Diabetes exacerbated sepsis-induced intestinal injury by promoting M1 macrophage polarization via miR-3061/Snail1 signaling.
Diabetes exacerbated sepsis-induced intestinal injury by promoting M1 macrophage polarization via miR-3061/Snail1 signaling.
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糖尿病通过 miR-3061/Snail1 信号传导促进 M1 巨噬细胞极化，从而加剧脓毒症引起的肠道损伤
DOI：
10.3389/fimmu.2022.922614
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
巨噬细胞在糖尿病和败血症相关的肠道损伤中发挥重要作用。越来越多的证据表明 microRNA (miRNA) 是巨噬细胞极化和组织损伤之间的基本联系。然而，miRNA 在糖尿病和脓毒症条件下调节巨噬细胞极化相关肠道损伤的潜在机制仍不清楚。在雄性野生型（WT）和糖尿病小鼠中建立盲肠结扎穿刺（CLP）诱导的脓毒症模型。使用氯膦酸盐脂质体来消耗巨噬细胞。 H&E 染色、炎症细胞因子 [肿瘤坏死因子-α (TNF-α)、白细胞介素-1β (IL-1β) 和 IL-6] 和肠粘膜屏障功能标记物 [occludin、ZO-1、脂多糖 (LPS) 和肠脂肪酸结合蛋白 (iFABP)] 用于评估肠道损伤程度。通过 miRNA 阵列、RNA-seq 和生物信息学分析来检测 miRNA 和信使 RNA (mRNA) 的表达及其潜在的调控机制。在体外，分别在不存在或存在高葡萄糖和 LPS、miR-3061 模拟物和 Snail 小干扰 RNA 刺激的情况下培养 RAW264.7 细胞，以进行进一步的机制研究。荧光素酶报告基因检测用于确认 miRNA 与其靶基因之间的相互作用。与WT CLP小鼠相比，糖尿病CLP小鼠表现出严重的肠道损伤，其特征是Chui评分、炎症细胞因子（TNF-α、IL-1β和IL-6）表达、血清LPS和iFABP浓度显着升高，紧密连接蛋白occludin和ZO-1水平显着降低。巨噬细胞耗竭逆转了 CLP 引起的肠道损伤。生物信息学分析表明miR-3061/Snail1可能是巨噬细胞极化的潜在调控轴。此外，高葡萄糖和 LPS 刺激会增加 M1 巨噬细胞并降低 miR-3061 的水平，而 miR-3061 与 RAW264.7 细胞中的 Snail1 呈负相关。机制研究表明，miR-3061 通过靶向 Snail1 mRNA 3'非翻译区来调节巨噬细胞极化。此外，miR-3061过表达抑制Snail1表达并抑制M1巨噬细胞和炎症细胞因子。该研究阐明糖尿病通过促进M1巨噬细胞极化加剧脓毒症引起的肠道损伤，并进一步证明miR-3061/Sani1轴可能是巨噬细胞极化的潜在靶点。
Macrophages play important roles in diabetes and sepsis-related intestinal injury. Accumulating evidence suggests that microRNAs (miRNAs) act as the fundamental link between macrophage polarization and tissue injury. However, the underlying mechanisms of miRNAs in regulating macrophage polarization–related intestinal injury under diabetes and sepsis conditions remain unclear. The cecal ligation and puncture (CLP)–induced sepsis models were established in male wild-type (WT) and diabetic mice. Clodronate liposome was used to deplete macrophage. H&E staining, inflammatory cytokines [tumor necrosis factor–α (TNF-α), interleukin-1β (IL-1β), and IL-6], and intestinal mucosal barrier function markers [occludin, ZO-1, lipopolysaccharide (LPS), and intestinal fatty acid binding protein (iFABP)] were used to assess elevated intestinal damage. miRNA array, RNA-seq, and bioinformatic analysis were performed to detect the miRNA and messenger RNA (mRNA) expression and the potential regulation mechanism. In vitro, RAW264.7 cells were cultured in the absence or presence of high glucose and LPS, miR-3061 mimics, and Snail small interfering RNA stimulation, respectively, for further mechanism studies. Luciferase reporter assay was used to confirm the interplay between miRNA and its target genes. Compared with WT CLP mice, the diabetic CLP mice showed severe intestinal damage characterized by significant increases in Chui’s scores, expression of inflammatory cytokines (TNF-α, IL-1β, and IL-6), serum LPS and iFABP concentration, and significant reductions in tight junction protein occludin and ZO-1 levels. Macrophage depletion reversed the intestinal damage caused by CLP. The bioinformatic analysis revealed that miR-3061/Snail1 might be a potential regulation axis of macrophage polarization. Furthermore, high glucose and LPS stimulation increased M1 macrophage and reduced the levels of miR-3061, which was negatively associated with Snail1 in RAW264.7 cells. Mechanistic studies demonstrated that miR-3061 regulated macrophage polarization by targeting the Snail1 mRNA 3′‐untranslated region. Moreover, miR-3061 overexpression suppressed Snail1 expression and inhibited M1 macrophage and inflammatory cytokines. This study elucidated that diabetes exacerbated sepsis-induced intestinal injury by promoting M1 macrophage polarization and further demonstrated that the miR-3061/Sani1 axis may be the potential target of macrophage polarization.
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影响因子：
6.2
作者：
Brenot A;Knolhoff BL;DeNardo DG;Longmore GD
通讯作者：
Longmore GD
DOI：
10.1111/febs.15715
发表时间：
2021-06
期刊：
The FEBS journal
影响因子：
--
作者：
Kieler M;Hofmann M;Schabbauer G
通讯作者：
Schabbauer G
影响因子：
13.6
作者：
Lee, Byung-Chul;Lee, Jin Young;Kang, Kyung-Sun
通讯作者：
Kang, Kyung-Sun
影响因子：
2
作者：
Napolitano, Lena M.
通讯作者：
Napolitano, Lena M.
miR-23a〜27a〜24-2 microRNA簇促进巨噬细胞的炎症极化。
DOI：
10.4049/jimmunol.1901277
发表时间：
2021-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Boucher A;Klopfenstein N;Hallas WM;Skibbe J;Appert A;Jang SH;Pulakanti K;Rao S;Cowden Dahl KD;Dahl R
通讯作者：
Dahl R