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

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.