CircPTK2-miR-181c-5p-HMGB1: a new regulatory pathway for microglia activation and hippocampal neuronal apoptosis induced by sepsis

Background Circular RNA hsa_circ_0008305 (circPTK2), miR-181c-5p and High mobility group box-1 (HMGB1) had a targeted regulatory relationship through bioinformatics analysis. This study explained the effects of these genes in microglia and sepsis mice. Methods Lipopolysaccharide (LPS) or Cecal Ligation and Puncture (CLP) was used to induce inflammation cell model or sepsis mouse model, as needed. Gene levels were measured by enzyme linked immunosorbent assay (ELISA), quantitative real-time PCR or Western blot, as required. Apoptosis was detected by TUNEL assay, and RNase R was used to test the stability of circPTK2. Targeting relationships between genes were analyzed using bioinformatics analysis and dual luciferase assay. Morris water maze test and mitochondrial membrane potential (MMP) detection were conducted to analyze the effects of genes on cognitive dysfunction of mice. Results Lipopolysaccharide induction triggered the release of pro-inflammatory cytokines, the upregulation of HMGB1 and circPTK2, and the downregulation of miR-181c-5p in microglia. Overexpression of HMGB1 enhanced the effect of LPS, while silencing HMGB1 partially counteracted the effect of LPS. Moreover, miR-181c-5p was a target of circPTK2 and bound to HMGB1. MiR-181c-5p mimic partially reversed the functions of LPS and HMGB1 overexpression, reduced the levels of TNF-alpha, IL-1 beta, and HMGB1, and inhibited apoptosis. CircPTK2 knockdown had the same effect as miR-181c-5p up-regulation. In vivo, sicircPTK2 improved cognitive function, restored MMP level, inhibited apoptosis, reduced the levels of inflammatory factors and apoptotic factors, and increased the survival rate of CLP-induced mice. Conclusion Our research reveals that circPTK2 regulates microglia activation and hippocampal neuronal apoptosis induced by sepsis via miR-181c-5p-HMGB1 signaling.

Automated summary

The study demonstrates the regulatory relationship between circPTK2, miR-181c-5p, and HMGB1 in microglia and sepsis mice. HMGB1 and circPTK2 were upregulated, while miR-181c-5p was downregulated in response to LPS induction in microglia. Targeting circPTK2/miR-181c-5p/HMGB1 signaling pathway may offer potential therapeutic targets for sepsis-induced cognitive dysfunction and neuronal apoptosis.