miR-155 and miR-146a collectively regulate meningitic Escherichia coli infection-mediated neuroinflammatory responses

• Published in: Journal of neuroinflammation Vol. 18; no. 1; p. 114
• Main Authors: Yang, Bo, Yang, Ruicheng, Xu, Bojie, Fu, Jiyang, Qu, Xinyi, Li, Liang, Dai, Menghong, Tan, Chen, Chen, Huanchun, Wang, Xiangru
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 13.05.2021; BioMed Central; BMC
• Subjects: Astrocytes; Bacteria; Bioinformatics; Brain; Central nervous system; Chemokines; Cloning; Cytokines; Development and progression; E coli; Epidermal growth factor receptors; Escherichia coli; Escherichia coli infections; Genes; Genetic aspects; Health aspects; Immune response; Infections; Inflammation; IRAK protein; Meningitis; Microglia; MicroRNA; MicroRNAs; miR-146a; miR-155; miRNA; Morbidity; Mortality; Neuroinflammation; NF-κB protein; Plasmids; Proteins; Reagents; Signal transduction; Survival; TRAF6 protein; Transcription activation; Transcription factors; Western blotting; China; United States > US; Neuroinflammation; miR-146a; Astrocytes; Escherichia coli; miR-155
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-021-02165-4

Escherichia coli is the most common Gram-negative bacterium causing meningitis, and E. coli meningitis is associated with high mortality and morbidity throughout the world. Our previous study showed that E. coli can colonize the brain and cause neuroinflammation. Increasing evidence supports the involvement of miRNAs as key regulators of neuroinflammation. However, it is not clear whether these molecules participate in the regulation of meningitic E. coli-mediated neuroinflammation. The levels of miR-155 and miR-146a, as well as their precursors, in E. coli-infected astrocytes were measured using quantitative real-time PCR (qPCR). Overexpression and knockdown studies of miR-155 and miR-146a were performed to observe the effects on bacterial loads, cytokines, chemokines, and NF-κB signaling pathways. Bioinformatics methods were utilized to predict the target genes, and these target genes were validated using qPCR, Western blotting, and luciferase reporter system. In vivo knockdown of miR-155 and miR-146a was carried out to observe the effects on bacterial loads, inflammatory genes, astrocyte activation, microglia activation, and survival in a mouse model. The levels of miR-155, miR-146a, and their precursors were significantly increased in astrocytes during E. coli infection. miR-155 and miR-146a were induced by the NF-κB-p65 signaling pathway upon infection. Overexpressing and inhibiting miR-155 and miR-146a in astrocytes did not affect the bacterial loads. Further, the in vitro overexpression of miR-155 and miR-146a suppressed the E. coli-induced inflammatory response, whereas the inhibition of miR-155 and miR-146a enhanced it. Mechanistically, miR-155 inhibited TAB2, and miR-146a targeted IRAK1 and TRAF6; therefore, they functioned collaboratively to modulate TLR-mediated NF-κB signaling. In addition, both miR-155 and miR-146a could regulate the EGFR-NF-κB signaling pathway. Finally, the in vivo suppression of E. coli-induced miR-155 and miR-146a further promoted the production of inflammatory cytokines, aggravated astrocyte and microglia activation, and decreased mouse survival time, without affecting the bacterial loads in the blood and brain. E. coli infection induced miR-155 and miR-146a, which collectively regulated bacteria-triggered neuroinflammatory responses through negative feedback regulation involving the TLR-mediated NF-κB and EGFR-NF-κB signaling pathways, thus protecting the central nervous system from further neuroinflammatory damage.