Dual engagement of the NLRP3 and AIM2 inflammasomes by plasmodium-derived hemozoin and DNA during malaria.
Dual engagement of the NLRP3 and AIM2 inflammasomes by plasmodium-derived hemozoin and DNA during malaria.
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DOI：
10.1016/j.celrep.2013.12.014
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发表时间：
2014-01-16
期刊：
影响因子：
8.8
通讯作者：
Fitzgerald KA
中科院分区：
文献类型：
--
作者：
Kalantari P;DeOliveira RB;Chan J;Corbett Y;Rathinam V;Stutz A;Latz E;Gazzinelli RT;Golenbock DT;Fitzgerald KA
疟原虫色素（Hz）是疟原虫感染红细胞中血红蛋白的结晶解毒产物。我们先前提出Hz可以携带疟原虫DNA进入Toll样受体9（TLR 9）可接近的亚细胞区室，诱导炎症信号。疟原虫色素还激活致敏细胞中的NLRP 3炎性体。我们发现，Hz似乎与感染的红细胞中的DNA共定位，甚至在RBC破裂或吞噬溶酶体消化之前。使用合成的Hz包被在体外与疟原虫基因组DNA（gDNA）或CpG-寡核苷酸，我们观察到，DNA复合的Hz诱导TLR 9易位，提供了一个引发和炎症体的激活信号。吞噬后，Hz和DNA解离。Hz随后诱导吞噬溶酶体不稳定，允许吞噬溶酶体内容物进入细胞溶质，其中DNA受体被激活。对疟原虫感染的RBC也进行了类似的观察。最后，感染的红细胞激活NLRP 3和AIM 2炎性小体。这些观察结果表明，Hz和DNA共同作用，在疟疾期间诱导全身炎症。
Hemozoin (Hz) is the crystalline detoxification product of hemoglobin in plasmodial-infected erythrocytes. We previously proposed that Hz can carry plasmodial DNA into a subcellular compartment accessible to Toll-like receptor 9 (TLR9), inducing an inflammatory signal. Hemozoin also activates the NLRP3 inflammasome in primed cells. We found that Hz appears to co localize with DNA in infected erythrocytes, even prior to RBC rupture or phagolysosomal digestion. Using synthetic Hz coated in vitro with plasmodial genomic DNA (gDNA) or CpG-oligonucleotides, we observed that DNA-complexed Hz induced TLR9 translocation, providing a priming and an activation signal for inflammasomes. After phagocytosis, Hz and DNA dissociate. Hz subsequently induces phagolysosomal destabilization, allowing phagolysosomal contents access to the cytosol where DNA receptors become activated. Similar observations were made with plasmodial-infected RBC. Finally, infected erythrocytes activated both the NLRP3 and AIM2 inflammasomes. These observations suggest that Hz and DNA work together to induce systemic inflammation during malaria.
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