Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, 1105 BK Amsterdam, The Netherlands.
Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
Cells. 2021 Dec 25;11(1):58. doi: 10.3390/cells11010058.
Antimicrobial responses play an important role in maintaining intestinal heath. Recently we reported that miR-511 may regulate TLR4 responses leading to enhanced intestinal inflammation. However, the exact mechanism remained unclear. In this study we investigated the effect of miR-511 deficiency on anti-microbial responses and DSS-induced intestinal inflammation. miR-511-deficient mice were protected from DSS-induced colitis as shown by significantly lower disease activity index, weight loss and histology scores in the miR-511-deficient group. Furthermore, reduced inflammatory cytokine responses were observed in colons of miR-511 deficient mice. In vitro studies with bone marrow-derived M2 macrophages showed reduced TLR3 and TLR4 responses in miR-511-deficient macrophages compared to WT macrophages. Subsequent RNA sequencing revealed Wdfy1 as the potential miR-511 target. WDFY1 deficiency is related to impaired TLR3/TLR4 immune responses and the expression was downregulated in miR-511-deficient macrophages and colons. Together, this study shows that miR-511 is involved in the regulation of intestinal inflammation through downstream regulation of TLR3 and TLR4 responses via Wdfy1.
抗菌反应在维持肠道健康方面发挥着重要作用。最近我们报道，miR-511 可能通过调节 TLR4 反应导致肠道炎症加重。然而，确切的机制尚不清楚。在这项研究中，我们研究了 miR-511 缺失对抗菌反应和 DSS 诱导的肠道炎症的影响。与野生型（WT）相比，miR-511 缺失的小鼠对 DSS 诱导的结肠炎具有更强的抵抗力，表现在疾病活动指数（disease activity index）、体重减轻和组织学评分均显著降低。此外，miR-511 缺失的小鼠结肠中炎症细胞因子的反应也降低。体外研究表明，与 WT 巨噬细胞相比，骨髓来源的 M2 巨噬细胞中 TLR3 和 TLR4 反应在 miR-511 缺失的巨噬细胞中降低。随后的 RNA 测序显示 Wdfy1 是潜在的 miR-511 靶基因。WDFY1 缺陷与 TLR3/TLR4 免疫反应受损有关，并且在 miR-511 缺失的巨噬细胞和结肠中表达下调。综上所述，这项研究表明，miR-511 通过下游调节 TLR3 和 TLR4 反应，通过 Wdfy1 参与调节肠道炎症。
