FOXO-dependent regulation of innate immune homeostasis
FOXO-dependent regulation of innate immune homeostasis
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DOI：
10.1038/nature08698
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发表时间：
2010-01-21
期刊：
影响因子：
64.8
通讯作者：
Hoch, Michael
中科院分区：
文献类型：
--
作者：
Becker, Thomas;Loch, Gerrit;Hoch, Michael
先天免疫系统代表了一种古老的宿主防御机制，可以防止微生物入侵。对抗病原体感染的一类重要的免疫效应分子是植物和动物中产生的抗菌肽 (AMP)(1)。在果蝇中，响应感染而诱导 AMP 是通过激活进化上保守的 Toll 和免疫缺陷 (IMD) 途径来调节的 (2)。在这里，我们表明，AMP 激活可以通过转录因子 FOXO 独立于这些免疫调节途径实现，FOXO 是应激抵抗、代谢和衰老的关键调节因子。在未感染的动物中，当饥饿、使用胰岛素信号突变体或应用小分子抑制剂诱导时，AMP 基因响应核 FOXO 活性而被激活。 AMP 诱导在 Foxo 无效突变体中消失，但在 FOXO 过表达时增强。由于 Toll 和 IMD 途径缺陷而无法应对免疫挑战的动物也会触发 AMP 基因响应 FOXO 活性的表达。 Drosomycin 启动子的分子实验表明，FOXO 直接与其调节区结合，从而诱导其转录。果蝇的体内研究以及人类肺、肠、肾和皮肤细胞的研究表明，FOXO 依赖性的 AMP 调节在进化上是保守的。我们的结果表明了代谢和先天免疫交叉调节的新机制，通过该机制，AMP 基因可以在正常生理条件下激活，以响应细胞和组织的振荡能量状态。这种调节似乎独立于病原体反应性先天免疫途径，其激活通常与组织损伤和修复相关。上皮组织中响应 FOXO 的 AMP 生成稀疏可能有助于调节防御反应而不伤害宿主组织，特别是当动物遭受能量短缺或压力时。
The innate immune system represents an ancient host defence mechanism that protects against invading microorganisms. An important class of immune effector molecules to fight pathogen infections are antimicrobial peptides (AMPs) that are produced in plants and animals(1). In Drosophila, the induction of AMPs in response to infection is regulated through the activation of the evolutionarily conserved Toll and immune deficiency (IMD) pathways(2). Here we show that AMP activation can be achieved independently of these immunoregulatory pathways by the transcription factor FOXO, a key regulator of stress resistance, metabolism and ageing. In non-infected animals, AMP genes are activated in response to nuclear FOXO activity when induced by starvation, using insulin signalling mutants, or by applying small molecule inhibitors. AMP induction is lost in foxo null mutants but enhanced when FOXO is overexpressed. Expression of AMP genes in response to FOXO activity can also be triggered in animals unable to respond to immune challenges due to defects in both the Toll and IMD pathways. Molecular experiments at the Drosomycin promoter indicate that FOXO directly binds to its regulatory region, thereby inducing its transcription. In vivo studies in Drosophila, but also studies in human lung, gut, kidney and skin cells indicate that a FOXO-dependent regulation of AMPs is evolutionarily conserved. Our results indicate a new mechanism of cross-regulation of metabolism and innate immunity by which AMP genes can be activated under normal physiological conditions in response to the oscillating energy status of cells and tissues. This regulation seems to be independent of the pathogen-responsive innate immunity pathways whose activation is often associated with tissue damage and repair. The sparse production of AMPs in epithelial tissues in response to FOXO may help modulating the defence reaction without harming the host tissues, in particular when animals are suffering from energy shortage or stress.