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<p>Liver X receptors (LXRs) are members of the nuclear receptor superfamily, and LXR agonists have been recognized for their neuroprotective potential. This study aimed to investigate the regulatory effects and underlying molecular mechanisms of the LXR agonist LXR623 in modulating microglial polarization during infection with Japanese encephalitis virus (JEV). JEV infection significantly upregulated the expression of host LXRs. Treatment with LXR623 ameliorated JEV-induced morphological alterations and cellular damage in BV2 microglial cells. LXR623 also suppressed M1 macrophage polarization and promoted a shift toward the M2 phenotype, thereby attenuating the inflammatory response associated with JEV infection. These effects may be exerted through the pathway involving Toll-like receptor 4, nuclear factor-κB, and the NOD-like receptor family pyrin domain containing 3. The LXR inverse agonist SR9243 partially blocked the protective effect of LXR623. In JEV-infected mice, LXR623 administration significantly reduced mortality and alleviated clinical symptoms of encephalitis. These findings indicate that LXR activation modulates JEV-induced microglial polarization and confers neuroprotective effects in vivo, establishing a novel host-directed strategy with cross-species applicability for the prevention of Japanese encephalitis.</p>

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Liver X receptor agonist LXR623 inhibits the TLR4/NF-κB/NLRP3 pathway to regulate microglial polarization induced by Japanese encephalitis virus infection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月10日

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  • Anqi Wei,
  • Zhiwei Huang,
  • Kaining Li,
  • Pengcheng Li,
  • Xiaoyu Cen,
  • Changqin Gu

摘要

Liver X receptors (LXRs) are members of the nuclear receptor superfamily, and LXR agonists have been recognized for their neuroprotective potential. This study aimed to investigate the regulatory effects and underlying molecular mechanisms of the LXR agonist LXR623 in modulating microglial polarization during infection with Japanese encephalitis virus (JEV). JEV infection significantly upregulated the expression of host LXRs. Treatment with LXR623 ameliorated JEV-induced morphological alterations and cellular damage in BV2 microglial cells. LXR623 also suppressed M1 macrophage polarization and promoted a shift toward the M2 phenotype, thereby attenuating the inflammatory response associated with JEV infection. These effects may be exerted through the pathway involving Toll-like receptor 4, nuclear factor-κB, and the NOD-like receptor family pyrin domain containing 3. The LXR inverse agonist SR9243 partially blocked the protective effect of LXR623. In JEV-infected mice, LXR623 administration significantly reduced mortality and alleviated clinical symptoms of encephalitis. These findings indicate that LXR activation modulates JEV-induced microglial polarization and confers neuroprotective effects in vivo, establishing a novel host-directed strategy with cross-species applicability for the prevention of Japanese encephalitis.