Abstract
Our previous studies have shown that meningitic Escherichia coli can colonize the brain and cause neuroinflammation. Controlling the balance of inflammatory responses in the host central nervous system is particularly vital. Emerging evidence has shown the important regulatory roles of long non-coding RNAs (lncRNAs) in a wide range of biological and pathological processes. However, whether lncRNAs participate in the regulation of meningitic E. coli-mediated neuroinflammation remains unknown. In the present study, we characterized a cytoplasm-enriched antisense lncRNA DDIT4-AS1, which showed similar concordant expression patterns with its parental mRNA DDIT4 upon E. coli infection. DDIT4-AS1 modulated DDIT4 expression at both mRNA and protein levels. Mechanistically, DDIT4-AS1 promoted the stability of DDIT4 mRNA through RNA duplex formation. DDIT4-AS1 knockdown and DDIT4 knockout both attenuated E. coli-induced NF-κB signaling as well as pro-inflammatory cytokines expression, and DDIT4-AS1 regulated the inflammatory response by targeting DDIT4. In summary, our results show that DDIT4-AS1 promotes E. coli-induced neuroinflammatory responses by enhancing the stability of DDIT4 mRNA through RNA duplex formation, providing potential nucleic acid targets for new therapeutic interventions in the treatment of bacterial meningitis.
Highlights
Bacterial meningitis is the most important life-threatening infection of the central nervous system (CNS) and continues to be a significant cause of mortality and morbidity [1, 2].Despite advances in antimicrobial treatment, survivors suffer from neurological sequelae including cognitive impairment, developmental delay, and hearing loss [1, 3]
These findings reveal that damage inducible transcript 4 (DDIT4)-AS1 regulates meningitic E. coli-induced neuroinflammation by promoting DDIT4 mRNA stability, providing novel nucleic acid targets for future prevention and treatment of bacterial meningitis
To characterize the role of antisense long non-coding RNAs (lncRNAs) in the pathological process of meningitic E. coli infection, we evaluated the expression of 21 antisense lncRNAs and their corresponding protein-coding mRNAs
Summary
Bacterial meningitis is the most important life-threatening infection of the central nervous system (CNS) and continues to be a significant cause of mortality and morbidity [1, 2].Despite advances in antimicrobial treatment, survivors suffer from neurological sequelae including cognitive impairment, developmental delay, and hearing loss [1, 3]. Our earlier studies have shown that meningitic E. coli can colonize the brain and cause neuroinflammation [6, 7]. There has been increasing interest in long non-coding RNAs (lncRNAs). These are defined as RNAs longer than 200 nucleotides in length with no protein-coding capacity [8] and can be further classified as antisense lncRNAs, long intergenic noncoding RNAs (lincRNAs), intronic lncRNAs, and enhancer RNAs (eRNAs) based on their genome position [9]. Accumulating evidence has shown that lncRNAs play significant regulatory roles in diverse biological processes [10].
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