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. 2023 Oct:123:110763.
doi: 10.1016/j.intimp.2023.110763. Epub 2023 Aug 9.

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

Juan Yin  1 , Tong Hu  2 , Lijuan Xu  2 , Liping Zhang  2 , Jianyun Zhu  1 , Yulan Ye  3 , Zhi Pang  4
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Free article

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

Juan Yin et al. Int Immunopharmacol. 2023 Oct.
Free article

Abstract

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.

Keywords: Crohn’s Disease; Macrophage polarization; NF-κB; TLR4; hsa_circRNA_103124.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.