Myeloid differentiation antigen 88 deficiency impairs pathogen clearance but does not alter inflammation in Borrelia burgdorferi-infected mice
Myeloid differentiation antigen 88 deficiency impairs pathogen clearance but does not alter inflammation in Borrelia burgdorferi-infected mice
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DOI：
10.1128/iai.72.6.3195-3203.2004
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发表时间：
2004-06-01
影响因子：
3.1
通讯作者：
Bockenstedt, LK
中科院分区：
文献类型：
--
作者：
Liu, NY;Montgomery, RR;Bockenstedt, LK
螺旋体伯氏疏螺旋体引起小鼠急性炎症，随着病原体特异性适应性免疫的发展而消退。B。burgdorferi脂蛋白通过Toll样受体2（TLR 2）激活先天性免疫细胞，但TLR 2缺陷小鼠对B不耐药。这表明其他TLR或非TLR机制参与了急性炎症的诱导。在这项研究中，我们使用了细胞内衔接分子髓样分化抗原88（MyD 88）缺陷的小鼠，这是所有TLR诱导的炎症反应所必需的，以确定该途径的中断是否会改变B。伯氏症引起的疾病感染的MyD 88（-/-）小鼠发生心脏炎和关节炎，与在其高峰期（第14天和第28天）和消退期间（第45天）分析的野生型（WT）小鼠中的疾病相似。MyD 88（-/-）巨噬细胞仅在螺旋体被调理时产生肿瘤坏死因子α，提示B的作用。在疾病表达中的伯氏特异性抗体。MyD 88（-/-）小鼠产生更强的病原体特异性Th 2依赖性免疫球蛋白G1（IgG 1）的反应比野生型小鼠，和他们的IgM滴度保持显着升高，通过90天的感染。尽管有特异性抗体，但感染后45天，MyD 88（-/-）小鼠的病原体负荷比WT小鼠高250倍;到感染后90天，MyD 88（-/-）小鼠的病原体负荷大幅减少，但与WT小鼠相比仍有所升高。病原体负荷的增加可以部分解释为以下发现。MyD 88（-/-）腹腔巨噬细胞可以摄取螺旋体，但降解螺旋体的速度比WT巨噬细胞慢。我们的研究结果表明，MyD 88依赖的信号通路是不需要的B。这是由Burgdorferi诱导的炎症引起的，但对于吞噬细胞有效控制病原体负荷是必要的。
The spirochete Borrelia burgdorferi causes acute inflammation in mice that resolves with the development of pathogen-specific adaptive immunity. B. burgdorferi lipoproteins activate innate immune cells via Toll-like receptor 2 (TLR2), but TLR2-deficient mice are not resistant to B. burgdorferi-induced disease, suggesting the involvement of other TLRs or non-TLR mechanisms in the induction of acute inflammation. For this study, we used mice that were deficient in the intracellular adapter molecule myeloid differentiation antigen 88 (MyD88), which is required for all TLR-induced inflammatory responses, to determine whether the interruption of this pathway would alter B. burgdorferi-induced disease. Infected MyD88(-/-) mice developed carditis and arthritis, similar to the disease in wild-type (WT) mice analyzed at its peak (days 14 and 28) and during regression (day 45). MyD88(-/-) macrophages produced tumor necrosis factor alpha only when spirochetes were opsonized, suggesting a role for B. burgdorferi-specific antibody in disease expression. MyD88(-/-) mice produced stronger pathogen-specific Th2-dependent immunoglobulin G1 (IgG1) responses than did WT mice, and their IgM titers remained significantly elevated through 90 days of infection. Despite specific antibodies, the pathogen burden was 250-fold higher in MyD88(-/-) mice than in WT mice 45 days after infection; by 90 days of infection, the pathogen burden had diminished substantially in MyD88(-/-) mice, but it was still elevated compared to that in WT mice. The elevated pathogen burden may be explained in part by the finding that. MyD88(-/-) peritoneal macrophages could ingest spirochetes but degraded them more slowly than WT macrophages. Our results show that MyD88-dependent signaling pathways are not required for B. burgdorferi-induced inflammation but are necessary for the efficient control of the pathogen burden by phagocytes.