Accelerated Clearance of Plasmodium-infected Erythrocytes in Sickle Cell Trait and Annexin-A7 Deficiency

Lang, Philipp A.; Kasinathan, Ravi S.; Brand, Verena; Duranton, Christophe; Lang, Camelia; Koka, Saisudha; Shumilina, Ekaterina; Kempe, Daniela S.; Tanneur, Valérie; Akel, Ahmad; Lang, Karl S.; Föller, Michael; Kun, Jürgen F. J.; Kremsner, Peter G.; Wesselborg, Sebastian; Laufer, Stefan; Clemen, Christoph S.; Herr, Claudia; Noegel, Angelika A.; Wieder, Thomas; Gulbins, Erich; Läng, Florian; Huber, Stephan M.

doi:10.1159/000257529

Cited by 126 publications

(113 citation statements)

References 71 publications

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“…Earlier experiments revealed that coating of eryptotic erythrocytes with annexin-V interfered with the engulfment of the eryptotic cells by macrophages (37). According to the present observations, the clearance of erythrocytes could be fostered by interaction of CXCL16/SR-PSOX highly expressed on macrophages and phosphatidylserine exposed on erythrocyte surfaces.…”

Section: Discussionsupporting

confidence: 66%

Dynamic adhesion of eryptotic erythrocytes to endothelial cells via CXCL16/SR-PSOX

Borst

Abed²,

Alesutan³

et al. 2012

American Journal of Physiology-Cell Physiology

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222

215

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Suicidal death of erythrocytes, or eryptosis, is characterized by cell shrinkage and cell membrane scrambling leading to phosphatidylserine exposure at the cell surface. Eryptosis is triggered by increase of cytosolic Ca2+activity, which may result from treatment with the Ca2+ionophore ionomycin or from energy depletion by removal of glucose. The present study tested the hypothesis that phosphatidylserine exposure at the erythrocyte surface fosters adherence to endothelial cells of the vascular wall under flow conditions at arterial shear rates and that binding of eryptotic cells to endothelial cells is mediated by the transmembrane CXC chemokine ligand 16 (CXCL16). To this end, human erythrocytes were exposed to energy depletion (for 48 h) or treated with the Ca2+ionophore ionomycin (1 μM for 30 min). Phosphatidylserine exposure was quantified utilizing annexin-V binding, cell volume was estimated from forward scatter in FACS analysis, and erythrocyte adhesion to human vascular endothelial cells (HUVEC) was determined in a flow chamber model. As a result, both, ionomycin and glucose depletion, triggered eryptosis and enhanced the percentage of erythrocytes adhering to HUVEC under flow conditions at arterial shear rates. The adhesion was significantly blunted in the presence of erythrocyte phosphatidylserine-coating annexin-V (5 μl/ml), of a neutralizing antibody against endothelial CXCL16 (4 μg/ml), and following silencing of endothelial CXCL16 with small interfering RNA. The present observations demonstrate that eryptotic erythrocytes adhere to endothelial cells of the vascular wall in part by interaction of phosphatidylserine exposed at the erythrocyte surface with endothelial CXCL16.

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Section: Discussionsupporting

confidence: 66%

Dynamic adhesion of eryptotic erythrocytes to endothelial cells via CXCL16/SR-PSOX

Borst

Abed²,

Alesutan³

et al. 2012

American Journal of Physiology-Cell Physiology

Self Cite

222

215

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“…Interestingly, pharmacological inhibition of COX1/2 enzymes significantly attenuated the enhanced production of PGE 2 in AnxA7 -/-erythrocytes, indicating that AnxA7 negatively regulates COX-dependent PGE 2 formation. This observation may have clinical significance, as accelerated eryptosis of plasmodium-infected erythrocytes from the AnxA7 KO mice confers partial protection to malaria in vivo (Lang et al, 2009). Intriguingly, although earlier research linked several annexins with inhibition of PLA 2 (Gerke and Moss, 2002), only COX but not PLA 2 inhibitors abolished the differences in parasitemia and survival between AnxA7…”

Section: Anxa7 Ko Micementioning

confidence: 90%

Annexins – insights from knockout mice

Grewal

Wason

Enrich

et al. 2016

Biological Chemistry

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Annexins are a highly conserved protein family that bind to phospholipids in a calcium (Ca 2+ ) -dependent manner. Studies with purified annexins, as well as overexpression and knockdown approaches identified multiple functions predominantly linked to their dynamic and reversible membrane binding behavior. However, most annexins are found at multiple locations and interact with numerous proteins. Furthermore, similar membrane binding characteristics, overlapping localizations and shared interaction partners have complicated identification of their precise functions. To gain insight into annexin function in vivo, mouse models deficient of annexin A1 (AnxA1), A2, A4, A5, A6 and A7 have been generated. Interestingly, with the exception of one study, all mice strains lacking one or even two annexins are viable and develop normally. This suggested redundancy within annexins, but examining these knockout (KO) strains under stress conditions revealed striking phenotypes, identifying underlying mechanisms specific for individual annexins, often supporting Ca 2+ homeostasis and membrane transport as central for annexin biology. Conversely, mice lacking AnxA1 or A2 show extracellular functions relevant in health and disease that appear independent of membrane trafficking or Ca 2+ signaling. This review will summarize the mechanistic insights gained from studies utilizing mouse models lacking members of the annexin family.

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“…Prostaglandins, COX metabolites of arachidonic acid, can serve as indicators of inflammatory conditions, 40,41 for example, during ischemia and inflammatory conditions. 17,29,42 Lungs perfused with HbSS erythrocytes produced more PGE 2 , suggesting that HbSS erythrocytes can also induce acute inflammatory condition in the pulmonary microvasculature, perhaps because of reperfusion injury. Sustained production of PGE 2 also suggests tissue injury compounded with inflammatory conditions.…”

Section: Discussionmentioning

confidence: 99%

Sickle Erythrocytes and Platelets Augment Lung Leukotriene Synthesis with Downregulation of Anti‐Inflammatory Proteins: Relevance in the Pathology of the Acute Chest Syndrome

et al. 2014

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Initiation, progression, and resolution of vaso-occlusive pain episodes in sickle cell disease (SCD) have been recognized as reperfusion injury, which provokes an inflammatory response in the pulmonary circulation. Some 5-lipoxygenase (5-lox) metabolites are potent vasoconstrictors in the pulmonary circulation. We studied stimulation of production of the inflammatory eicosanoids leukotrienes (LTs) and prostaglandin E 2 (PGE 2 ) by isolated rat lungs perfused with sickle (HbSS) erythrocytes. Our hypothesis is that HbSS erythrocytes produce more LTs than normal (HbAA) erythrocytes, which can induce vaso-occlusive episodes in SCD patients. Lung perfusates were collected at specific time points and purified by high-pressure liquid chromatography, and LTC 4 and PGE 2 contents were measured by enzyme-linked immunosorbent assay (ELISA). Rat lung explants were also cultured with purified HbAA and HbSS peptides, and 5-lox, cyclooxygenase 1/2, and platelet-activating factor receptor (PAFR) proteins were measured by Western blotting, while prostacyclin and LTs produced by cultured lung explants were measured by ELISA. Lung weight gain and blood gas data were not different among the groups. HbSS-perfused lungs produced more LTC 4 and PGE 2 than HbAA-perfused lungs: 10.40 AE 0.62 versus 0.92 AE 0.2 ng/g dry lung weight (mean AE SEM; P ¼ 0.0001) for LTC 4 . Inclusion of autologous platelets (platelet-rich plasma) elevated LTC 4 production to 12.6 AE 0.96 and 7 AE 0.60 ng/g dry lung weight in HbSS and HbAA perfusates, respectively. HbSS lungs also expressed more 5-lox and PAFR. The data suggest that HbSS erythrocytes and activated platelets in patient's pulmonary microcirculation will enhance the synthesis and release of the proinflammatory mediators LTC 4 and PGE 2 , both of which may contribute to onset of the acute chest syndrome in SCD.

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Accelerated Clearance of Plasmodium-infected Erythrocytes in Sickle Cell Trait and Annexin-A7 Deficiency

Cited by 126 publications

References 71 publications

Dynamic adhesion of eryptotic erythrocytes to endothelial cells via CXCL16/SR-PSOX

Dynamic adhesion of eryptotic erythrocytes to endothelial cells via CXCL16/SR-PSOX

Annexins – insights from knockout mice

Sickle Erythrocytes and Platelets Augment Lung Leukotriene Synthesis with Downregulation of Anti‐Inflammatory Proteins: Relevance in the Pathology of the Acute Chest Syndrome

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