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<p>Lipopolysaccharide (LPS) activates the Toll-like receptor 4 (TLR4)-dependent signalling cascade, leading to nuclear translocation of NF-κB, a key transcription factor that regulates pro-inflammatory gene expression including Tnfα. However, the regulation of <i>NF-κB</i> and additional transcription factors in the management of neuroinflammation is not clear. This report is intended to evaluate the impacts of the Pax6 on the TLR4-dependent neuroinflammation. Chromatin immunoprecipitation (ChIP) with anti-Pax6, followed by sequencing and motif analysis, identified regulatory sequence elements. Additionally, ChIP-qPCR was performed and the expression of Pax6-binding genes was analysed using semi-quantitative PCR and western blotting in the brains of the control and LPS-treated mice. The impact of <i>Pax6</i> on genes associated with <i>NF-κB</i> mediated inflammatory responses was estimated by siRNA-mediated knockdown and overexpression of Pax6 in the N2a cell line. The Pax6 and NF-κB (NF<i>κ</i>B1 and RelA) have multiple binding sites on the regulatory sequence elements, which were also confirmed by sequencing. The analysis also revealed binding of Pax6 on the consensus DNA motif of NF-κB and within the regulatory sequence elements of <i>Tlr4</i>, <i>Tab2</i> and <i>Tank</i>. ChIP-qPCR demonstrated increased binding capacity of Pax6 on promoter sequence elements of NFκB1, RelA, Tab2 and Tank, but decreased binding at Tlr4. The expressions of Pax6, NFκB1, RelA, Tlr4, Tab2, Tank and NF-κB inducible gene Tnfα were also altered. The expression of NFκB1, RelA, Tnfα, Tlr4, Tab2 and Tank was affected by Pax6 knockdown and overexpression. Collectively these findings suggest anti-inflammatory potential of Pax6 through NF-κB regulation.</p>

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Pax6 Binds to NF-κB DNA Motif and Regulates Genes Involved in NF-κB Activation in the Brains of LPS-Treated Mice

  • 期刊论文

  • 发表日期：

    2025年11月15日

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  • Nidhi Ghosh,
  • Rajnikant Mishra

摘要

Lipopolysaccharide (LPS) activates the Toll-like receptor 4 (TLR4)-dependent signalling cascade, leading to nuclear translocation of NF-κB, a key transcription factor that regulates pro-inflammatory gene expression including Tnfα. However, the regulation of NF-κB and additional transcription factors in the management of neuroinflammation is not clear. This report is intended to evaluate the impacts of the Pax6 on the TLR4-dependent neuroinflammation. Chromatin immunoprecipitation (ChIP) with anti-Pax6, followed by sequencing and motif analysis, identified regulatory sequence elements. Additionally, ChIP-qPCR was performed and the expression of Pax6-binding genes was analysed using semi-quantitative PCR and western blotting in the brains of the control and LPS-treated mice. The impact of Pax6 on genes associated with NF-κB mediated inflammatory responses was estimated by siRNA-mediated knockdown and overexpression of Pax6 in the N2a cell line. The Pax6 and NF-κB (NFκB1 and RelA) have multiple binding sites on the regulatory sequence elements, which were also confirmed by sequencing. The analysis also revealed binding of Pax6 on the consensus DNA motif of NF-κB and within the regulatory sequence elements of Tlr4, Tab2 and Tank. ChIP-qPCR demonstrated increased binding capacity of Pax6 on promoter sequence elements of NFκB1, RelA, Tab2 and Tank, but decreased binding at Tlr4. The expressions of Pax6, NFκB1, RelA, Tlr4, Tab2, Tank and NF-κB inducible gene Tnfα were also altered. The expression of NFκB1, RelA, Tnfα, Tlr4, Tab2 and Tank was affected by Pax6 knockdown and overexpression. Collectively these findings suggest anti-inflammatory potential of Pax6 through NF-κB regulation.