MK2 mediates macrophage activation and acute lung injury by regulating let-7e miRNA
MK2 mediates macrophage activation and acute lung injury by regulating let-7e miRNA
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MK2通过调节let-7e miRNA介导巨噬细胞激活和急性肺损伤
DOI：
10.1152/ajplung.00019.2018
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发表时间：
2018-09-01
影响因子：
4.9
通讯作者：
Qian, Feng
中科院分区：
文献类型：
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作者：
Wu, Yaxian;He, Huiqiong;Qian, Feng
MAPK活化的蛋白激酶2（MK2）在炎症的发展中起着关键作用。然而，巨噬细胞活化和急性肺损伤（ALI）的调节机制尚未完全确定。在此，我们报道了MK2缺陷小鼠（MK2（-/-））对脓毒症诱导的ALI的保护作用。对脂多糖（LPS）攻击的反应。MK2（-/-）小鼠和骨髓细胞特异性MK2条件性敲除小鼠（MK2（Lyz 2-KO））表现出减弱的炎症反应，特别是产生更少量的肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-6和巨噬细胞炎性蛋白2（MIP-2）。体外LPS处理导致MK2（-/-）骨髓源性巨噬细胞（BMDM）中细胞因子表达减少。此外。我们发现LPS诱导的micmRNAlethal-7 e（let-7 e）表达在MK2（-/-）巨噬细胞中显著增加。将let-7 e β-内酰胺酶转染入MK2（-/-）BMDM挽救了LPS诱导的TNF-α、IL-6和MIP-2的表达。相反。let-7 e模拟物转染入MK 2 ′ BMDM降低了细胞因子表达。同时，I，PS诱导的cAMP反应元件结合（CREB）蛋白（MK 2的底物）磷酸化在MK 2（-/-）BMDM中下调。在MK 2（-/-）巨噬细胞中，let-7的抑制分子Lin 28显著减少。我们的研究结果表明，MK 2通过增加CREB的活化，从而增加Lin 28的表达和let-7 e的下调，增强LPS诱导的巨噬细胞活化和ALI。
MAPK-activated protein kinase 2 (MK2) plays a critical role in the development of inflammation. However, the modulatory mechanisms in macrophage activation and acute lung injury (ALI) have not been completely defined. Here, we reported that MK2-deficient mice (MK2(-/-)) protected against sepsisinduced ALI. In response to lipopolysaccharide (LPS) challenge. MK2(-/-) mice and myeloid cell-specific MK2 conditional knockout mice (MK2(Lyz2-KO)) exhibited attenuated inflammatory response, especially producing fewer amounts of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and macrophage inflammatory protein 2 (MIP-2). LPS treatment in vitro resulted in reduced cytokine expression in MK2(-/-) bone marrow-derived macrophages (BMDMs). Furthermore. we found that LPS-induced micmRNA lethal-7e (let-7e) expression was significantly increased in MK2(-/-) macrophages. Transfection of let-7e antagomirs into MK2(-/-) BMDM rescued LPS-induced expression of TNF-alpha, IL-6, and MIP-2. In contrast. transfection of let-7e mimics into MK2'BMDM decreased cytokine expression. Meanwhile, I,PS-induced phosphorylation of cAMP response element-binding (CREB) protein, a substrate of MK2, was downregulated in MK2(-/-) BMDMs. Lin28, an inhibitory molecule of let-7, was significantly reduced in MK2(-/-) macrophages. Our results suggested that MK2 boosts LPS-induced macrophage activation and ALI via increasing activation of CREB and consequently, the expression of Lin28 and downregulation of let-7e.