Kinins Released by Erythrocytic Stages of Plasmodium falciparum Enhance Adhesion of Infected Erythrocytes to Endothelial Cells and Increase Blood Brain Barrier Permeability via Activation of Bradykinin Receptors

Silva, Leandro S.; Pinheiro, Alessandro S.; Teixeira, Douglas E.; Silva-Aguiar, Rodrigo P.; Peruchetti, Diogo B.; Scharfstein, Júlio; Caruso-Neves, Celso; Pinheiro, Ana Acácia S.

doi:10.3389/fmed.2019.00075

Cited by 18 publications

(15 citation statements)

References 42 publications

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“…Bradykinin is the major end-product of KKS activation, which affects the integrity of BBB by regulating the tight junction (TJ) protein ZO-1 in BMVECs; 32,33 thus, we investigated whether TK may increase normal BBB permeability by disrupting expression of ZO-1. The protein expression of ZO-1 did not change when BMVECs were treated with standard dose of TK though the abundance of B2R and the mRNA levels of B2R and eNOS were increased (Figures 5A-D and 6B and D).…”

Section: High Dose Of Tk Upregulates Normal Bbb Via B2r/enos Signal Pathwaymentioning

confidence: 99%

Increase in Blood–Brain Barrier Permeability is Modulated by Tissue Kallikrein via Activation of Bradykinin B1 and B2 Receptor-Mediated Signaling

Zhang¹,

Tan²,

Wan³

et al. 2021

JIR

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Aim: Disruption of the blood-brain barrier (BBB) is a critical pathological feature after stroke. Although tissue kallikrein (TK) has used in the treatment of stroke in China, the role of TK in modulating BBB permeability is not clear. Methods: We investigated the effect of different doses of TK on BBB by in vivo assessments of Evans blue (EB) and sodium-fluorescein isothiocyanate (FITC) leakage and in vitro assessments of the integrity of BBB and monolayers of microvascular endothelial cells (BMVECs). The expression of zonula occludens-1 (ZO-1) and bradykinin receptormediated signaling in BMVECs was detected. Results: A significant increase in BBB permeability was observed in the mice treated with high dose of TK. However, standard and medium doses of TK could only enable sodium-FITC to enter the brain. The result of in vitro study indicated that high-doses of TK, but not standard and medium-dose of TK, reduced normal BBB integrity accompanied by a decreased expression of zonula occludens-1 (ZO-1), upregulated the mRNA levels of bradykinin 2 receptor (B2R) and endothelial nitric oxide synthase (eNOS) and the abundance of B2R. Moreover, standard-dose of TK exacerbated lipopolysaccharide-induced BBB hyperpermeability, upregulated the mRNA levels of bradykinin 1 receptor (B1R) and inducible nitric oxide synthase (iNOS), increased the abundance of B1R and reduced the abundance of ZO-1; these effects were inhibited by TK inhibitor. Conclusion: TK can disrupt tight junctions and increase normal BBB permeability via B2Rdependent eNOS signaling pathway, aggravate impairment of BBB via B1R-dependent iNOS signaling pathway, and consequently serve as a useful adjunctive treatment for enhancing the efficacy of other neurotherapeutics.

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Section: High Dose Of Tk Upregulates Normal Bbb Via B2r/enos Signal Pathwaymentioning

confidence: 99%

Increase in Blood–Brain Barrier Permeability is Modulated by Tissue Kallikrein via Activation of Bradykinin B1 and B2 Receptor-Mediated Signaling

Zhang¹,

Tan²,

Wan³

et al. 2021

JIR

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“…P.falciparum has already been shown to affect host cells by modifying the culture medium 33,34 . As reticulocyte rate from uninfected erythroblasts was lower in infected culture compared to that in uninfected culture (Figure S5B), we hypothesized that parasites not only hamper the maturation of their host cells but also induce a bystander effect on the other uninfected cells in the culture.…”

Section: Parasite-conditioned Medium Induces a Delay In Erythroid Maturationmentioning

confidence: 99%

Plasmodium falciparum sexual parasites develop in human erythroblasts and affect erythropoiesis

Neveu

Richard

Dupuy

et al. 2020

Blood

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Plasmodium falciparum gametocytes, the sexual stages responsible for malaria parasites transmission from humans to mosquitoes, are key targets for malaria elimination. Immature gametocytes develop in the human bone marrow parenchyma, where they accumulate around erythroblastic islands. Notably though, the interactions between gametocytes and this hematopoietic niche have not been investigated. Here we identify late erythroblasts as a new host cell for P.falciparum sexual stages and show that gametocytes can fully develop inside these nucleated cells in vitro and in vivo, leading to infectious mature gametocytes within reticulocytes. Strikingly, we found that infection of erythroblasts by gametocytes and parasite-derived extracellular vesicles delay the erythroid differentiation, thereby allowing gametocyte maturation to coincide with the release of their host cell from the bone marrow. Taken together, our findings highlight new mechanisms that are pivotal for the maintenance of immature gametocytes in the bone marrow, and provide further insights on how Plasmodium parasites interfere with erythropoiesis and contribute to anemia in malaria patients.

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“…Other work has implicated a role for β-catenin in regulating brain barrier integrity ( Gallego-Delgado et al , 2016 ), showing that IE-derived soluble mediators are able to cause a reduction in TEER of brain endothelial cells over several hours. Similarly, parasite kinins were also shown to reduced brain endothelial cell barrier function, as well as enhancing IE cytoadherence ( Silva et al , 2019 ), and HRP2 has been implicated in modifying barrier function ( Pal et al , 2016 ). Parasite histones have also been shown to cause barrier disruption on lung and brain endothelial cells and to be released in culture by IE and in vivo in patients with CM ( Gillrie et al , 2012 ) and are increased in children with CM and associated with blood brain barrier breakdown and brain swelling ( Moxon et al , 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Testing the effect of PAR1 inhibitors on Plasmodium falciparum-induced loss of endothelial cell barrier function

et al. 2020

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Background: Sequestration and cytoadherence of Plasmodium falciparum-infected erythrocytes (IE) to microvascular endothelium alters endothelial barrier function and plays a role in the pathogenesis of severe malaria. Binding of IE is mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1) and the PfEMP1 variants that binds to endothelial protein C receptor (EPCR) have, in particular, been associated with the dysregulation of the coagulation/inflammation pathways in endothelial cells. This has prompted speculation about the role of protease-activated receptor-1 (PAR1) activation and signalling in causing endothelial activation and loss of barrier function in cerebral malaria. Methods: We used a co-culture of primary human brain microvascular endothelial cells (HBMEC) with P. falciparum material, recombinant PfEMP1 or lysates from IE, and measured barrier function by trans endothelial electrical resistance (TEER). A selection of PAR1 inhibitors was tested for their ability to reverse the P. falciparum and thrombin induced decrease in barrier function. Results: An initial screen in the presence of recombinant PfEMP1 identified a few inhibitors that were able to reduce the rapid thrombin-induced barrier disruption even when activated protein C (aPC) was unable to do so. However, PAR1 inhibitors did not rescue the barrier dysfunction after co-culture with IE lysate. Conclusions: The selected PAR1 inhibitors were able to reverse the disruption of barrier function by thrombin but did not reverse the IE lysate induced disruption of barrier function, implicating a different PAR1-independent mechanism. These findings have implications for the design of adjunct therapies to reduce brain swelling in cerebral malaria.

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Kinins Released by Erythrocytic Stages of Plasmodium falciparum Enhance Adhesion of Infected Erythrocytes to Endothelial Cells and Increase Blood Brain Barrier Permeability via Activation of Bradykinin Receptors

Cited by 18 publications

References 42 publications

Increase in Blood–Brain Barrier Permeability is Modulated by Tissue Kallikrein via Activation of Bradykinin B1 and B2 Receptor-Mediated Signaling

Increase in Blood–Brain Barrier Permeability is Modulated by Tissue Kallikrein via Activation of Bradykinin B1 and B2 Receptor-Mediated Signaling

Plasmodium falciparum sexual parasites develop in human erythroblasts and affect erythropoiesis

Testing the effect of PAR1 inhibitors on Plasmodium falciparum-induced loss of endothelial cell barrier function

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