Production of anti-LPS IgM by B1a B cells depends on IL-1β and is protective against lung infection with Francisella tularensis LVS.
Production of anti-LPS IgM by B1a B cells depends on IL-1β and is protective against lung infection with Francisella tularensis LVS.
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DOI：
10.1371/journal.ppat.1004706
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发表时间：
2015-03
期刊：
影响因子：
6.7
通讯作者：
Re F
中科院分区：
文献类型：
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作者：
del Barrio L;Sahoo M;Lantier L;Reynolds JM;Ceballos-Olvera I;Re F
IL-1β 和 IL-18 在革兰氏阴性菌土拉弗朗西斯菌 LVS 肺部感染过程中的作用尚未得到详细表征。在这里，我们使用肺炎兔热病小鼠模型表明，两种细胞因子都具有保护作用，但通过不同的机制。与野生型 C57BL/6J 小鼠相比，IL-18-/- 小鼠很快死于感染，器官中细菌负荷较高，BALF 和血清中 IFNγ 水平较低。给予 IFNγ 挽救了 Il-18-/- 小鼠的存活，表明它们对兔热病的抵抗力下降是由于无法产生 IFNγ。相比之下，缺乏 IL-1 受体或 IL-1β（而非 IL-1α）的小鼠似乎在早期阶段控制了感染，但最终死亡。 IFNγ给药对IL-1r1-/-小鼠的存活没有影响。相反，发现 Il-1r1-/- 小鼠的 Ft LPS 特异性 IgM 滴度显着降低。抗 Ft LPS IgM 以 IL-1β、TLR2 和 ASC 依赖性方式产生，促进细菌凝集和吞噬作用，并在被动免疫实验中具有保护作用。 B1a B 细胞产生抗 Ft LPS IgM，与 C57BL/6J 小鼠相比，这些细胞在受感染的 Il-1b-/- 小鼠的脾脏和腹膜腔中显着减少。总的来说，我们的结果表明 IL-1β 和 IL-18 激活针对兔热病的非冗余保护性反应，并确定 IL-1β 在 B1a B 细胞快速生成病原体特异性 IgM 中的重要作用。 土拉弗朗西斯菌是一种革兰氏阴性细菌，可感染巨噬细胞和其他细胞类型，引起土拉菌病。 F. tularensis 被认为是一种潜在的生物恐怖主义制剂，并且是研究病原体与宿主免疫系统相互作用的主要模型细胞内细菌。促炎细胞因子 IL-1β 和 IL-18 在土拉弗朗西斯肺部感染过程中的作用尚未得到详细表征。在这里，我们使用肺炎兔热病小鼠模型表明，两种细胞因子都具有保护作用，但通过不同的机制。缺乏 IL-18 的小鼠很快就会死于感染，但施用 IFNγ 挽救了它们的生存。相比之下，缺乏 IL-1β 的小鼠似乎在早期阶段控制了感染，但最终死亡，并且无法通过施用 IFNγ 来挽救。相反，IL-1β缺陷小鼠的血清中土拉弗拉菌LPS特异性IgM抗体水平显着降低。这些抗体以 IL-1β、TLR2 和 ASC 依赖性方式产生，促进细菌凝集和吞噬作用，并在被动免疫实验中具有保护作用。 B1a B细胞产生抗F。土拉热菌 IgM 在感染 IL-1β 缺陷小鼠的脾脏和腹膜腔中显着降低。总的来说，我们的结果表明 IL-1β 和 IL-18 激活针对兔热病的非冗余保护性反应，并确定 IL-1β 在 B1a B 细胞快速生成病原体特异性 IgM 中的重要作用。
The role of IL-1β and IL-18 during lung infection with the gram-negative bacterium Francisella tularensis LVS has not been characterized in detail. Here, using a mouse model of pneumonic tularemia, we show that both cytokines are protective, but through different mechanisms. Il-18-/- mice quickly succumb to the infection and showed higher bacterial burden in organs and lower level of IFNγ in BALF and serum compared to wild type C57BL/6J mice. Administration of IFNγ rescued the survival of Il-18-/- mice, suggesting that their decreased resistance to tularemia is due to inability to produce IFNγ. In contrast, mice lacking IL-1 receptor or IL-1β, but not IL-1α, appeared to control the infection in its early stages, but eventually succumbed. IFNγ administration had no effect on Il-1r1-/- mice survival. Rather, Il-1r1-/- mice were found to have significantly reduced titer of Ft LPS-specific IgM. The anti-Ft LPS IgM was generated in a IL-1β-, TLR2-, and ASC-dependent fashion, promoted bacteria agglutination and phagocytosis, and was protective in passive immunization experiments. B1a B cells produced the anti-Ft LPS IgM and these cells were significantly decreased in the spleen and peritoneal cavity of infected Il-1b-/- mice, compared to C57BL/6J mice. Collectively, our results show that IL-1β and IL-18 activate non-redundant protective responses against tularemia and identify an essential role for IL-1β in the rapid generation of pathogen-specific IgM by B1a B cells. Francisella tularensis is a Gram-negative bacterium that infects macrophages and other cell types causing tularemia. F. tularensis is considered a potential bioterrorism agent and is a prime model intracellular bacterium to study the interaction of pathogens with the host immune system. The role of the proinflammatory cytokines IL-1β and IL-18 during lung infection with F. tularensis has not been characterized in detail. Here, using a mouse model of pneumonic tularemia, we show that both cytokines are protective, but through different mechanisms. Mice deficient in IL-18 quickly succumbed to the infection but administration of IFNγ rescued their survival. In contrast, mice lacking IL-1β appeared to control the infection in its early stages, but eventually succumbed and were not rescued by administration of IFNγ. Rather, IL-1β-deficient mice had significantly reduced serum level of IgM antibodies specific for F. tularensis LPS. These antibodies were generated in a IL-1β-, TLR2-, and ASC-dependent fashion, promoted bacteria agglutination and phagocytosis, and were protective in passive immunization experiments. B1a B cells produced the anti-F. tularensis IgM and were significantly decreased in the spleen and peritoneal cavity of infected IL-1β-deficient mice. Collectively, our results show that IL-1β and IL-18 activate non-redundant protective responses against tularemia and identify an essential role for IL-1β in the rapid generation of pathogen-specific IgM by B1a B cells.
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影响因子：
8.7
作者：
Broz P;Monack DM
通讯作者：
Monack DM
DOI：
10.1073/pnas.0813411106
发表时间：
2009-03-17
影响因子：
11.1
作者：
Cole, Leah E.;Yang, Yang;Vogel, Stefanie N.
通讯作者：
Vogel, Stefanie N.
影响因子：
3.1
作者：
Dreisbach, VC;Cowley, S;Elkins, KL
通讯作者：
Elkins, KL
DOI：
10.1196/annals.1409.014
发表时间：
2007-01-01
期刊：
FRANCISELLA TULARENSIS: BIOLOGY, PATHOGENICITY, EPIDEMIOLOGY, AND BIODEFENSE
影响因子：
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作者：
Elkins, Karen L.;Cowley, Siobhan C.;Bosio, Catharine M.
通讯作者：
Bosio, Catharine M.
DOI：
10.1038/nri3383
发表时间：
2013-02
期刊：
Nature reviews. Immunology
影响因子：
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作者：
通讯作者：
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