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Intravital Microscopy of the Mouse Brain Microcirculation using a Closed Cranial Window
Published on: November 18, 2010
Probing cerebral malaria inflammation in 3D human brain microvessels
Caitlin Howard1, Fatou Joof2, Ruoqian Hu1
1Department of Bioengineering, University of Washington, Seattle, WA, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.
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.
Insights
Cerebral malaria involves Plasmodium falciparum-infected red blood cells blocking brain vessels. This study reveals how parasites and inflammation interact in a 3D brain model, causing unique damage and stress responses.
Area of Science:
- Neuroscience
- Immunology
- Infectious Diseases
Background:
- Cerebral malaria (CM) is caused by Plasmodium falciparum-infected erythrocytes sequestering in brain microcirculation.
- This sequestration triggers endothelial activation, brain swelling, and potentially fatal outcomes.
Purpose of the Study:
- To investigate the inflammatory mechanisms of CM using a perfusable 3D human brain microvessel model.
- To differentiate the roles of tumor necrosis factor α (TNF-α) and parasite-induced effects on brain endothelium.
Main Methods:
- Utilized a 3D human brain microvessel model for in situ studies.
- Employed transcriptional analysis, advanced imaging, and leukocyte perfusion techniques.
- Combined these methods to analyze inflammatory responses and cellular changes.
Main Results:
- The 3D model supported parasite binding and maturation, inducing TNF-α-driven inflammation.
- Parasites triggered distinct stress responses, localized endothelial disruptions, and apoptosis.
- Parasites altered TNF-α response kinetics, suggesting amplified inflammatory damage.
Conclusions:
- Parasite sequestration and TNF-α induce complex, intersecting inflammatory pathways in the brain endothelium.
- Findings provide mechanistic insights into CM pathogenesis using a novel 3D brain mimetic platform.
- This research highlights the critical interplay of factors contributing to brain barrier inflammation in CM.
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