Hsa_circRNA_103124 在克罗恩病中的上调通过激活 AKT2 和 TLR4/NF-κB 通路促进巨噬细胞 M1 极化，以维持炎症微环境。
Hsa_circRNA_103124 upregulation in Crohn's disease promoted macrophage M1 polarization to maintain an inflammatory microenvironment via activation of the AKT2 and TLR4/NF-κB pathways.
机构信息
Department of Digestive Disease and Nutrition Research Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu Province, PR China.
Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu Province, PR China.
出版信息
Int Immunopharmacol. 2023 Oct;123:110763. doi: 10.1016/j.intimp.2023.110763. Epub 2023 Aug 9.
An accumulating body of research indicates that circular RNAs participate in the pathogenesis of Crohn's disease (CD). Hsa_circRNA_103124, which was upregulated in the peripheral blood mononuclear cells of patients with CD, was reported to inhibit autophagy in our previous studies. However, how hsa_circRNA_103124 participates in CD progression remains unclear. In this study, TLR4 was found to be upregulated in THP1 cells overexpressing hsa_circRNA_103124. Bioinformatic analysis indicated that overexpressed hsa_circRNA_103124 was associated with the PI3K/AKT signaling pathway and TLR4-associated innate immunity in inflammatory bowel disease. Therefore, we inferred a possible role for hsa_circRNA_103124 in macrophage polarization. Hsa_circRNA_103124, AKT2 and TLR4 were significantly upregulated in the PBMCs of patients with CD. Further analysis revealed a positive correlation between hsa_circRNA_103124 and AKT2 (r = 0.8029, p < 0.0001), TLR4 (r = 0.2529, p = 0.0089) and the Crohn's disease activity index (r = 0.4535, p < 0.0001) in patients with CD. Notably, hsa_circRNA_103124 promoted macrophage M1 polarization with increased expression of CD80 and CD86, while it inhibited macrophage M2 polarization with decreased expression of CD206 and CD163. Hsa_circRNA_103124 promoted an inflammatory microenvironment by activating the AKT2 and TLR4/NF-κB signaling pathways in M1 polarized THP1 cells. Nevertheless, hsa-miR-650 reversed the role of hsa_circRNA_103124 in M1 polarization. Hsa_circRNA_103124 promoted the formation of neutrophil extracellular traps and reduced the expression of ZO-1. In summary, the results of this study indicated that hsa_circRNA_103124 promoted macrophage M1 polarization to maintain an inflammatory microenvironment via activation of the TLR4/NF-κB pathway in a hsa-miR-650/AKT2 dependent manner. Hsa_circRNA_103124 could serve as a potential biomarker and a novel therapeutic target in CD progression.
越来越多的研究表明，环状 RNA 参与了克罗恩病 (CD) 的发病机制。我们之前的研究表明，在 CD 患者的外周血单核细胞中上调的 hsa_circRNA_103124 可抑制自噬。然而，hsa_circRNA_103124 如何参与 CD 的进展尚不清楚。在这项研究中，我们发现过表达 hsa_circRNA_103124 的 THP1 细胞中 TLR4 上调。生物信息学分析表明，过表达的 hsa_circRNA_103124 与 PI3K/AKT 信号通路和炎症性肠病中的 TLR4 相关固有免疫有关。因此，我们推断 hsa_circRNA_103124 可能在巨噬细胞极化中发挥作用。CD 患者的 PBMCs 中 hsa_circRNA_103124、AKT2 和 TLR4 显著上调。进一步分析显示，hsa_circRNA_103124 与 AKT2(r=0.8029，p<0.0001)、TLR4(r=0.2529，p=0.0089)和克罗恩病活动指数(r=0.4535，p<0.0001)之间呈正相关。值得注意的是，hsa_circRNA_103124 通过激活 M1 极化的 THP1 细胞中的 AKT2 和 TLR4/NF-κB 信号通路，促进巨噬细胞 M1 极化，增加 CD80 和 CD86 的表达，同时抑制巨噬细胞 M2 极化，减少 CD206 和 CD163 的表达。hsa_circRNA_103124 在 M1 极化的 THP1 细胞中通过激活 AKT2 和 TLR4/NF-κB 信号通路促进炎症微环境的形成。然而，hsa-miR-650 逆转了 hsa_circRNA_103124 在 M1 极化中的作用。hsa_circRNA_103124 促进中性粒细胞胞外诱捕网的形成，并降低 ZO-1 的表达。综上所述，本研究结果表明，hsa_circRNA_103124 通过 hsa-miR-650/AKT2 依赖性方式激活 TLR4/NF-κB 通路，促进巨噬细胞 M1 极化，维持炎症微环境，在 CD 进展中可能作为一种潜在的生物标志物和新的治疗靶点。
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