TGF-β1 Released from Activated Platelets Can Induce TNF-Stimulated Human Brain Endothelium Apoptosis: A New Mechanism for Microvascular Lesion during Cerebral Malaria

Wassmer, Samuel C.; Souza, J. Brian de; Frère, Corinne; Candal, Francisco J.; Juhan‐Vague, I.; Grau, Georges E.

doi:10.4049/jimmunol.176.2.1180

Cited by 93 publications

(81 citation statements)

References 21 publications

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“…Platelets play a dual role in the development of CM (30,31). On the one hand, they initiate the repair of the injured endothelial barrier; on the other hand, they trigger multiple pathogenic processes, leading to microvascular alteration (10,32). Platelet reactivity involves sulfhydryl-dependent reactions on exofacial proteins.…”

Section: Discussionmentioning

confidence: 99%

Protection against cerebral malaria by the low-molecular-weight thiol pantethine

Penet

Abou-Hamdan

Coltel

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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102

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We report that administration of the low-molecular-weight thiol pantethine prevented the cerebral syndrome in Plasmodium berghei ANKA-infected mice. The protection was associated with an impairment of the host response to the infection, with in particular a decrease of circulating microparticles and preservation of the blood-brain barrier integrity. Parasite development was unaffected. Pantethine modulated one of the early steps of the inflammation-coagulation cascade, i.e., the transbilayer translocation of phosphatidylserine at the cell surface that we demonstrated on red blood cells and platelets. In this, pantethine mimicked the inactivation of the ATP-binding-cassette transporter A1 (ABCA1), which also prevents the cerebral syndrome in this malaria model. However, pantethine acts through a different pathway, because ABCA1 activity was unaffected by the treatment. The mechanisms of pantethine action were investigated, using the intact molecule and its constituents. The disulfide group (oxidized form) is necessary to lower the platelet response to activation by thrombin and collagen. Thio-sensitive mechanisms are also involved in the impairment of microparticle release by TNF-activated endothelial cells. In isolated cells, the effects were obtained by cystamine that lacks the pantothenic moiety of the molecule; however, the complete molecule is necessary to protect against cerebral malaria. Pantethine is well tolerated, and it has already been administered in other contexts to man with limited side effects. Therefore, trials of pantethine treatment in adjunctive therapy for severe malaria are warranted.blood-brain barrier ͉ phosphatidylserine ͉ Plasmodium ͉ platelet activation L ow-molecular-weight thiols, widely distributed in the living world, show broad physiological activity involving multiple targets. Among them, the dietary provitamin pantethine, a dimer of pantothenic acid linked by disulfide cystamine (1), has been the subject of much research. As a part of CoA, pantethine is a key regulator of lipid metabolism (2-4). Pantethine has been shown also to inhibit in vitro platelet aggregation in a dosedependent manner (5-7), an action that was not clearly understood (5).Because platelets play a central role in the pathological process associated with cerebral malaria (CM), we examined the effects of pantethine administration to mice infected with Plasmodium berghei strain ANKA (PbA). The processes identified by using this model are relevant to the human pathology (8). Susceptible strains of mice infected with PbA develop neurological manifestations rapidly followed by death. The pathology is due not to the direct action of the parasite but to a deleterious immune response of the infected host, involving cerebral vascular inflammation with microcirculatory dysfunction (9-13). The ultimate consequence is disruption of the brain microvasculature, enhancement of blood-brain barrier (BBB) permeability, and edema formation leading to major hemodynamic dysfunction (14-16).One of the earliest steps of the inflamm...

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Section: Discussionmentioning

confidence: 99%

Protection against cerebral malaria by the low-molecular-weight thiol pantethine

Penet

Abou-Hamdan

Coltel

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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102

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“…Sequestration of the neuropathology. The levels of anti-inflammatory cytokines such as IL-10 and TGF-β have been shown to be inversely associated with the occurrence of CM in murine malaria [7,8]. However, no consensus has been reached concerning the role of regulatory T (Treg) cells in regulation of CM pathogenesis [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Role of IL‐10‐producing regulatory B cells in control of cerebral malaria in Plasmodium berghei infected mice

Liu

Chen

et al. 2013

Eur J Immunol

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IntroductionMalaria caused by infection with protozoan parasites of Plasmodium spp. is one of the most serious infectious diseases of humans and causes about one million deaths annually. Plasmodium infection may induce multiple disease syndromes including severe anemia, metabolic acidosis, and neurological dysfunction, e.g. cerebral malaria (CM) [1]. Sequestration of the Correspondence: Dr. Zhong Su e-mail: su_zhong@gibh.ac.cn parasitized red blood cells (pRBCs) in brain microvessels is a characteristic histopathology feature observed in human and murine CM and is believed to be the primary cause of the neurological syndrome [2,3]. Evidence from more recent studies supports the notion that CM is an immune-driven pathology. The proinflammatory cytokines and mediators produced in the "cytokine storm" during malaria induce activation and recruitment of cytotoxic CD8 + cells in brain blood vessels and upregulate the expression of adhesion receptors by brain endothelial cells, leading to leukocyte accumulation and capillary obstruction, cerebral hemorrhage, and hypoxia in brain tissues [1,[4][5][6]. Therefore, the immune regulatory cells and cytokines may be critical in counteracting the inflammatory response and prevention of malaria-associated www.eji-journal.eu 2908 Yunfeng Liu et al. Eur. J. Immunol. 2013. 43: 2907-2918 neuropathology. The levels of anti-inflammatory cytokines such as IL-10 and TGF-β have been shown to be inversely associated with the occurrence of CM in murine malaria [7,8]. However, no consensus has been reached concerning the role of regulatory T (Treg) cells in regulation of CM pathogenesis [9][10][11].B cells have been traditionally considered antibody-producing cell and APC. Many studies in recent years showed the existence of a subset of B cells that exhibit the immune regulatory functions (reviewed in [12]). An early study by Fillatreau et al.[13] reported a subset of B cells that produce IL-10 and inhibit the immune pathology in murine EAE. Further studies revealed that these regulatory B (Breg) cells play important roles in control of immunopathology in autoimmune diseases [14], cancer [15], and organ transplantation [16]. Breg cells have also been shown to modulate immune responses and immunopathology in infectious diseases. Protective immunities against Salmonella typhimurium and Brucella abortus infections were inhibited by transfer of Breg cells in mouse models [17,18]. Transfer of CD1d + CD5 hi Breg cells rendered the BALB/c mice more susceptible to Leishmania major infection [19]. Adoptive transfer of IL-10-producing B cells isolated from helminth-infected mice inhibited the allergic responses and autoimmune inflammation in recipient mice [20]. Thus, Breg cells are an important component of immunoregulatory system and plays critical roles in immune homeostasis.The immunomodulatory roles of Breg cells have been studied in autoimmune and infectious disease settings, but little is known of its role in regulation of immune response and immunopathology of malaria. In this study, we i...

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“…Platelets release many immunoregulatory molecules in response to activation stimuli [32], including components of the TGF-β complex [33][34][35]. TGF-β signaling is a recognized regulator of CD8 + T-cell function [36].…”

Section: T Cells With Thrombin Induced Par-1 Internalization On Cx3cr1mentioning

confidence: 99%

Inflammatory Function of CX3CR1⁺CD8⁺T Cells in Treated HIV Infection Is Modulated by Platelet Interactions

et al. 2016

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Increases in inflammation, coagulation, and CD8 + T-cell numbers are associated with an elevated cardiovascular disease (CVD) risk in human immunodeficiency virus (HIV)-infected antiretroviral therapy (ART) recipients. Circulating memory CD8 + T cells that express the vascular endothelium-homing receptor CX3CR1 (fractalkine receptor) are enriched in HIV-infected ART recipients. Thrombin-activated receptor (PAR-1) expression is increased in HIV-infected ART recipients and is particularly elevated on CX3CR1 + CD8 + T cells, suggesting that these cells could interact with coagulation elements. Indeed, thrombin directly enhanced T-cell receptor-mediated interferon γ production by purified CD8 + T cells but was attenuated by thrombin-induced release of transforming growth factor β by platelets. We have therefore identified a population of circulating memory CD8 + T cells in HIV infection that may home to endothelium, can be activated by clot-forming elements, and are susceptible to platelet-mediated regulation. Complex interactions between inflammatory elements and coagulation at endothelial surfaces may play an important role in CVD risk in HIV-infected ART recipients.

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TGF-β1 Released from Activated Platelets Can Induce TNF-Stimulated Human Brain Endothelium Apoptosis: A New Mechanism for Microvascular Lesion during Cerebral Malaria

Cited by 93 publications

References 21 publications

Protection against cerebral malaria by the low-molecular-weight thiol pantethine

Protection against cerebral malaria by the low-molecular-weight thiol pantethine

Role of IL‐10‐producing regulatory B cells in control of cerebral malaria in Plasmodium berghei infected mice

Inflammatory Function of CX3CR1⁺CD8⁺T Cells in Treated HIV Infection Is Modulated by Platelet Interactions

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TGF-β1 Released from Activated Platelets Can Induce TNF-Stimulated Human Brain Endothelium Apoptosis: A New Mechanism for Microvascular Lesion during Cerebral Malaria

Cited by 93 publications

References 21 publications

Protection against cerebral malaria by the low-molecular-weight thiol pantethine

Protection against cerebral malaria by the low-molecular-weight thiol pantethine

Role of IL‐10‐producing regulatory B cells in control of cerebral malaria in Plasmodium berghei infected mice

Inflammatory Function of CX3CR1+CD8+T Cells in Treated HIV Infection Is Modulated by Platelet Interactions

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Inflammatory Function of CX3CR1⁺CD8⁺T Cells in Treated HIV Infection Is Modulated by Platelet Interactions