Mechanisms of increased mitochondria-dependent necrosis in Wiskott-Aldrich syndrome platelets

Obydennyi, Sergey I.; Artemenko, Elena O.; Sveshnikova, Anastasia; Ignatova, Anastasia A.; Варламова, Т. В.; Gambaryan, Stepan; Lomakina, G. Yu.; Ugarova, N. N.; Kireev, Igor I.; Ataullakhanov, Fazoil I.; Novichkova, Galina; Maschan, Aleksey; Shcherbina, Anna; Panteleev, Mikhail A.

doi:10.3324/haematol.2018.214460

Cited by 29 publications

(35 citation statements)

References 40 publications

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“…The WASP-deficient neutrophils also showed reduced integrin-dependent degranulation and respiratory burst (47). On the other hand, enhanced granulocyte recruitment to the growing thrombi, observed in our study, can be the result of the higher proportion of procoagulant platelets in WAS patients (48,49). Therefore, the findings of our study are consistent with previous reports on platelets and granulocytes in WAS.…”

Section: Discussionsupporting

confidence: 93%

Ex vivoobservation of granulocyte activity during thrombus formation

Martyanov

et al. 2020

Preprint

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Infiltration of growing thrombi by leukocytes, being the key part of the thromboinflammation, is well established in vivo. The study was aimed at the development of an ex vivo simulation of this phenomenon. Thrombus formation in anticoagulated whole blood from healthy volunteers and patients was visualized by fluorescent microscopy in parallel-plate flow chambers with fibrillar collagen type I coverslips.Moving CD66b-positive cells (granulocytes) were observed in hirudinated or recalcified blood under low wall shear rate conditions (<200 s−1). These cells crawled around thrombi in a step-wise manner with an average rate of 70 nm/s. Pre-incubation of blood with leukocyte priming agents lead to a significant increase in average cell velocity. On the contrary, leukocytes from Wiskott-Aldrich syndrome patients demonstrated a 1.5-fold lower average velocity, in line with their impaired actin polymerization.Thereby, the observed features of granulocytes crawling are consistent with the neutrophil chemotaxis phenomenon. We conclude that the proposed ex vivo experimental setting allows us to observe granulocytes activity in near-physiological conditions.

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Section: Discussionsupporting

confidence: 93%

Ex vivoobservation of granulocyte activity during thrombus formation

Martyanov

et al. 2020

Preprint

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“…Another inherited disorder in which elevated PS exposure and Ca 2+ cyt is observed with resting platelets is the microthrombocytopenia, Wiskott-Aldrich syndrome (WAS) Upon stimulation, WAS platelets have increased susceptibility to PS exposure that occurs as a result of MPTP opening (125,126).…”

Section: Pathologies Of Phosphatidylserine Exposurementioning

confidence: 99%

Procoagulant Phosphatidylserine-Exposing Platelets in vitro and in vivo

Reddy

Rand

2020

Front. Cardiovasc. Med.

107

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The physiological heterogeneity of platelets leads to diverse responses and the formation of discrete subpopulations upon platelet stimulation. Procoagulant platelets are an example of such subpopulations, a key characteristic of which is exposure either of the anionic aminophospholipid phosphatidylserine (PS) or of tissue factor on the activated platelet surface. This review focuses on the former, in which PS exposure on a subpopulation of platelets facilitates assembly of the intrinsic tenase and prothrombinase complexes, thereby accelerating thrombin generation on the activated platelet surface, contributing importantly to the hemostatic process. Mechanisms involved in platelet PS exposure, and accompanying events, induced by physiologically relevant agonists are considered then contrasted with PS exposure resulting from intrinsic pathway-mediated apoptosis in platelets. Pathologies of PS exposure, both inherited and acquired, are described. A consideration of platelet PS exposure as an antithrombotic target concludes the review.

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“…The discovery of a metabolic defect in WAS MDMs is, to our knowledge, the first description of its kind. However, the idea of a metabolic defect in WAS platelets was inferred as early as 40–50 years ago, with several studies observing a paucity of mitochondria and impaired mitochondrial energy production ( Trung et al, 1975 ; Verhoeven et al, 1989 ; Akkerman et al, 1982 ; Obydennyi et al, 2020 ). Although as yet unstudied, extending these metabolic defects to other immune cell lineages may go some way to explaining other immunophenotypic features of WAS including T cell anergy, progressive reduction in B and T lymphocytes with age and increasing development of autoinflammatory symptoms.…”

Section: Discussionmentioning

confidence: 99%

Wiskott Aldrich syndrome protein regulates non-selective autophagy and mitochondrial homeostasis in human myeloid cells

Rivers

Rai

Lötscher

et al. 2020

eLife

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The actin cytoskeletal regulator Wiskott Aldrich syndrome protein (WASp) has been implicated in maintenance of the autophagy-inflammasome axis in innate murine immune cells. Here, we show that WASp deficiency is associated with impaired rapamycin-induced autophagosome formation and trafficking to lysosomes in primary human monocyte-derived macrophages (MDMs). WASp reconstitution in vitro and in WAS patients following clinical gene therapy restores autophagic flux and is dependent on the actin-related protein complex ARP2/3. Induction of mitochondrial damage with CCCP, as a model of selective autophagy, also reveals a novel ARP2/3-dependent role for WASp in formation of sequestrating actin cages and maintenance of mitochondrial network integrity. Furthermore, mitochondrial respiration is suppressed in WAS patient MDMs and unable to achieve normal maximal activity when stressed, indicating profound intrinsic metabolic dysfunction. Taken together, we provide evidence of new and important roles of human WASp in autophagic processes and immunometabolic regulation, which may mechanistically contribute to the complex WAS immunophenotype.

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Mechanisms of increased mitochondria-dependent necrosis in Wiskott-Aldrich syndrome platelets

Cited by 29 publications

References 40 publications

Ex vivoobservation of granulocyte activity during thrombus formation

Ex vivoobservation of granulocyte activity during thrombus formation

Procoagulant Phosphatidylserine-Exposing Platelets in vitro and in vivo

Wiskott Aldrich syndrome protein regulates non-selective autophagy and mitochondrial homeostasis in human myeloid cells

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