Kalantari Parisa, Harandi Omid F, Agarwal Sarika, Rus Florentina, Kurt-Jones Evelyn A, Fitzgerald Katherine A, Caffrey Daniel R, Golenbock Douglas T
From the Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and
the Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215.
J Biol Chem. 2017 Apr 7;292(14):5634-5644. doi: 10.1074/jbc.M116.749325. Epub 2017 Feb 16.
Bacterial sepsis involves a complex interaction between the host immune response and bacterial LPS. LPS binds Toll-like receptor (TLR) 4, which leads to the release of proinflammatory cytokines that are essential for a potent innate immune response against pathogens. The innate immune system is tightly regulated, as excessive inflammation can lead to organ failure and death. MicroRNAs have recently emerged as important regulators of the innate immune system. Here we determined the function of miR-718, which is conserved across mammals and overlaps with the 5' UTR of the interleukin 1 receptor-associated kinase () gene. As IRAK1 is a key component of innate immune signaling pathways that are downstream of most TLRs, we hypothesized that miR-718 helps regulate the innate immune response. Activation of TLR4, but not TLR3, induced the expression of miR-718 in macrophages. miR-718 expression was also induced in the spleens of mice upon LPS injection. miR-718 modulates PI3K/Akt signaling by directly down-regulating phosphatase and tensin homolog (PTEN), thereby promoting phosphorylation of Akt, which leads to a decrease in proinflammatory cytokine production. Phosphorylated Akt induces let-7e expression, which, in turn, down-regulates TLR4 and further diminishes TLR4-mediated proinflammatory signals. Decreased miR-718 expression is associated with bacterial burden during infection and alters the infection dynamics of Furthermore, miR-718 regulates the induction of LPS tolerance in macrophages. We propose a role for miR-718 in controlling TLR4 signaling and inflammatory cytokine signaling through a negative feedback regulation loop involving down-regulation of TLR4, IRAK1, and NF-κB.
细菌败血症涉及宿主免疫反应与细菌脂多糖（LPS）之间的复杂相互作用。LPS与Toll样受体（TLR）4结合，导致促炎细胞因子的释放，这些细胞因子对于针对病原体的有效先天性免疫反应至关重要。先天性免疫系统受到严格调控，因为过度炎症会导致器官衰竭和死亡。微小RNA最近已成为先天性免疫系统的重要调节因子。在这里，我们确定了miR-718的功能，它在哺乳动物中保守，并与白细胞介素1受体相关激酶（IRAK）基因的5'非翻译区重叠。由于IRAK1是大多数TLR下游先天性免疫信号通路的关键组成部分，我们假设miR-718有助于调节先天性免疫反应。TLR4而非TLR3的激活诱导巨噬细胞中miR-718的表达。LPS注射后小鼠脾脏中也诱导了miR-718的表达。miR-718通过直接下调磷酸酶和张力蛋白同源物（PTEN）来调节PI3K/Akt信号传导，从而促进Akt的磷酸化，导致促炎细胞因子产生减少。磷酸化的Akt诱导let-7e表达，进而下调TLR4并进一步减少TLR4介导的促炎信号。miR-718表达降低与感染期间的细菌负荷相关，并改变感染动态。此外，miR-718调节巨噬细胞中LPS耐受性的诱导。我们提出miR-718在通过涉及TLR4、IRAK1和NF-κB下调的负反馈调节环控制TLR4信号传导和炎性细胞因子信号传导中发挥作用。
