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Probing cerebral malaria inflammation in 3D human brain microvessels.

ABSTRACT: Sequestration of Plasmodium falciparum-infected erythrocytes (IEs) in the brain microcirculation is a hallmark of cerebral malaria (CM), which leads to endothelial activation, brain swelling, and death. Here, we probed CM inflammation in a perfusable 3D human brain microvessel model. 3D brain microvessels supported in vivo-like capacities for parasite binding and maturation in situ, leading to a distinct inflammatory response from the pro-inflammatory cytokine tumor necrosis factor α (TNF-α). By combining transcriptional analysis, imaging, and leukocyte perfusion, we showed that whereas TNF-α promotes a reversible inflammatory phenotype with widespread leukocyte recruitment, parasites induce unique stress response pathways and cause localized cell adhesivity changes, focal endothelial disruptions, and apoptosis. Furthermore, parasites modified the temporal kinetics of the TNF transcriptional response, suggesting augmented inflammatory damage with the two sequential stimuli. Our findings offer mechanistic insights into CM biology in a 3D brain microvessel mimetic platform and suggest that multiple events intersect to promote brain barrier inflammation in CM.

SUBMITTER: Howard C

PROVIDER: S-EPMC10710687 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Probing cerebral malaria inflammation in 3D human brain microvessels.

Howard Caitlin C Joof Fatou F Hu Ruoqian R Smith Joseph D JD Zheng Ying Y

Cell reports 20231017 10

Sequestration of Plasmodium falciparum-infected erythrocytes (IEs) in the brain microcirculation is a hallmark of cerebral malaria (CM), which leads to endothelial activation, brain swelling, and death. Here, we probed CM inflammation in a perfusable 3D human brain microvessel model. 3D brain microvessels supported in vivo-like capacities for parasite binding and maturation in situ, leading to a distinct inflammatory response from the pro-inflammatory cytokine tumor necrosis factor α (TNF-α). By ...[more]

PMID: 37819760

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Project description:BackgroundSepsis is an emergency medical condition that can lead to death and it is defined as a life-threatening organ dysfunction caused by immune dysregulation in response to an infection. It is considered the main killer in intensive care units. Sepsis associated-encephalopathy (SAE) is mostly caused by a sepsis-induced systemic inflammatory response. Studies report SAE in 14-63% of septic patients. Main SAE symptoms are not specific and usually include acute impairment of consciousness, delirium and/or coma, along with electroencephalogram (EEG) changes. For those who recover from sepsis and SAE, impaired cognitive function, mobility and quality of life are often observed months to years after hospital discharge, and there is no treatment available today to prevent that. Inflammation and oxidative stress are key players for the SAE pathophysiology. Gold nanoparticles have been demonstrated to own important anti-inflammatory properties. It was also reported 20 nm citrate-covered gold nanoparticles (cit-AuNP) reduce oxidative stress. In this context, we tested whether 20 nm cit-AuNP could alleviate the acute changes caused by sepsis in brain of mice, with focus on inflammation. Sepsis was induced in female C57BL/6 mice by cecal ligation and puncture (CLP), 20 nm cit-AuNP or saline were intravenously (IV) injected 2 h after induction of sepsis and experiments performed 6 h after induction. Intravital microscopy was used for leukocyte and platelet adhesion study in brain, blood brain barrier (BBB) permeability carried out by Evans blue assay, cytokines measured by ELISA and real time PCR, cell adhesion molecules (CAMs) by flow cytometry and immunohistochemistry, and transcription factors, by western blotting.Results20 nm cit-AuNP treatment reduced leukocyte and platelet adhesion to cerebral blood vessels, prevented BBB failure, reduced TNF- concentration in brain, and ICAM-1 expression both in circulating polymorphonuclear (PMN) leukocytes and cerebral blood vessels of mice with sepsis. Furthermore, 20 nm cit-AuNP did not interfere with the antibiotic effect on the survival rate of mice with sepsis.ConclusionsCit-AuNP showed important anti-inflammatory properties in the brain of mice with sepsis, being a potential candidate to be used as adjuvant drug along with antibiotics in the treatment of sepsis to avoid SAE.

Dataset Information

Probing cerebral malaria inflammation in 3D human brain microvessels.

Publications

Probing cerebral malaria inflammation in 3D human brain microvessels.

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