A helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages.
A helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages.
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DOI：
10.1371/journal.ppat.1001248
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发表时间：
2011-01-06
期刊：
影响因子：
6.7
通讯作者：
Hartmann S
中科院分区：
文献类型：
--
作者：
Klotz C;Ziegler T;Figueiredo AS;Rausch S;Hepworth MR;Obsivac N;Sers C;Lang R;Hammerstein P;Lucius R;Hartmann S
寄生蠕虫使用非常有效的免疫调节分子来改变宿主的免疫系统，以减少针对它们的炎症反应。我们之前已经证明，蠕虫免疫调节剂胱抑素(AvCystatin)通过调节巨噬细胞来显著减少炎症性疾病的进展。在这里，我们阐明了AvCystatin在巨噬细胞中触发的信号事件。标记的AvCystatin主要被巨噬细胞摄取，随后诱导丝裂原活化蛋白激酶(MAPK)ERK1/2和p38的磷酸化。AvCystatin诱导巨噬细胞表达IL-10对酪氨酸激酶敏感，并依赖于两个MAP激酶的激活，这与IL-12/23p40的表达形成鲜明对比。此外，转录因子CREB和STAT3的磷酸化受AvCystatin诱导，并受磷酸化ERK调节。化学抑制磷脂酰肌醇3-激酶(PI3K)可减少AvCystatin诱导的细胞因子释放，但AvCystatin作用后，PI3K下游靶点AKT不被激活。为了表征参与巨噬细胞表型改变的信号元件，我们应用了数学模型。对电子产生的假说的实验测试发现，双特异性磷酸酶(DUSP)1和2是AvCystatin在体外和体内触发巨噬细胞的调节因子。特别是，DUSP1随后被发现负责调节ERK和p38的磷酸化，并通过AvCystatin控制巨噬细胞中IL-10的表达。因此，我们证明了AvCystatin利用MAP激酶的激活和失活途径来诱导调节性巨噬细胞。这项研究提供了对寄生虫操纵巨噬细胞的分子机制的见解，并强调了数学建模对于阐明免疫细胞调节电路的作用。蠕虫有能力干扰宿主的免疫反应，从而下调炎症反应。我们先前通过巨噬细胞和IL-10依赖机制展示了蠕虫感染或分离的蠕虫蛋白在抑制过敏和结肠炎小鼠模型中旁观者免疫反应中的作用。目前的研究阐明了寄生虫免疫调节剂AvCystatin诱导的信号事件，导致巨噬细胞表型的改变。AvCystatin主要被巨噬细胞摄取，并通过丝裂原活化蛋白激酶(MAPK)、ERK1/2和p38的磷酸化诱导细胞因子的产生。为了确定参与调节IL-10产生的分子，我们开发了一个数学模型。在电子计算机生成的数据中，表明了一种通过使ERK1/2和p38失活的负反馈机制。随后的实验验证了该模型，并发现AvCystatin诱导的双特异性磷酸酶(DUSPs)在体外和体内都是MAPK激活和IL-10表达的负调控因子。综上所述，线虫免疫调节剂AvCystatin针对MAPK的激活和失活途径来诱导调节性巨噬细胞。
Parasitic worms alter their host's immune system to diminish the inflammatory responses directed against them, using very efficient immunomodulating molecules. We have previously shown that the helminth immunomodulator cystatin (AvCystatin) profoundly reduces the progression of inflammatory diseases via modulation of macrophages. Here we elucidate the signaling events in macrophages triggered by AvCystatin. Labeled AvCystatin was predominantly taken up by macrophages and subsequently induced the phosphorylation of the mitogen-activated protein kinases (MAPK) ERK1/2 and p38. IL-10 expression induced by AvCystatin in macrophages was tyrosine kinase sensitive and dependent on activation of both MAP kinases, in clear contrast to expression of IL-12/23p40. In addition, phosphorylation of the transcription factors CREB and STAT3 was induced by AvCystatin and regulated by phospho-ERK. Chemical inhibition of phosphoinositide 3-kinase (PI3K) reduced AvCystatin-induced cytokine release; however, AKT, the downstream target of PI3K, was not activated following AvCystatin exposure. To characterize signaling elements involved in alteration of the macrophage phenotype we applied mathematical modeling. Experimental testing of the in silico generated hypotheses identified dual specificity phosphatase (DUSP) 1 and 2, as regulators in AvCystatin triggered macrophages in vitro and in vivo. In particular, DUSP1 was subsequently found to be responsible for regulation of ERK- and p38-phosphorylation and controlled the IL-10 expression in macrophages by AvCystatin. Thus, we show that AvCystatin exploits activation and deactivation pathways of MAP kinases to induce regulatory macrophages. This study provides insights into molecular mechanisms of macrophage manipulation by parasites and highlights the utility of mathematical modeling for the elucidation of regulatory circuits of immune cells. Helminths have the ability to interfere with their host's immune response, thus downregulating inflammatory responses. We previously demonstrated the role of helminth infections or isolated helminth proteins in suppressing bystander immune responses in mouse models of allergy and colitis via a macrophage and IL-10 dependent mechanism. The current study elucidates the signaling events induced by the parasite immunomodulator AvCystatin, leading to alteration of the macrophage phenotype. AvCystatin was predominantly taken up by macrophages and induced cytokine production by phosphorylation of mitogen-activated protein kinases (MAPK) ERK1/2 and p38. To identify molecules involved in the regulation of IL-10 production we developed a mathematical model. In silico generated data suggested a negative feedback mechanism via deactivating ERK1/2 and p38. Ensuing experiments validated the model and revealed AvCystatin-induced dual specificity phosphatases (DUSPs) as negative regulators of MAPK activation and IL-10 expression in vitro and in vivo. Taken together, the nematode immunomodulator AvCystatin targets activating and deactivating pathways of MAPK to induce regulatory macrophages.
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