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.

中文翻译：

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MicroRNA出口商HuR通过促进感染的巨噬细胞的促炎反应来清除内在的病原体。

HuR是一种miRNA阻遏蛋白，可以充当特定miRNA的miRNA海绵，以抵消其对靶mRNA的作用。在这里，我们已经确定了HuR如何通过诱导细胞外小泡介导的miRNA的输出，来确保miRNA抑制的细胞因子的强烈抑制，这对于激活的哺乳动物巨噬细胞中强烈的促炎反应至关重要。相反，内脏利什曼病的病原体利什曼原虫多诺万尼通过多种复杂的机制改变宿主巨噬细胞的免疫反应，从而促进了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作。在被感染的巨噬细胞中 利什曼原虫还上调作用于Ago2蛋白质的蛋白质磷酸酶2A，以使其保持脱磷酸化和与miRNA相关的形式。这会导致针对miRNA的促炎细胞因子的强烈抑制，从而在感染的巨噬细胞中建立抗炎反应。HuR对蛋白磷酸酶2A的表达具有抑制作用，并且巨噬细胞激活过程的数学模型支持HuR和蛋白磷酸酶2A的拮抗miRNA调节作用，后者通过靶向miRNA功能相互平衡巨噬细胞的免疫反应。支持该模型的是，蛋白HuR的异位表达和蛋白磷酸酶2A的同时抑制在宿主巨噬细胞中诱导了强烈的促炎反应，以防止强毒的对药性或耐药性的多诺氏乳杆菌感染。从而，