Importância da interação entre a integrina Mac-1 dos leucócitos e a glicoproteína Iba das plaquetas para o recrutamento de leucócitos pelas plaquetas e para a resposta inflamatória à lesão vascular

Zago, Alexandre do Canto; Simon, Daniel I.; Wang, Yunmei; Sakuma, Masashi; Chen, Zhiping; Croce, Kevin; Ustinov, Valentin; Shi, Chun; Filho, Eulógio Emílio Martinez

doi:10.1590/s0066-782x2008000100009

Cited by 11 publications

(8 citation statements)

References 91 publications

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“…24, 25 To further understand the role of GPIb-IX in potentially influencing outcome in murine CLP, we assessed whether disrupting GPIb-IX altered the extent of platelet association with neutrophils and monocytes. Whole blood collected from wild-type, hIL-4R/Ibα, and VWF KO mice was stained using a platelet-specific marker (CD41), a neutrophil/granulocyte marker (Gr-1), and a monocyte/macrophage marker (CD115).…”

Section: Resultsmentioning

confidence: 99%

“…This interaction most likely reflects the known GP Ib-IX/Mac-1 axis. 25, 42 However, even in the absence of GPIb-IX, there still exists platelet/neutrophil and platelet/monocyte populations. While the GP Ib-IX relevance in platelet/neutrophil and platelet/monocyte interaction seems modest, the effects on cytokine release and Mac-1 expression 24 hrs following CLP seems robust.…”

Section: Discussionmentioning

confidence: 99%

“…23 One such ligand is the leukocyte integrin Mac-1 (CD11b/CD18) which plays an integral role in promoting the migration of immune cells into extravascular tissues. 24, 25 Although there has been limited data addressing the in vivo consequences of this interaction, it establishes a potential involvement for GP Ib-IX in the process of inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Platelet Glycoprotein Ib-IX as a Regulator of Systemic Inflammation

Corken

Russell

Dent

et al. 2014

ATVB

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Objective The platelet glycoprotein (GP) Ib-IX receptor is a well characterized adhesion receptor supporting hemostasis and thrombosis via interactions with von Willebrand factor (VWF). We examine the GPIb-IX/VWF axis in murine polymicrobial sepsis, as modeled by cecal ligation and puncture (CLP). Approach and Results Genetic absence of the GPIb-IX ligand, VWF, prolongs survival following CLP, but absence of the receptor, GP Ib-IX, does not. Since absence of either VWF or GP Ib-IX significantly impairs hemostasis and thrombosis we sought to define additional GP Ib-IX-dependent pathways impacting survival in the CLP model. We document the absence of GPIb-IX leads to reduced platelet-neutrophil and platelet-monocyte interactions. Twenty four hours following CLP, absence of GP Ib-IX coincides with an alteration in cytokine levels, such as TNFα secreted by monocytes, and increased Mac-1 expression by neutrophils. Conclusions In contrast, to the well-characterized pro-inflammatory properties of platelets, we describe in the CLP model an anti-inflammatory property associated with platelet GP Ib-IX. Thus, a single platelet receptor displays a dual modulatory role in both the thrombotic and inflammatory pathways associated with polymicrobial sepsis. In sharing leucine rich motifs with toll-like receptors, platelet GPIb-IX can be considered a multi-functional participant in hemostasis, thrombosis, and the inflammatory cascade. The results highlight a dynamic role for platelets in systemic inflammation and add to the complex pathophysiologic events that occur during the dysregulated coagulation and inflammation associated with sepsis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Platelet Glycoprotein Ib-IX as a Regulator of Systemic Inflammation

Corken

Russell

Dent

et al. 2014

ATVB

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“…7,8 In particular, the integrin Mac-1 (α M β 2 or CD11b/CD18) is responsible for firm leukocyte adhesion to platelets through its interaction with the platelet surface receptor glycoprotein GPIbα (CD42b). 9,10 …”

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confidence: 99%

Adhesion Maturation of Neutrophils on Nanoscopically Presented Platelet Glycoprotein Ibα

et al. 2013

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Neutrophilic granulocytes play a fundamental role in cardiovascular disease. They interact with platelet aggregates via the integrin Mac-1 and the platelet receptor glycoprotein Ibα (GPIbα). In vivo, GPIbα presentation is highly variable under different physiological and pathophysiological conditions. Here, we quantitatively determined the conditions for neutrophil adhesion in a biomimetic in vitro system, which allowed precise adjustment of the spacings between human GPIbα presented on the nanoscale from 60 to 200 nm. Unlike most conventional nanopatterning approaches, this method provided control over the local receptor density (spacing) rather than just the global receptor density. Under physiological flow conditions, neutrophils required a minimum spacing of GPIbα molecules to successfully adhere. In contrast, under low-flow conditions, neutrophils adhered on all tested spacings with subtle but nonlinear differences in cell response, including spreading area, spreading kinetics, adhesion maturation, and mobility. Surprisingly, Mac-1-dependent neutrophil adhesion was very robust to GPIbα density variations up to 1 order of magnitude. This complex response map indicates that neutrophil adhesion under flow and adhesion maturation are differentially regulated by GPIbα density. Our study reveals how Mac-1/GPIbα interactions govern cell adhesion and how neutrophils process the number of available surface receptors on the nanoscale. In the future, such in vitro studies can be useful to determine optimum therapeutic ranges for targeting this interaction.

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“…Binding to platelets via MAC-1 and LFA-1 (integrins αM/β2 and αL/β2) contribute to priming for oxidative burst [124-126]. …”

Section: Methodsmentioning

confidence: 99%

Investigation of the essential role of platelet-tumor cell interactions in metastasis progression using an agent-based model

Uppal

Wightman

Ganai³

et al. 2014

Theor Biol Med Model

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BackgroundMetastatic tumors are a major source of morbidity and mortality for most cancers. Interaction of circulating tumor cells with endothelium, platelets and neutrophils play an important role in the early stages of metastasis formation. These complex dynamics have proven difficult to study in experimental models. Prior computational models of metastases have focused on tumor cell growth in a host environment, or prediction of metastasis formation from clinical data. We used agent-based modeling (ABM) to dynamically represent hypotheses of essential steps involved in circulating tumor cell adhesion and interaction with other circulating cells, examine their functional constraints, and predict effects of inhibiting specific mechanisms.MethodsWe developed an ABM of Early Metastasis (ABMEM), a descriptive semi-mechanistic model that replicates experimentally observed behaviors of populations of circulating tumor cells, neutrophils, platelets and endothelial cells while incorporating representations of known surface receptor, autocrine and paracrine interactions. Essential downstream cellular processes were incorporated to simulate activation in response to stimuli, and calibrated with experimental data. The ABMEM was used to identify potential points of interdiction through examination of dynamic outcomes such as rate of tumor cell binding after inhibition of specific platelet or tumor receptors.ResultsThe ABMEM reproduced experimental data concerning neutrophil rolling over endothelial cells, inflammation-induced binding between neutrophils and platelets, and tumor cell interactions with these cells. Simulated platelet inhibition with anti-platelet drugs produced unstable aggregates with frequent detachment and re-binding. The ABMEM replicates findings from experimental models of circulating tumor cell adhesion, and suggests platelets play a critical role in this pre-requisite for metastasis formation. Similar effects were observed with inhibition of tumor integrin αV/β3. These findings suggest that anti-platelet or anti-integrin therapies may decrease metastasis by preventing stable circulating tumor cell adhesion.ConclusionCirculating tumor cell adhesion is a complex, dynamic process involving multiple cell-cell interactions. The ABMEM successfully captures the essential interactions necessary for this process, and allows for in-silico iterative characterization and invalidation of proposed hypotheses regarding this process in conjunction with in-vitro and in-vivo models. Our results suggest that anti-platelet therapies and anti-integrin therapies may play a promising role in inhibiting metastasis formation.

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Importância da interação entre a integrina Mac-1 dos leucócitos e a glicoproteína Iba das plaquetas para o recrutamento de leucócitos pelas plaquetas e para a resposta inflamatória à lesão vascular

Cited by 11 publications

References 91 publications

Platelet Glycoprotein Ib-IX as a Regulator of Systemic Inflammation

Platelet Glycoprotein Ib-IX as a Regulator of Systemic Inflammation

Adhesion Maturation of Neutrophils on Nanoscopically Presented Platelet Glycoprotein Ibα

Investigation of the essential role of platelet-tumor cell interactions in metastasis progression using an agent-based model

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