MicroRNA-33 Regulates the Innate Immune Response via ATP Binding Cassette Transporter-mediated Remodeling of Membrane Microdomains
MicroRNA-33 Regulates the Innate Immune Response via ATP Binding Cassette Transporter-mediated Remodeling of Membrane Microdomains
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MicroRNA-33 通过 ATP 结合盒转运蛋白介导的膜微结构域重塑调节先天免疫反应
DOI：
10.1074/jbc.m116.723056
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发表时间：
2016-09-09
影响因子：
4.8
通讯作者：
Fessler, Michael B.
中科院分区：
文献类型：
--
作者：
Lai, Lihua;Azzam, Kathleen M.;Fessler, Michael B.
微小RNA（microRNAs，miRNAs）是一类短的非编码RNA，通过促进特定靶mRNA的降解和/或抑制其翻译来调节基因表达。已经鉴定了几种通过直接靶向Toll样受体（TLR）途径成员和/或细胞因子来调节先天免疫应答的幅度的miRNA。miR-33 a和miR-33 b（后者存在于灵长类动物中，但在啮齿类动物和低等物种中不存在）位于固醇调节元件结合蛋白（SREBP）编码基因的内含子中，并与其宿主基因产物一起控制胆固醇/脂质稳态。这些miRNA通过靶向脂质流出转运蛋白ATP结合盒（ABC）A1和ABCG 1来调节巨噬细胞胆固醇。我们和其他人以前曾报道过，由于脂筏胆固醇增加，Abca 1（-/-）和Abcg 1（-/-）巨噬细胞增加了TLR促炎反应。鉴于此，我们假设miR-33将通过筏胆固醇依赖性机制增强巨噬细胞中的TLR信号传导。在此，我们报道了多种TLR配体下调小鼠巨噬细胞中的miR-33。在脂多糖的情况下，这是一种延迟的、含有Toll/白细胞介素-1受体（TIR）结构域的衔接子诱导的干扰素依赖性应答，其也下调miR-33的宿主基因Srebf-2。miR-33增加巨噬细胞脂筏并增强LPS诱导的促炎细胞因子诱导和NF-B活化。这通过ABCA 1和ABCG 1依赖性机制发生，并且通过对筏胆固醇的干预和ABC转运蛋白诱导的肝X受体激动剂是可逆的。总之，这些发现扩展了miR-33的范围，将其鉴定为先天免疫的间接调节剂，介导脂质稳态和炎症之间的双向串扰。
MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression by promoting degradation and/or repressing translation of specific target mRNAs. Several miRNAs have been identified that regulate the amplitude of the innate immune response by directly targeting Toll-like receptor (TLR) pathway members and/or cytokines. miR-33a and miR-33b (the latter present in primates but absent in rodents and lower species) are located in introns of the sterol regulatory element-binding protein (SREBP)-encoding genes and control cholesterol/lipid homeostasis in concert with their host gene products. These miRNAs regulate macrophage cholesterol by targeting the lipid efflux transporters ATP binding cassette (ABC)A1 and ABCG1. We and others have previously reported that Abca1(-/-) and Abcg1(-/-) macrophages have increased TLR proinflammatory responses due to augmented lipid raft cholesterol. Given this, we hypothesized that miR-33 would augment TLR signaling in macrophages via a raft cholesterol-dependent mechanism. Herein, we report that multiple TLR ligands down-regulate miR-33 in murine macrophages. In the case of lipopolysaccharide, this is a delayed, Toll/interleukin-1 receptor (TIR) domain-containing adapter-inducing interferon--dependent response that also down-regulates Srebf-2, the host gene for miR-33. miR-33 augments macrophage lipid rafts and enhances proinflammatory cytokine induction and NF-B activation by LPS. This occurs through an ABCA1- and ABCG1-dependent mechanism and is reversible by interventions upon raft cholesterol and by ABC transporter-inducing liver X receptor agonists. Taken together, these findings extend the purview of miR-33, identifying it as an indirect regulator of innate immunity that mediates bidirectional cross-talk between lipid homeostasis and inflammation.