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TLR4 promotes microglial pyroptosis via lncRNA-F630028O10Rik by activating PI3K/AKT pathway after spinal cord injury
Shun Xu1,2, Jin Wang2, Jianyuan Jiang2
1Department of Orthopedics, Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200240, China.
Abstract:
Neuroinflammation plays a crucial role in the secondary phase of spinal cord injury (SCI), and is initiated following the activation of toll-like receptor 4 (TLR4). However, the downstream mechanism remains unknown. Pyroptosis is a form of inflammatory programmed cell death, which is closely involved in neuroinflammation, and it can be regulated by TLR4 according to a recent research. In addition, several studies have shown that long non-coding RNAs (lncRNAs) based mechanisms were related to signal transduction downstream of TLR4 in the regulation of inflammation. Thus, in this study, we want to determine whether TLR4 can regulate pyroptosis after SCI via lncRNAs. Our results showed that TLR4 was activated following SCI and promoted the expression of lncRNA-F630028O10Rik. This lncRNA functioned as a ceRNA for miR-1231-5p/Col1a1 axis and enhanced microglial pyroptosis after SCI by activating the PI3K/AKT pathway. Furthermore, we determined STAT1 was the upstream transcriptional factor of IncRNA-F630028O10Rik and was induced by the damage-responsive TLR4/MyD88 signal. Our findings provide new insights and a novel therapeutic strategy for treating SCI.
Insights
Toll-like receptor 4 (TLR4) activation drives spinal cord injury (SCI) inflammation via pyroptosis. This study reveals a novel pathway involving lncRNA-F630028O10Rik, miR-1231-5p, and the PI3K/AKT pathway, offering new therapeutic targets for SCI.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Neuroinflammation is critical in secondary spinal cord injury (SCI) pathogenesis.
- Toll-like receptor 4 (TLR4) activation initiates this inflammatory response, but downstream mechanisms are unclear.
- Pyroptosis, an inflammatory cell death pathway, is implicated in neuroinflammation and potentially regulated by TLR4.
Purpose of the Study:
- To investigate if TLR4 regulates pyroptosis in SCI through long non-coding RNAs (lncRNAs).
- To elucidate the specific molecular mechanisms linking TLR4 activation to pyroptosis post-SCI.
Main Methods:
- Analysis of TLR4 activation and lncRNA expression following SCI.
- Investigating the role of lncRNA-F630028O10Rik as a competing endogenous RNA (ceRNA) for miR-1231-5p/Col1a1.
- Assessing the impact on microglial pyroptosis and the PI3K/AKT pathway.
- Identifying upstream transcriptional factors of the identified lncRNA.
Main Results:
- TLR4 activation post-SCI increased the expression of lncRNA-F630028O10Rik.
- This lncRNA promotes microglial pyroptosis by acting as a ceRNA for miR-1231-5p/Col1a1, activating the PI3K/AKT pathway.
- STAT1 was identified as the upstream transcriptional factor of lncRNA-F630028O10Rik, induced by the TLR4/MyD88 signaling pathway.
Conclusions:
- TLR4 signaling initiates a cascade involving STAT1 and lncRNA-F630028O10Rik, leading to pyroptosis and exacerbating neuroinflammation after SCI.
- This pathway, involving the lncRNA-F630028O10Rik/miR-1231-5p/Col1a1 axis and PI3K/AKT activation, represents a novel therapeutic target for spinal cord injury treatment.
