Eosinophils and IL-4 Support Nematode Growth Coincident with an Innate Response to Tissue Injury.
Eosinophils and IL-4 Support Nematode Growth Coincident with an Innate Response to Tissue Injury.
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DOI：
10.1371/journal.ppat.1005347
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发表时间：
2015-12
期刊：
影响因子：
6.7
通讯作者：
Appleton JA
中科院分区：
文献类型：
--
作者：
Huang L;Beiting DP;Gebreselassie NG;Gagliardo LF;Ruyechan MC;Lee NA;Lee JJ;Appleton JA
越来越清楚的是，嗜酸性粒细胞的功能超出了宿主防御和过敏的范围，涉及新陈代谢和组织再生。这些影响很可能与蠕虫感染有关，其中嗜酸性粒细胞占主导地位，寄生虫依赖宿主的营养来支持生长或繁殖。本研究的目的是探讨嗜酸性粒细胞促进骨骼肌中旋毛虫幼虫生长的机制。我们的结果表明，IL-4 和嗜酸性粒细胞是正常幼虫生长所必需的，并且来自 IL-4 活性小鼠的嗜酸性粒细胞足以支持生长。嗜酸性粒细胞介导的作用在缺乏适应性免疫的情况下发挥作用。新生幼虫入侵后，骨骼肌中的宿主基因表达与感染组织中的再生反应和能量来源的转变相一致。嗜酸性粒细胞的存在抑制了局部炎症，同时也影响了肌肉中的营养稳态。在护士细胞中观察到葡萄糖转运蛋白 4 (GLUT4) 的重新分布和 Akt 的磷酸化，这与已知的幼虫葡萄糖摄取和糖原储存的增强一致。这些数据与嗜酸性粒细胞通过 IL-4 依赖性机制促进幼虫生长的机制一致，该机制限制了局部干扰素驱动的反应，否则会改变受感染肌肉中的营养代谢。我们的研究结果记录了寄生虫和宿主之间的一种新颖的相互作用，其中蠕虫进化出了一种策略，以促进其生长的方式选择先天的宿主细胞反应。嗜酸性粒细胞增多是由寄生虫感染引起的 2 型免疫的主要特征。尽管早期研究表明嗜酸性粒细胞可以在体外粘附并损伤寄生虫幼虫，但多年来嗜酸性粒细胞在蠕虫感染过程中的明确作用仍然难以捉摸。最近的研究揭示了嗜酸性粒细胞在调节代谢和组织重塑中的新作用，观察结果表明嗜酸性粒细胞可能充当调节细胞并在蠕虫感染期间调节此类过程。我们研究了促进旋毛虫幼虫生长的嗜酸性粒细胞依赖性机制。我们发现幼虫生长独立于适应性免疫，并且需要嗜酸性粒细胞中的 IL-4/STAT6 信号传导。受感染肌肉中的基因转录谱表明，嗜酸性粒细胞通过抑制局部炎症和增强营养吸收和代谢来促进幼虫生长。我们的研究为寄生虫与其宿主之间的相互作用提供了新的见解。
It has become increasingly clear that the functions of eosinophils extend beyond host defense and allergy to metabolism and tissue regeneration. These influences have strong potential to be relevant in worm infections in which eosinophils are prominent and parasites rely on the host for nutrients to support growth or reproduction. The aim of this study was to investigate the mechanism underlying the observation that eosinophils promote growth of Trichinella spiralis larvae in skeletal muscle. Our results indicate that IL-4 and eosinophils are necessary for normal larval growth and that eosinophils from IL-4 competent mice are sufficient to support growth. The eosinophil-mediated effect operates in the absence of adaptive immunity. Following invasion by newborn larvae, host gene expression in skeletal muscle was compatible with a regenerative response and a shift in the source of energy in infected tissue. The presence of eosinophils suppressed local inflammation while also influencing nutrient homeostasis in muscle. Redistribution of glucose transporter 4 (GLUT4) and phosphorylation of Akt were observed in nurse cells, consistent with enhancement of glucose uptake and glycogen storage by larvae that is known to occur. The data are consistent with a mechanism in which eosinophils promote larval growth by an IL-4 dependent mechanism that limits local interferon-driven responses that otherwise alter nutrient metabolism in infected muscle. Our findings document a novel interaction between parasite and host in which worms have evolved a strategy to co-opt an innate host cell response in a way that facilitates their growth. Eosinophilia is a central feature of Type 2 immunity induced by infection with parasitic worms. Although early work showed that eosinophils could adhere to and damage parasite larvae in vitro, a definitive role for eosinophils during worm infection remained elusive for many years. Recent studies uncovered novel roles of eosinophils in regulating metabolism and tissue remodeling, observations that suggest that eosinophils may function as regulatory cells and modulate such processes during helminth infections. We investigated the eosinophil-dependent mechanism that promotes growth of Trichinella spiralis larvae. We found that larval growth is independent of adaptive immunity and requires IL-4/STAT6 signaling in eosinophils. Gene transcription profiles in infected muscle suggested that eosinophils promote larval growth by suppressing local inflammation and enhancing nutrient uptake and metabolism. Our study provides new insights into the interactions between a parasitic worm and its host.