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首页> 外文期刊>Journal of inflammation. >Suppression of LPS-induced inflammatory responses in macrophages infected with Leishmania
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Suppression of LPS-induced inflammatory responses in macrophages infected with Leishmania

机译：LPS诱导的利什曼原虫感染巨噬细胞的炎症反应的抑制。

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Background Chronic inflammation activated by macrophage innate pathogen recognition receptors such as TLR4 can lead to a range of inflammatory diseases, including atherosclerosis, Crohn's disease, arthritis and cancer. Unlike many microbes, the kinetoplastid protozoan pathogen Leishmania has been shown to avoid and even actively suppress host inflammatory cytokine responses, such as LPS-induced IL-12 production. The nature and scope of Leishmania-mediated inflammatory cytokine suppression, however, is not well characterized. Advancing our knowledge of such microbe-mediated cytokine suppression may provide new avenues for therapeutic intervention in inflammatory disease. Methods We explored the kinetics of a range of cytokine and chemokine responses in primary murine macrophages stimulated with LPS in the presence versus absence of two clinically distinct species of Leishmania using sensitive multiplex cytokine analyses. To confirm that these effects were parasite-specific, we compared the effects of Leishmania uptake on LPS-induced cytokine expression with uptake of inert latex beads. Results Whilst Leishmania uptake alone did not induce significant levels of any cytokine analysed in this study, Leishmania uptake in the presence of LPS caused parasite-specific suppression of certain LPS-induced pro-inflammatory cytokines, including IL-12, IL-17 and IL-6. Interestingly, L. amazonensis was generally more suppressive than L. major. We also found that other LPS-induced proinflammatory cytokines, such as IL-1α, TNF-α and the chemokines MIP-1α and MCP-1 and also the anti-inflammatory cytokine IL-10, were augmented during Leishmania uptake, in a parasite-specific manner. Conclusions During uptake by macrophages, Leishmania evades the activation of a broad range of cytokines and chemokines. Further, in the presence of a strong inflammatory stimulus, Leishmania suppresses certain proinflammatory cytokine responses in a parasite-specific manner, however it augments the production of other proinflammatory cytokines. Our findings highlight the complexity of inflammatory cytokine signalling regulation in the context of the macrophage and Leishmania interaction and confirm the utility of the Leishmania/macrophage infection model as an experimental system for further studies of inflammatory regulation. Such studies may advance the development of therapies against inflammatory disease.
机译：背景技术巨噬细胞先天病原体识别受体（例如TLR4）激活的慢性炎症可导致一系列炎性疾病，包括动脉粥样硬化，克罗恩病，关节炎和癌症。与许多微生物不同，动素体原生动物病原体利什曼原虫已被证明可以避免甚至主动抑制宿主的炎症细胞因子反应，例如LPS诱导的IL-12产生。然而，利什曼原虫介导的炎性细胞因子抑制的性质和范围尚未很好地表征。促进我们对这种微生物介导的细胞因子抑制的认识可能为炎症性疾病的治疗干预提供新途径。方法我们使用敏感的多重细胞因子分析方法，探讨了在存在和不存在两种临床上不同的利什曼原虫物种存在或不存在的情况下，LPS刺激的原代鼠巨噬细胞中一系列细胞因子和趋化因子反应的动力学。为证实这些作用是寄生虫特异性的，我们比较了利什曼原虫摄取对LPS诱导的细胞因子表达的影响与惰性乳胶珠摄取的影响。结果虽然仅利什曼原虫摄取并未诱导本研究中分析的任何细胞因子的显着水平，但是在存在LPS的情况下利什曼原虫摄取会引起某些LPS诱导的促炎性细胞因子（包括IL-12，IL-17和IL）的寄生虫特异性抑制。 -6。有趣的是，亚马逊L. amazonensis通常比L. major更具抑制性。我们还发现，其他LPS诱导的促炎细胞因子，例如IL-1α，TNF-α和趋化因子MIP-1α和MCP-1，以及抗炎细胞因子IL-10，在寄生虫利什曼原虫摄取期间均增加了。特定的方式。结论在被巨噬细胞摄取期间，利什曼原虫回避了多种细胞因子和趋化因子的活化。此外，在强烈的炎症刺激下，利什曼原虫以寄生虫特异性方式抑制某些促炎细胞因子的反应，但是它增加了其他促炎细胞因子的产生。我们的发现突出了在巨噬细胞和利什曼原虫相互作用的背景下炎症细胞因子信号调节的复杂性，并证实了利什曼原虫/巨噬细胞感染模型作为进一步研究炎症调节的实验系统的实用性。这样的研究可以促进针对炎性疾病的疗法的发展。

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