Mice genetically inactivated in interleukin-17A receptor are defective in long-term control of Mycobacterium tuberculosis infection
Mice genetically inactivated in interleukin-17A receptor are defective in long-term control of Mycobacterium tuberculosis infection
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DOI：
10.1111/imm.12130
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发表时间：
2013-10-01
期刊：
影响因子：
6.4
通讯作者：
Romano, Marta
中科院分区：
文献类型：
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作者：
Freches, Danielle;Korf, Hannelie;Romano, Marta
白细胞介素-17A（IL-17 A）是一种促炎细胞因子，作用于中性粒细胞募集，已知在结核分枝杆菌感染期间发挥重要作用，但IL-17 A受体信号传导在针对这种细胞内病原体的免疫防御中的作用仍缺乏文献记载。在这里，我们使用在IL-17受体A亚基（IL-17 RA（-/-））中遗传失活的C57 BL/6小鼠分析了这种信号传导。尽管感染后早期细菌生长被控制到与野生型小鼠相同的程度，但IL-17 RA（-/-）小鼠在长期控制M.肺结核感染，表现为肺细菌负荷逐渐增加和生存时间缩短。与感染的野生型小鼠相比，IL-17 RA（-/-）小鼠在感染的早期而非晚期显示中性粒细胞向肺的募集受损。肺肿瘤坏死因子-α，IL-6，特别是IL-10水平在IL-17 RA信号传导的情况下降低，而IL-1 β增加。在IL-17 RA（-/-）小鼠中，CD 4（+）介导和γ δ介导的IL-17 A产生显著增加（证实了它们的部分表型），而干扰素-γ的产生和杀菌酶诱导型一氧化氮合酶的表达不受影响。总的来说，我们的数据表明，早期而非晚期中性粒细胞募集对于IL-17 A介导的M的长期控制至关重要。结核感染和功能性干扰素-γ反应不足以控制M。当IL-17 RA途径缺乏时，结核病生长。由于用抗IL-17 A抗体治疗自身免疫性疾病实际上正在临床研究中进行测试，我们的数据表明，应谨慎考虑结核病的可能再活化。
SummaryInterleukin-17A (IL-17A), a pro-inflammatory cytokine acting on neutrophil recruitment, is known to play an important role during Mycobacterium tuberculosis infection, but the role of IL-17A receptor signalling in immune defence against this intracellular pathogen remains poorly documented. Here we have analysed this signalling using C57BL/6 mice genetically inactivated in the IL-17 receptor A subunit (IL-17RA(-/-)). Although early after infection bacterial growth was controlled to the same extent as in wild-type mice, IL-17RA(-/-) mice were defective in exerting long-term control of M. tuberculosis infection, as demonstrated by a progressively increasing pulmonary bacterial burden and shortened survival time. Compared with infected wild-type mice, IL-17RA(-/-) mice showed impaired recruitment of neutrophils to the lungs at the early but not the late stage of infection. Pulmonary tumour necrosis factor-alpha, IL-6 and particularly IL-10 levels were decreased in the absence of IL-17RA signalling, whereas IL-1 beta was increased. CD4(+)-mediated and gamma delta-mediated IL-17A production was dramatically increased in IL-17RA(-/-) mice (confirming part of their phenotype), whereas production of interferon-gamma and expression of the bactericidal enzyme inducible nitric oxide synthase were not affected. Collectively, our data suggest that early but not late neutrophil recruitment is essential for IL-17A-mediated long-term control of M. tuberculosis infection and that a functional interferon-gamma response is not sufficient to control M. tuberculosis growth when the IL-17RA pathway is deficient. As treatment of auto-immune diseases with anti-IL-17A antibodies is actually being tested in clinical studies, our data suggest that caution should be taken with respect to possible reactivation of tuberculosis.