Probing cerebral malaria inflammation in 3D human brain microvessels.
Probing cerebral malaria inflammation in 3D human brain microvessels.
复制标题
DOI：
10.1016/j.celrep.2023.113253
复制
发表时间：
2023-10-31
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
恶性疟原虫感染的红细胞（IE）在脑微循环中的隔离是脑型疟疾（CM）的标志，其导致内皮激活、脑肿胀和死亡。在这里，我们探讨CM炎症灌注三维人脑微血管模型。3D脑微血管支持体内类似寄生虫结合和原位成熟的能力，导致与促炎细胞因子肿瘤坏死因子α（TNF-α）不同的炎症反应。通过结合转录分析、成像和白细胞灌注，我们发现TNF-α促进可逆的炎症表型和广泛的白细胞募集，而寄生虫诱导独特的应激反应途径并引起局部细胞粘附性变化、局灶性内皮破坏和凋亡。此外，寄生虫修改了TNF转录反应的时间动力学，这表明两个连续刺激增强了炎症损伤。我们的研究结果在3D脑微血管模拟平台中提供了对CM生物学的机制见解，并表明多个事件交叉促进CM中的脑屏障炎症。霍华德等人采用可灌注3D人脑微血管平台对脑疟疾炎症的时空动力学进行建模，并显示寄生虫促进血管壁上促炎细胞因子TNF-α的不同炎症反应，并改变TNF-α介导的炎症反应的时间动力学。
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. Howard et al. employ a perfusable 3D human brain microvessel platform for modeling the spatiotemporal dynamics of cerebral malaria inflammation and show that parasites promote a distinct inflammatory response from the pro-inflammatory cytokine TNF-α on the vessel wall and modify the temporal kinetics of the TNF-α-mediated inflammatory response.
登录
查看更多内容
影响因子：
3.6
作者：
Idro R;Marsh K;John CC;Newton CR
通讯作者：
Newton CR
影响因子：
6.4
作者：
Bernabeu, Maria;Gunnarsson, Celina;Smith, Joseph D.
通讯作者：
Smith, Joseph D.
影响因子：
82.9
作者：
Miller LH;Ackerman HC;Su XZ;Wellems TE
通讯作者：
Wellems TE
影响因子：
16.6
作者：
Mantel PY;Hjelmqvist D;Walch M;Kharoubi-Hess S;Nilsson S;Ravel D;Ribeiro M;Grüring C;Ma S;Padmanabhan P;Trachtenberg A;Ankarklev J;Brancucci NM;Huttenhower C;Duraisingh MT;Ghiran I;Kuo WP;Filgueira L;Martinelli R;Marti M
通讯作者：
Marti M
影响因子：
14.8
作者：
Morgan, John P.;Delnero, Peter F.;Stroock, Abraham D.
通讯作者：
Stroock, Abraham D.