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Background <p>Sepsis-associated encephalopathy (SAE) significantly increases mortality in critically ill patients, with blood–brain barrier (BBB) disruption and pyroptosis-driven neuroinflammation recognized as key pathogenic drivers. Long non-coding RNAs (lncRNAs) regulate inflammatory processes, yet their role in pyroptosis-associated BBB dysfunction during SAE remains unexplored.</p> Methods <p>Using integrated bioinformatics analysis of the GSE135838 dataset, we identified dysregulated lncRNAs in SAE. Human brain microvascular endothelial cells (hBMECs) treated with lipopolysaccharide (LPS) were employed as an in vitro model to mimic SAE-associated BBB injury. Cecal ligation and puncture (CLP) was used to induce SAE in mice as an in vivo model. Mechanisms were investigated via RNA interference, luciferase assays, TEER/permeability measurements, and Neuro-behavioral evaluations.</p> Results <p>We identified lncRNA RP11-510J16.3 was markedly upregulated in SAE patients and LPS-stimulated hBMECs. Functionally, silencing RP11-510J16.3 significantly attenuated NLRP3 inflammasome activation and pyroptosis, evidenced by reduced levels of p-P65, GSDMD, and IL-1β. It also preserved BBB integrity by restoring zonula occludens-1(ZO-1) expression and TEER values. Mechanistically, RP11-510J16.3 functions as a competing endogenous RNA (ceRNA) by sequestering miR-1290, thereby effectively liberating its repression of NLRP3 translation. This mechanism was demonstrated by cytoplasmic colocalization and direct binding. Furthermore, rescue experiments demonstrated that miR-1290 inhibition reversed the suppression of pyroptosis. In vivo, AAV9-mediated miR-1290 overexpression significantly reduced BBB leakage, as evidenced by decreased Evans Blue extravasation. Furthermore, this treatment suppressed key brain pyroptosis markers. Concomitantly, miR-1290 overexpression improved neurocognitive function, demonstrated by enhanced performance in both open-field and maze tests.</p> Conclusions <p>This study identifies a novel lncRNA, RP11-510J16.3, which exacerbates SAE by promoting BBB breakdown through the miR-1290/NLRP3-pyroptosis axis. Therapeutic targeting of this pathway preserves neurovascular integrity, presenting a promising strategy for SAE intervention.</p>

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LncRNA RP11-510J16.3 exacerbates sepsis-associated encephalopathy by facilitating NLRP3-dependent pyroptosis through miR-1290 sequestering

  • 期刊论文

  • 发表日期：

    2026年4月1日

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  • Xinqiang Liu,
  • Yan Xiao,
  • Yaqi Lai,
  • Hongguang Ding,
  • Yin Wen,
  • Zhimei He,
  • Miner Chen,
  • Yongli Han,
  • Yuanwen Jing,
  • Miaoyun Wen

摘要

Background

Sepsis-associated encephalopathy (SAE) significantly increases mortality in critically ill patients, with blood–brain barrier (BBB) disruption and pyroptosis-driven neuroinflammation recognized as key pathogenic drivers. Long non-coding RNAs (lncRNAs) regulate inflammatory processes, yet their role in pyroptosis-associated BBB dysfunction during SAE remains unexplored.

Methods

Using integrated bioinformatics analysis of the GSE135838 dataset, we identified dysregulated lncRNAs in SAE. Human brain microvascular endothelial cells (hBMECs) treated with lipopolysaccharide (LPS) were employed as an in vitro model to mimic SAE-associated BBB injury. Cecal ligation and puncture (CLP) was used to induce SAE in mice as an in vivo model. Mechanisms were investigated via RNA interference, luciferase assays, TEER/permeability measurements, and Neuro-behavioral evaluations.

Results

We identified lncRNA RP11-510J16.3 was markedly upregulated in SAE patients and LPS-stimulated hBMECs. Functionally, silencing RP11-510J16.3 significantly attenuated NLRP3 inflammasome activation and pyroptosis, evidenced by reduced levels of p-P65, GSDMD, and IL-1β. It also preserved BBB integrity by restoring zonula occludens-1(ZO-1) expression and TEER values. Mechanistically, RP11-510J16.3 functions as a competing endogenous RNA (ceRNA) by sequestering miR-1290, thereby effectively liberating its repression of NLRP3 translation. This mechanism was demonstrated by cytoplasmic colocalization and direct binding. Furthermore, rescue experiments demonstrated that miR-1290 inhibition reversed the suppression of pyroptosis. In vivo, AAV9-mediated miR-1290 overexpression significantly reduced BBB leakage, as evidenced by decreased Evans Blue extravasation. Furthermore, this treatment suppressed key brain pyroptosis markers. Concomitantly, miR-1290 overexpression improved neurocognitive function, demonstrated by enhanced performance in both open-field and maze tests.

Conclusions

This study identifies a novel lncRNA, RP11-510J16.3, which exacerbates SAE by promoting BBB breakdown through the miR-1290/NLRP3-pyroptosis axis. Therapeutic targeting of this pathway preserves neurovascular integrity, presenting a promising strategy for SAE intervention.