Differential modulation of glial cell mediated neuroinflammation in Plasmodium berghei ANKA infection by TGF β and IL 6

Sarkar, Samrat; Keswani, Tarun; Sengupta, Anirban; Mitra, Sangeeta; Bhattacharyya, Arindam

doi:10.1016/j.cyto.2017.07.026

Cited by 18 publications

(10 citation statements)

References 49 publications

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“…6 and 7 ). Activation of microglia has been shown to be an important component of neuroinflammation and behavioral dysfunction associated with PbA infection [ 92 – 94 ]. Widespread microglial activation, not always restricted to areas of parasite sequestration, has also been identified in cases of human CM [ 95 , 96 ].…”

Section: Discussionmentioning

confidence: 99%

Elimination of intravascular thrombi prevents early mortality and reduces gliosis in hyper-inflammatory experimental cerebral malaria

Wilson

Ochoa

Solomon

et al. 2018

J Neuroinflammation

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BackgroundCerebral malaria (CM) is the most lethal outcome of Plasmodium infection. There are clear correlations between expression of inflammatory cytokines, severe coagulopathies, and mortality in human CM. However, the mechanisms intertwining the coagulation and inflammation pathways, and their roles in CM, are only beginning to be understood. In mice with T cells deficient in the regulatory cytokine IL-10 (IL-10 KO), infection with Plasmodium chabaudi leads to a hyper-inflammatory response and lethal outcome that can be prevented by anti-TNF treatment. However, inflammatory T cells are adherent within the vasculature and not present in the brain parenchyma, suggesting a novel form of cerebral inflammation. We have previously documented behavioral dysfunction and microglial activation in infected IL-10 KO animals suggestive of neurological involvement driven by inflammation. In order to understand the relationship of intravascular inflammation to parenchymal dysfunction, we studied the congestion of vessels with leukocytes and fibrin(ogen) and the relationship of glial cell activation to congested vessels in the brains of P. chabaudi-infected IL-10 KO mice.MethodsUsing immunofluorescence microscopy, we describe severe thrombotic congestion in these animals. We stained for immune cell surface markers (CD45, CD11b, CD4), fibrin(ogen), microglia (Iba-1), and astrocytes (GFAP) in the brain at the peak of behavioral symptoms. Finally, we investigated the roles of inflammatory cytokine tumor necrosis factor (TNF) and coagulation on the pathology observed using neutralizing antibodies and low-molecular weight heparin to inhibit both inflammation and coagulation, respectively.ResultsMany blood vessels in the brain were congested with thrombi containing adherent leukocytes, including CD4 T cells and monocytes. Despite containment of the pathogen and leukocytes within the vasculature, activated microglia and astrocytes were prevalent in the parenchyma, particularly clustered near vessels with thrombi. Neutralization of TNF, or the coagulation cascade, significantly reduced both thrombus formation and gliosis in P. chabaudi-infected IL-10 KO mice.ConclusionsThese findings support the contribution of cytokines, coagulation, and leukocytes within the brain vasculature to neuropathology in malaria infection. Strikingly, localization of inflammatory leukocytes within intravascular clots suggests a mechanism for interaction between the two cascades by which cytokines drive local inflammation without considerable cellular infiltration into the brain parenchyma.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1207-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Elimination of intravascular thrombi prevents early mortality and reduces gliosis in hyper-inflammatory experimental cerebral malaria

Wilson

Ochoa

Solomon

et al. 2018

J Neuroinflammation

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“…Regarding T-reg/Th-17, the major transcription factor of T-reg cells, FOXP3 expression was significantly higher in Anti-IL-6 treated infected group and significantly lower in Anti-TGFβ treated infected mice. The expression of IL-17, a major cytokine secreted by Th-17 cells, show the opposite result to that of FOXP3 in both the groups than the only Plasmodium berghei ANKA infected ones [43]. But the actual percentages of the T-reg and Th-17 in cerebral cortex and cerebellum and their changes upon neutralization of these two cytokines is not yet investigated.…”

Section: Role Of Cytokines (Tgfβ and Il-6) In Regulation Of T-reg/th-17 Balance In Malariamentioning

confidence: 87%

“…The major transcription factor of Th-17 cells shows the similar trend in both lethal and non-lethal malaria infection as does Th-17 cells [42]. Not only in spleen but also in cerebral cortex and cerebellum of the P. berghei ANKA infected mice, differential expression of FOXP3 and RORγT has been found to be critical in regulating the glial cell mediated neuroinflammation and neuronal cell death [43]. So, the contrasting behaviour shown…”

Section: Differential Role Of T-regulatory Cells and Th-17 Cells In Malariamentioning

confidence: 92%

Regulation of T-reg/Th-17 Balance: One Step Closer Towards Immunotherapy Against Malaria Infection

Mukherjee¹,

Ghosh²,

Bhattacharyya³

2021

Plasmodium Species and Drug Resistance

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According to World Malaria Report 2020, the rate of decline in malaria case incidence and deaths caused by malaria has ceased in latter half of the past decade. Though Artemisinin Combination Therapy (ACT) is still the major therapeutic approach globally to treat malaria patients, increased resistance of Plasmodium sp. to artemisinin can be looked upon as a major factor responsible for the rate of decline. In the present world, immunotherapeutic approaches are in the limelight to treat several infections, autoimmune disorders, cancers but application of such therapeutic measures in case of malaria are yet not available. Among different immune cells, T-regulatory cells (T-reg) and Th-17 cells and the balance between them, helps in determining the outcome of the immune response in host during both lethal and non-lethal malaria. TGFβ and IL-6 are two major cytokines that play important role in fine tuning the Treg/Th-17 balance by modulating dendritic cell responses, specially by regulating the ratio between myeloid DC and plasmacytoid DC (mDC/pDC). Studies in rodent malaria models have revealed that neutralization of IL-6 by using anti IL-6 monoclonal antibodies in-vivo has been found effective in declining the parasitemia, malaria induced deaths and also in reverting back the altered T-reg/Th-17 balance to normal levels. Apart from these, autophagy is one of the major factors which also contributes to regulate the T-reg/Th-17 balance. In malaria infected mice, autophagy induction has been found to normalise the dysregulated T-reg/Th-17 ratio and promote anti-inflammatory Th-2 pathway by supressing pro-inflammatory Th-1 pathway. So, Treg/Th-17 balance and its associated regulators can be important immunotherapeutic targets for malaria prevention in near future.

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“…Cerebral malaria influences morphological and phenotypical changes in microglia, and increased major histocompatibility complex (MHC) class I expression was observed in activated cells [60]. Microglial activation was found to occur simultaneously with TLR4 engagement [61]. Cerebral malaria leads to an increase in monocyte/macrophage numbers, and activated microglia also induce accumulation of perivascular macrophages [60, 62].…”

Section: Cerebral Malaria and Microglia Cellsmentioning

confidence: 99%

Circulating Monocytes, Tissue Macrophages, and Malaria

Ozarslan

Robinson

Gaw

2019

Journal of Tropical Medicine

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Malaria is a significant cause of global morbidity and mortality. The Plasmodium parasite has a complex life cycle with mosquito, liver, and blood stages. The blood stages can preferentially affect organs such as the brain and placenta. In each of these stages and organs, the parasite will encounter monocytes and tissue-specific macrophages—key cell types in the innate immune response. Interactions between the Plasmodium parasite and monocytes/macrophages lead to several changes at both cellular and molecular levels, such as cytokine release and receptor expression. In this review, we summarize current knowledge on the relationship between malaria and blood intervillous monocytes and tissue-specific macrophages of the liver (Kupffer cells), central nervous system (microglia), and placenta (maternal intervillous monocytes and fetal Hofbauer cells). We describe their potential roles in modulating outcomes from infection and areas for future investigation.

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Differential modulation of glial cell mediated neuroinflammation in Plasmodium berghei ANKA infection by TGF β and IL 6

Cited by 18 publications

References 49 publications

Elimination of intravascular thrombi prevents early mortality and reduces gliosis in hyper-inflammatory experimental cerebral malaria

Elimination of intravascular thrombi prevents early mortality and reduces gliosis in hyper-inflammatory experimental cerebral malaria

Regulation of T-reg/Th-17 Balance: One Step Closer Towards Immunotherapy Against Malaria Infection

Circulating Monocytes, Tissue Macrophages, and Malaria

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