MyD88 Mediates Instructive Signaling in Dendritic Cells and Protective Inflammatory Response during Rickettsial Infection
MyD88 Mediates Instructive Signaling in Dendritic Cells and Protective Inflammatory Response during Rickettsial Infection
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DOI：
10.1128/iai.01361-15
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发表时间：
2016-04-01
影响因子：
3.1
通讯作者：
Fang, Rong
中科院分区：
文献类型：
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作者：
Bechelli, Jeremy;Smalley, Claire;Fang, Rong
斑点热族立克次体在全世界引起潜在危及生命的感染。 Toll 样受体 (TLR) 家族的几个成员参与宿主对立克次体的反应，但这些 TLR 介导宿主免疫的机制仍不完全清楚。在本研究中，我们发现MyD88(-/-)小鼠对康氏立克次体或澳大利亚立克次体感染的宿主易感性显着高于野生型(WT)小鼠，这与体内细菌清除严重受损有关。与WT小鼠相比，R. australis感染的MyD88(-/-)小鼠的γ干扰素(IFN-β)、白细胞介素-6(IL-6)和IL-1β的表达水平显着降低，同时感染组织中巨噬细胞和中性粒细胞的炎症浸润显着减少。与WT小鼠相比，感染MyD88(-/-)小鼠的血清IFN-β、IL-12、IL-6和粒细胞集落刺激因子水平显着降低，而单核细胞趋化蛋白1、巨噬细胞炎症蛋白1α和RANTES显着升高。引人注目的是，与WT BMDC相比，R. australis感染不能促进MyD88(-/-)骨髓源性树突状细胞(BMDC)中MHC-IIhigh表达的增加和IL-12p40的产生，尽管两种类型的BMDC中的共刺激分子均上调。此外，与WT对照相比，MyD88(-/-)小鼠中立克次体感染的BMDC和感染小鼠血清中IL-1β的分泌水平显着降低，表明IL-1β的体外和体内产生是MyD88依赖性的。综上所述，我们的结果表明，MyD88 信号传导介导 DC 中的指导信号以及 IL-1 β 和 1 型免疫细胞因子的分泌，这可能解释立克次体感染期间的保护性炎症反应。
Spotted fever group rickettsiae cause potentially life-threatening infections throughout the world. Several members of the Tolllike receptor (TLR) family are involved in host response to rickettsiae, and yet the mechanisms by which these TLRs mediate host immunity remain incompletely understood. In the present study, we found that host susceptibility of MyD88(-/-) mice to infection with Rickettsia conorii or Rickettsia australis was significantly greater than in wild-type (WT) mice, in association with severely impaired bacterial clearance in vivo. R. australis-infected MyD88(-/-) mice showed significantly lower expression levels of gamma interferon (IFN-beta), interleukin-6 (IL-6), and IL-1 beta, accompanied by significantly fewer inflammatory infiltrates of macrophages and neutrophils in infected tissues, than WT mice. The serum levels of IFN-beta, IL-12, IL-6, and granulocyte colony-stimulating factor were significantly reduced, while monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha, and RANTES were significantly increased in infected MyD88(-/-) mice compared to WT mice. Strikingly, R. australis infection was incapable of promoting increased expression of MHC-IIhigh and production of IL-12p40 in MyD88(-/-) bone marrow-derived dendritic cells (BMDCs) compared to WT BMDCs, although costimulatory molecules were upregulated in both types of BMDCs. Furthermore, the secretion levels of IL-1 beta by Rickettsia-infected BMDCs and in the sera of infected mice were significantly reduced in MyD88(-/-) mice compared to WT controls, suggesting that in vitro and in vivo production of IL-1 beta is MyD88 dependent. Taken together, our results suggest that MyD88 signaling mediates instructive signals in DCs and secretion of IL-1 beta and type 1 immune cytokines, which may account for the protective inflammatory response during rickettsial infection.