and this alteration of the plasma membrane was proposed to be involved in the process of membrane fusion, a critical feature of both myotube formation and platelet release from progenitor cells. 11 A large proportion of nonapoptotic B cells in mice were also reported to bind annexin V, and PS externalization in this cell population was suggested to play a role in antigen receptor-mediated signaling. 15 Moreover, transient, caspaseindependent PS externalization occurs on the surface of numerous cell types upon Chlamydia trachomatis and Chlamydia pneumoniae infection.…”

Section: Emerging Roles For Ps Signaling In Nonapoptotic Cellsmentioning

confidence: 99%

“…24 Others have speculated that PS molecules on viable cells could somehow be masked, and unavailable for recognition by macrophages. 11 However, masking of externalized PS in vivo by administration of a mutant form of MFG-E8 was recently found to trigger autoantibody production in mice, 25 making this an unlikely explanation. On the other hand, it is conceivable that viable cells could express other, dominant signals that discourage engulfment in spite of PS externalization.…”

Section: Emerging Roles For Ps Signaling In Nonapoptotic Cellsmentioning

confidence: 99%

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PS externalization: from corpse clearance to drug delivery

Fadeel¹,

Xue²

2005

Cell Death Differ

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Phosphatidylserine (PS) externalization on the plasma membrane of aging red blood cells and on apoptotic cell corpses serves as a common recognition signal for macrophages. 1 Perturbation of phospholipid asymmetry and rapid redistribution of PS also occurs in platelets and provides a procoagulant surface that promotes blood clotting. 2 In addition, several recent studies have revealed novel roles for altered plasma membrane phospholipid distribution in nonapoptotic cells. The aim of the present discourse is to highlight these emerging roles for PS externalization, and some of the putative therapeutic implications thereof. PS signaling is required for programmed cell clearancePhospholipid asymmetry is a common feature of all eukaryotic membranes. Moreover, mitotic and quiescent cells invest considerable amounts of energy to generate and maintain membrane lipid sidedness. Loss of phospholipid asymmetry and the concomitant externalization of PS can be readily monitored by the use of fluorescence-conjugated annexin V, an endogenous protein that specifically binds to PS, and this process has been well studied in platelets. Thus, when platelets are activated by agonists, such as thrombin and collagen, PS is rapidly brought to the surface of the cell. Exposed PS then catalyzes the assembly of proteins of the coagulation system, leading to a conversion of soluble fibrinogen into an insoluble fibrin clot. 2 The pivotal role of PS externalization is illustrated in Scott syndrome, a bleeding disorder characterized by an impaired Ca 2 þ -induced phospholipid scrambling, and hence an inability of platelets to promote blood coagulation. 2 Apoptotic cells are also procoagulant, and annexin V can completely abolish the procoagulant activity, suggesting that this effect is PS-dependent. 3 More recent findings suggest that annexin V-induced internalization of tissue factor (TF), the initiator of blood coagulation, may also contribute to the anticoagulant functions of annexin V (discussed below).The ability of PS to act as a signal for in vivo recognition and clearance of effete cells was demonstrated 20 years ago in studies of red blood cells. 4 Subsequent studies by Fadok et al. 5 showed that PS externalization also can trigger specific recognition and removal of apoptotic cells, and the exposition of PS was soon found to be a common, if not universal, event during apoptosis. 6 More recent studies have shown that PS externalization is, in fact, essential for corpse clearance by macrophages and nonprofessional phagocytes (fibroblasts). 1 Moreover, our studies have indicated that the generation of oxidized PS species (PS-OX) is an integral part of the apoptosis program. 7 Externalization of PS-OX on the cell surface potentiates macrophage engulfment of apoptotic cells, and could also serve to promote the binding of so-called bridging molecules (serum proteins) to apoptotic cell corpses. 8 Interestingly, deletion in mice of the PS-binding bridging molecule, milk fat globule epidermal growth factor 8 (MFG-E8) (also known as lactadhe...

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“…13 Another method utilizes fluorescently labeled Annexin-V to detect the loss of membrane phospholipid asymmetry that occurs from early stages of apoptosis. 14 15 Fluorescent zinc(II) probe FluoZin-3, developed by Molecular Probes (Eugene, OR), was invented by modifying the chelating BAPTA portion of fluorescent Ca(II) indicators by stripping one of its four carboxyl groups to retain good zinc(II) affinity while abolishing Ca(II) affinity. 16 This new fluorescent probe, mostly used to detect zinc(II) coreleasing with insulin from pancreatic, is more sensitive toward zinc(II) over Ca(II), and has a large dynamic range that can be exploited for measuring relatively high zinc(II) concentrations.…”

Section: Introductionmentioning

confidence: 99%

Tracing of intracellular zinc(II) fluorescence flux to monitor cell apoptosis by using FluoZin‐3AM

Shi

et al. 2009

Cell Biochemistry & Function

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Changes in the free zinc(II) concentration are closely related to cell proliferation and apoptosis, especially during the early apoptotic process. In the present paper, we demonstrated that zinc(II) probe FluoZin-3AM owns sensitive properties to distinguish different stages of apoptotic cell (induced by an anticancer agent, etoposide) according to trace intracellular zinc(II) fluorescence flux. When apoptosis in HeLa or K562 cells was artificially induced, FluoZin-3AM selectively and strongly stained apoptotic cells only at early and middle stages, which was attributed to significantly increased free zinc(II) flux during these stages. This conclusion was further verified by comparing it with the conventional apoptosis detector probe Annexin-V-FITC and PI. Furthermore, FluoZin-3AM was found cell permeable to detect the intracellular zinc(II) fluorescence enhancement to threefolds within 120 s with low cytotoxicity when zinc(II) was incorporated into the cell by zinc(II) ionophore pyrithione. All the above implied that monitoring intracellular zinc fluorescence flux was an effective method to distinguish cell apoptosis from necrosis, and FluoZin-3AM was found to be a suitable probe acting alone to fulfill the work.

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Phosphatidylserine, a death knell

Cited by 327 publications

References 163 publications

Clever‐1/Stabilin‐1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation

Clever‐1/Stabilin‐1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation

PS externalization: from corpse clearance to drug delivery

Tracing of intracellular zinc(II) fluorescence flux to monitor cell apoptosis by using FluoZin‐3AM

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