Enhanced Susceptibility to Leishmania Infection in Resistant Mice in the Absence of Immediate Early Response Gene X-1
Enhanced Susceptibility to Leishmania Infection in Resistant Mice in the Absence of Immediate Early Response Gene X-1
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DOI：
10.4049/jimmunol.0900866
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发表时间：
2009-12-15
影响因子：
4.4
通讯作者：
Wu, Mei X.
中科院分区：
文献类型：
--
作者：
Akilov, Oleg E.;Ustyugova, Irina V.;Wu, Mei X.
立即早期反应基因X-1（immediate early response gene X-1，IEX-1）是一种应激诱导基因，在巨噬细胞和T细胞中大量表达。为了探索IEX-1在控制对主要利什曼原虫感染的易感性中的潜在作用，在存在或不存在IEX-1的情况下，在129 Sv/C57 BL/6抗性小鼠中评价了皮肤利什曼原虫病期间的炎症反应。IEX-1基因突变可增强小鼠对L.严重感染，并且与野生型对照小鼠相比炎症反应加重。过度炎症不是由于Th 2偏向的免疫应答或Th 1极化缺陷，而是由于γ δ T和CD 4（+）细胞产生的IL-17水平升高，伴随着感染早期中性粒细胞募集的增加。IEX-1的缺乏也抑制了巨噬细胞和T细胞中TNF-α的产生，导致病灶内寄生虫的高负荷和病灶的延迟愈合，这两者都被TNF-α治疗逆转。这些发现表明IL-17和TNF-α在决定L.严重感染超过了Th 1和Th 2介导的免疫应答之间的平衡。免疫学杂志，2009，183：7994-8003.
Immediate early response gene X-1 (IEX-1) is a stress-inducible gene abundantly expressed in macrophages and T cells following various stimuli. To explore a potential role for IEX-1 in control of the susceptibility to Leishmania major infection, the inflammatory response during cutaneous leishmaniasis was evaluated in 129Sv/C57BL/6-resistant mice in the presence or absence of IEX-1. Null mutation of IEX-1 enhanced the susceptibility of the mice to L. major infection, and aggravated inflammatory responses in comparison with wild-type control mice. The excessive inflammation was not ascribed to a Th2-biased immune response or a defect in Th1 polarization, but rather to an elevated level of IL-17 production by both gamma delta T and CD4(+) cells, concomitant with an increase of the neutrophil recruitment early in the infection. The lack of IEX-1 also suppressed TNF-alpha production in both macrophages and T cells, resulting in a high intralesional load, of parasites-and delayed healing of the lesion, both of which were reversed by TNF-alpha treatment. These findings indicate the crucial role of IL-17 and TNF-alpha in determining the outcome of L. major infection beyond a balance between Th1- and Th2-mediated immune responses. The Journal of Immunology, 2009, 183: 7994-8003.