Monocyte- and Neutrophil-Derived CXCL10 Impairs Efficient Control of Blood-Stage Malaria Infection and Promotes Severe Disease
Monocyte- and Neutrophil-Derived CXCL10 Impairs Efficient Control of Blood-Stage Malaria Infection and Promotes Severe Disease
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DOI：
10.4049/jimmunol.1501562
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发表时间：
2016-02-01
影响因子：
4.4
通讯作者：
Hansen, Diana S.
中科院分区：
文献类型：
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作者：
Ioannidis, Lisa J.;Nie, Catherine Q.;Hansen, Diana S.
CXCL10或ifn - γ诱导蛋白10是与恶性疟原虫介导的脑型疟疾（CM）风险增加相关的生物标志物。与此一致的是，我们之前的研究表明CXCL10中和或基因缺失减轻了脑血管内炎症，并保护伯氏疟原虫anka感染小鼠免受CM。除了器官特异性作用外，感染期间缺乏CXCL10也会减少寄生虫生物量。为了确定负责这些过程的CXCL10的细胞来源，我们用野生型（WT）和CXCL10（-/-）小鼠的骨髓照射和重建野生型（WT）和CXCL10（-/-）小鼠。与CXCL10（-/-）小鼠类似，在造血源性细胞中不能表达CXCL10的嵌合体比WT对照组更有效地控制感染。相比之下，在WT骨髓重组的敲除小鼠中表达CXCL10导致较高的寄生虫生物量水平，更高的脑寄生虫和白细胞隔离率，并增加对CM的敏感性。中性粒细胞和炎性单核细胞被确定为CXCL10的主要细胞来源，负责诱导这些过程。在没有cxcl10介导的运输的情况下，寄生虫病的控制得到改善，这与脾脏中CXCR3(+)CD4(+) T滤泡辅助细胞的优先积累和对感染的Ab反应增强有关。这些结果与以下观点是一致的：疟疾感染引起的某些炎症反应促进了高寄生虫密度的发展，从而在靶器官中诱发严重疾病。
CXCL10, or IFN-gamma-inducible protein 10, is a biomarker associated with increased risk for Plasmodium falciparum-mediated cerebral malaria (CM). Consistent with this, we have previously shown that CXCL10 neutralization or genetic deletion alleviates brain intravascular inflammation and protects Plasmodium berghei ANKA-infected mice from CM. In addition to organ-specific effects, the absence of CXCL10 during infection was also found to reduce parasite biomass. To identify the cellular sources of CXCL10 responsible for these processes, we irradiated and reconstituted wild-type (WT) and CXCL10(-/-) mice with bone marrow from either WT or CXCL10(-/-) mice. Similar to CXCL10(-/-) mice, chimeras unable to express CXCL10 in hematopoietic-derived cells controlled infection more efficiently than WT controls. In contrast, expression of CXCL10 in knockout mice reconstituted with WT bone marrow resulted in high parasite biomass levels, higher brain parasite and leukocyte sequestration rates, and increased susceptibility to CM. Neutrophils and inflammatory monocytes were identified as the main cellular sources of CXCL10 responsible for the induction of these processes. The improved control of parasitemia observed in the absence of CXCL10-mediated trafficking was associated with a preferential accumulation of CXCR3(+)CD4(+) T follicular helper cells in the spleen and enhanced Ab responses to infection. These results are consistent with the notion that some inflammatory responses elicited in response to malaria infection contribute to the development of high parasite densities involved in the induction of severe disease in target organs.