2. Academic Validation
  3. Knockdown of long non-coding RNA BISPR attenuates the proinflammatory cytokine IL-6 production in human microglia

Knockdown of long non-coding RNA BISPR attenuates the proinflammatory cytokine IL-6 production in human microglia

  • Biochem Biophys Res Commun. 2025 Dec 31:793:153011. doi: 10.1016/j.bbrc.2025.153011.
Yingying Wang 1,  Xiaoyu Zhang 2,  Shengqiu Li 2,  Ruiying Zhu 2,  Jie Zhang 3,  Xiu-An Yang 4
Affiliations

Affiliations

  • 1 Hebei Key Laboratory of Nerve Injury and Repair, Chengde Medical University, Chengde, 067000, China; Laboratory of Gene Engineering and Genomics, School of Basic Medical Sciences, Chengde Medical University, 067000, Chengde, China.
  • 2 Laboratory of Gene Engineering and Genomics, School of Basic Medical Sciences, Chengde Medical University, 067000, Chengde, China.
  • 3 Laboratory of Gene Engineering and Genomics, School of Basic Medical Sciences, Chengde Medical University, 067000, Chengde, China. Electronic address: [email protected].
  • 4 Hebei Key Laboratory of Nerve Injury and Repair, Chengde Medical University, Chengde, 067000, China; Laboratory of Gene Engineering and Genomics, School of Basic Medical Sciences, Chengde Medical University, 067000, Chengde, China. Electronic address: [email protected].
PMID: 41275794 DOI: 10.1016/j.bbrc.2025.153011
Abstract

Background: Chronic microglial inflammation may cause neurodegenerative diseases. LncRNA BISPR, which is induced by IFN in various cells, has an unknown role in this inflammation. This study investigates lncRNA BISPR's role in modulating inflammatory responses in microglia to explore potential therapeutic applications.

Methods: RT-qPCR was used to measure the expression of lncRNA BISPR in HMC3 microglia following stimulation with IFN-γ, IFN-α 2b or TNF-α. A stable BISPR-knockdown (BISPR-KD) model was established in the HMC3 microglial cell line. Transcriptomic alterations in BISPR-KD cells under homeostatic, LPS (lipopolysaccharide) stimulated, and LPS/IFN-γ co-stimulated conditions were analyzed by RNA-seq. Protein levels of IL-6, TLR4, STAT1, and phosphorylated STAT1 (p-STAT1) were evaluated by Western blot.

Results: BISPR was significantly induced by IFN-γ, IFN-α 2b and TNF-α. BISPR knockdown significantly suppressed LPS or LPS/IFN-γ-induced IL-6 expression. Transcriptomic analysis revealed that differentially expressed genes were markedly enriched in the inflammatory response and JAK-STAT signaling pathways. Mechanistic studies demonstrated that BISPR knockdown did not alter the mRNA or protein levels of key components in the TLR4 pathway (TLR4, LBP, TRAF6, NFKB1), but substantially reduced the phosphorylation of STAT1 at tyrosine 701.

Conclusion: Our study unveils BISPR as a critical positive regulator of microglial inflammation. Its function does not appear to be mediated through the TLR4 pathway. This is possibly achieved by forming a positive feedback amplification loop within the JAK-STAT1 signaling pathway: inflammatory signals induce BISPR expression, which in turn potentiates STAT1 activation, thereby amplifying the inflammatory output, including IL-6. BISPR represents a potential novel therapeutic target for excessive neuroinflammation in microglia.

Keywords

IL-6; Microglia; Neuroinflammation; STAT1; lncRNA BISPR.

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