Although microRNAs regulate mRNA expression intracellularly, they are often released into the circulation in inflammatory diseases. During sepsis, secreted extracellular cold-inducible RNA-binding protein (eCIRP) acts as a damage-associated molecular pattern (DAMP), inducing tissue damage by elevating inflammatory cytokines and chemokines. Here, we report that the circulating microRNA 130b-3p inhibits eCIRP-mediated sterile and cecal ligation and puncture (CLP)-induced non-sterile inflammation. We find that levels of miR-130b-3p are increased in the serum of septic mice and patients and that it strongly interacts with recombinant murine (rm) CIRP in vitro and with eCIRP in the serum of septic mice in vivo. Combining a miR-130b-3p mimic with rmCIRP significantly decreases TNF-α release by macrophages compared to only rmCIRP-treated cells. This combined treatment also dose-dependently decreases the affinity of rmCIRP with its receptor TLR4/MD2. Finally, injection of a miR-130b-3p mimic significantly reduces rmCIRP- or CLP-induced systemic inflammation and acute lung injury in mice. These data show that extracellular miR-130b-3p functions as a novel endogenous inhibitor of eCIRP and point to an innovative therapeutic approach to treat inflammatory diseases.

中文翻译：

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细胞外 microRNA 130b-3p 抑制 eCIRP 诱导的炎症。

尽管 microRNA 在细胞内调节 mRNA 表达，但在炎症性疾病中它们经常释放到循环中。在脓毒症期间，分泌的细胞外冷诱导 RNA 结合蛋白 (eCIRP) 作为损伤相关分子模式 (DAMP)，通过升高炎症细胞因子和趋化因子来诱导组织损伤。在这里，我们报告循环的 microRNA 130b-3p 抑制 eCIRP 介导的无菌和盲肠结扎穿刺 (CLP) 诱导的非无菌炎症。我们发现脓毒症小鼠和患者血清中的 miR-130b-3p 水平升高，并且其在体外与重组鼠 (rm) CIRP 以及体内脓毒症小鼠血清中的 eCIRP 强烈相互作用。与仅用 rmCIRP 处理的细胞相比，将 miR-130b-3p 模拟物与 rmCIRP 组合可显着降低巨噬细胞释放 TNF-α。这种联合治疗还剂量依赖性地降低 rmCIRP 与其受体 TLR4/MD2 的亲和力。最后，注射 miR-130b-3p 模拟物可显着减少 rmCIRP 或 CLP 诱导的小鼠全身炎症和急性肺损伤。这些数据表明，细胞外 miR-130b-3p 作为 eCIRP 的新型内源性抑制剂发挥作用，并指出了治疗炎症性疾病的创新治疗方法。