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<p>Although the immune adaptor protein ADAP (adhesion and degranulation adaptor protein) plays a critical role in regulating macrophage inflammatory responses, its impact on intestinal inflammation remains elusive. This study reveals that ADAP-deficient mice have increased susceptibility to dextran sulfate sodium (DSS)-induced colitis and intestinal inflammation due to upregulation of S100A8/A9 expression (also known as MRP8 and MRP14, respectively) both in <i>vivo</i> and in <i>vitro</i>. Mechanistically, ADAP promotes proteasomal degradation of the transcription factor SPI1 (SPI-1 proto-oncogene) via the E3 ubiquitin ligase FBXW7 (F-box and WD repeat domain-containing 7)-mediated ubiquitination. ADAP deficiency increases SPI1 expression for transcription of the S100A8/A9 promoter. Blockade of SPI1 effectively prevents colitis-induced S100A8/A9 upregulation in macrophages. Thus, our findings highlight the potential link between ADAP and intestinal inflammation, while also paving the way for therapeutic interventions targeting the ADAP–SPI1–S100A8/A9 signaling axis in inflammatory colitis.</p>

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Inhibition of SPI1 by ADAP Regulates S100A8/A9 Signaling in Macrophages to Control the Development of Colitis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月6日

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  • Yanqi Wang,
  • Xiao Li,
  • Xinyue Lv,
  • Pengchao Zhang,
  • Hebin Liu

摘要

Although the immune adaptor protein ADAP (adhesion and degranulation adaptor protein) plays a critical role in regulating macrophage inflammatory responses, its impact on intestinal inflammation remains elusive. This study reveals that ADAP-deficient mice have increased susceptibility to dextran sulfate sodium (DSS)-induced colitis and intestinal inflammation due to upregulation of S100A8/A9 expression (also known as MRP8 and MRP14, respectively) both in vivo and in vitro. Mechanistically, ADAP promotes proteasomal degradation of the transcription factor SPI1 (SPI-1 proto-oncogene) via the E3 ubiquitin ligase FBXW7 (F-box and WD repeat domain-containing 7)-mediated ubiquitination. ADAP deficiency increases SPI1 expression for transcription of the S100A8/A9 promoter. Blockade of SPI1 effectively prevents colitis-induced S100A8/A9 upregulation in macrophages. Thus, our findings highlight the potential link between ADAP and intestinal inflammation, while also paving the way for therapeutic interventions targeting the ADAP–SPI1–S100A8/A9 signaling axis in inflammatory colitis.