MicroRNA exporter HuR clears the internalized pathogens by promoting pro-inflammatory response in infected macrophages
MicroRNA exporter HuR clears the internalized pathogens by promoting pro-inflammatory response in infected macrophages
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DOI：
10.15252/emmm.201911011
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发表时间：
2020-03-06
影响因子：
11.1
通讯作者：
Bhattacharyya, Suvendra N.
中科院分区：
文献类型：
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作者：
Goswami, Avijit;Mukherjee, Kamalika;Bhattacharyya, Suvendra N.
HuR是一种miRNA去阻遏蛋白，可以作为特定miRNA的miRNA海绵，以抵消它们对靶mRNA的作用。在这里，我们已经确定了HuR如何通过诱导细胞外囊泡介导的miRNA输出，确保对激活的哺乳动物巨噬细胞中强烈的促炎反应所必需的miRNA抑制的细胞因子的鲁棒去抑制。与此相反，内脏利什曼病的病原体杜氏利什曼原虫通过各种复杂的机制改变宿主巨噬细胞的免疫应答，以促进寄生虫生存所必需的抗炎反应。我们已经发现，在利什曼原虫感染期间，病原体靶向HuR以促进哺乳动物巨噬细胞中抗炎反应的发生。在感染的巨噬细胞中，利什曼原虫还上调蛋白磷酸酶2A，其作用于Ago2蛋白以使其保持去磷酸化和miRNA相关形式。这导致对miRNA靶向的促炎细胞因子的强烈抑制，以在感染的巨噬细胞中建立抗炎反应。HuR对蛋白磷酸酶2A表达具有抑制作用，并且巨噬细胞活化过程的数学建模支持HuR和蛋白磷酸酶2A的拮抗性miRNA调节作用，其通过靶向miRNA功能相互平衡巨噬细胞中的免疫应答。支持该模型，蛋白HuR的异位表达和蛋白磷酸酶2A的同时抑制诱导宿主巨噬细胞中的强烈促炎反应，以防止有毒的锑药物敏感或耐药形式的L. Donovani感染因此，HuR可以作为免疫应答的平衡因子来减少原生动物寄生虫对巨噬细胞的感染过程。
HuR is a miRNA derepressor protein that can act as miRNA sponge for specific miRNAs to negate their action on target mRNAs. Here we have identified how HuR, by inducing extracellular vesicles-mediated export of miRNAs, ensures robust derepression of miRNA-repressed cytokines essential for strong pro-inflammatory response in activated mammalian macrophages. Leishmania donovani, the causative agent of visceral leishmaniasis, on the contrary alters immune response of the host macrophage by a variety of complex mechanisms to promote anti-inflammatory response essential for the survival of the parasite. We have found that during Leishmania infection, the pathogen targets HuR to promote onset of anti-inflammatory response in mammalian macrophages. In infected macrophages, Leishmania also upregulate protein phosphatase 2A that acts on Ago2 protein to keep it in dephosphorylated and miRNA-associated form. This causes robust repression of the miRNA-targeted pro-inflammatory cytokines to establish an anti-inflammatory response in infected macrophages. HuR has an inhibitory effect on protein phosphatase 2A expression, and mathematical modelling of macrophage activation process supports antagonistic miRNA-modulatory roles of HuR and protein phosphatase 2A which mutually balances immune response in macrophage by targeting miRNA function. Supporting this model, ectopic expression of the protein HuR and simultaneous inhibition of protein phosphatase 2A induce strong pro-inflammatory response in the host macrophage to prevent the virulent antimonial drug-sensitive or drug-resistant form of L. donovani infection. Thus, HuR can act as a balancing factor of immune responses to curtail the macrophage infection process by the protozoan parasite.