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<p>The study by Bai and Guo (Biol Direct 20(1):73. <a href="https://doi.org/10.1186/s13062-025-00669-0">https://doi.org/10.1186/s13062-025-00669-0</a>, 2025) offers significant insights into the molecular mechanisms of LPS tolerance in macrophages. The authors identify a novel pathway wherein the transcription factor SPI1 (PU.1) directly upregulates the expression of the inhibitory receptor LILRB2, which in turn suppresses TLR8-mediated MyD88/NF-κB signaling to reinforce an immunosuppressive phenotype. While this work elegantly connects transcriptional regulation with functional immune modulation, several aspects warrant further discussion. The broad role of SPI1 necessitates confirming the specificity of its action on LILRB2 and excluding indirect effects on other tolerance regulators. The unconventional inhibition of TLR8, an endosomal viral RNA sensor, by LILRB2 raises questions about ligand specificity and context, particularly in scenarios of viral co-infection. Furthermore, the dominant role of TLR8 in LPS tolerance, a process canonically initiated by TLR4, merits additional validation to clarify its universality. Translational targeting of the SPI1/LILRB2 axis holds promise for reversing immune paralysis in sepsis or chronic inflammation, but potential risks demand careful evaluation using cell-specific approaches. Future work integrating epigenetic analyses, structural studies, single-cell transcriptomics from patients, and investigation of crosstalk with other immunoregulatory pathways will be crucial to fully establish the biological and clinical significance of these findings.</p>

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The SPI1/LILRB2 axis modulates macrophage tolerance via crosstalk with TLR8 signaling: implications for sepsis immunotherapy

  • 期刊论文

  • 发表日期：

    2025年10月27日

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  • DuJiang Yang,
  • Zhijun Ye,
  • Junjie Chen,
  • Shuang Wang,
  • Jiexiang Yang,
  • GuoYou Wang

摘要

The study by Bai and Guo (Biol Direct 20(1):73. https://doi.org/10.1186/s13062-025-00669-0, 2025) offers significant insights into the molecular mechanisms of LPS tolerance in macrophages. The authors identify a novel pathway wherein the transcription factor SPI1 (PU.1) directly upregulates the expression of the inhibitory receptor LILRB2, which in turn suppresses TLR8-mediated MyD88/NF-κB signaling to reinforce an immunosuppressive phenotype. While this work elegantly connects transcriptional regulation with functional immune modulation, several aspects warrant further discussion. The broad role of SPI1 necessitates confirming the specificity of its action on LILRB2 and excluding indirect effects on other tolerance regulators. The unconventional inhibition of TLR8, an endosomal viral RNA sensor, by LILRB2 raises questions about ligand specificity and context, particularly in scenarios of viral co-infection. Furthermore, the dominant role of TLR8 in LPS tolerance, a process canonically initiated by TLR4, merits additional validation to clarify its universality. Translational targeting of the SPI1/LILRB2 axis holds promise for reversing immune paralysis in sepsis or chronic inflammation, but potential risks demand careful evaluation using cell-specific approaches. Future work integrating epigenetic analyses, structural studies, single-cell transcriptomics from patients, and investigation of crosstalk with other immunoregulatory pathways will be crucial to fully establish the biological and clinical significance of these findings.