Abstract
BackgroundCircular 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.MethodsLipopolysaccharide (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.ResultsLipopolysaccharide 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-α, IL-1β, 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.ConclusionOur research reveals that circPTK2 regulates microglia activation and hippocampal neuronal apoptosis induced by sepsis via miR-181c-5p-HMGB1 signaling.
Highlights
Circular RNA hsa_circ_0008305, miR-181c-5p and High mobility group box-1 (HMGB1) had a targeted regulatory relationship through bioinformatics analysis
We explored the role of circPTK2-miR181c-5p-HMGB1 in hippocampal neuronal apoptosis induced by sepsis via miR-181c-5p-HMGB1 signaling
HMGB1 regulated the secretion and expressions of tumor necrosis factor (TNF)‐α, IL‐1β and HMGB1 in microglia According to reports, HMGB1 plays an important role in neurotoxicity in glial cell activation (Chavan et al 2012), but its role in sepsis neuroinflammation remains unclear
Summary
Circular RNA hsa_circ_0008305 (circPTK2), miR-181c-5p and High mobility group box-1 (HMGB1) had a targeted regulatory relationship through bioinformatics analysis. There is convincing evidence that microglia are the main immune effector cells of the central nervous system and play an important role (Kabba et al 2018). It can activate microglia to produce inflammatory factors, and inflammatory cytokines in turn promote the secretion of HMGB1, forming a positive feedback loop which can continuously aggravate the inflammatory response (Wang et al 2015). This positive feedback effect plays a vital part in maintaining the inflammatory response (Gonelevue et al 2018). Despite the discovery of the important role of HMGB1 in microglia activation, the mechanism of HMGB1 in sepsis neuroinflammation remains unclear
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