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<p>TMPRSS11E is a serine protease whose expression is upregulated in macrophages during inflammation. Here, we identify TFR1 as an interacting protein of TMPRSS11E via LC-MS/MS. In vitro experiments reveal that TMPRSS11E cleaves TFR1 and releases soluble TFR1 (sTFR1). In alveolar macrophages isolated from pneumonia patients and inflammatory animal models or cultured LPS-challenged cell lines, upregulated TMPRSS11E expression and significantly increased sTFR1 release are observed. Moreover, THP-1 cells stably expressing TMPRSS11E present decreased iron uptake, increased cell surface IFN-γR2 accumulation, and a stronger response to IFN-γ stimulation. During M0 macrophage differentiation to the pro-inflammatory M1 phenotype, the specific induction of TMPRSS11E, decreased cell surface TFR1, and increased IFN-γR2 cell membrane localization are also observed. Taken together, our results suggest that TMPRSS11E contributes to M1 macrophage differentiation by regulating iron uptake and affecting IFN-γR2 internalization through TFR1 cleavage, indicating that TMPRSS11E plays an important role in iron homeostasis and the innate immune response.</p>

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TMPRSS11E-mediated TFR1 cleavage influences IFN-γR2 internalization and the macrophage innate response

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月3日

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  • Ting Wang,
  • Zhenfa Chen,
  • Yiwei Jiang,
  • Nannan Wang,
  • Wei Zhang,
  • Xihua Wang,
  • Jie Ding,
  • Ling Liu,
  • Zichun Hua,
  • Lei Fang,
  • Shufeng Li

摘要

TMPRSS11E is a serine protease whose expression is upregulated in macrophages during inflammation. Here, we identify TFR1 as an interacting protein of TMPRSS11E via LC-MS/MS. In vitro experiments reveal that TMPRSS11E cleaves TFR1 and releases soluble TFR1 (sTFR1). In alveolar macrophages isolated from pneumonia patients and inflammatory animal models or cultured LPS-challenged cell lines, upregulated TMPRSS11E expression and significantly increased sTFR1 release are observed. Moreover, THP-1 cells stably expressing TMPRSS11E present decreased iron uptake, increased cell surface IFN-γR2 accumulation, and a stronger response to IFN-γ stimulation. During M0 macrophage differentiation to the pro-inflammatory M1 phenotype, the specific induction of TMPRSS11E, decreased cell surface TFR1, and increased IFN-γR2 cell membrane localization are also observed. Taken together, our results suggest that TMPRSS11E contributes to M1 macrophage differentiation by regulating iron uptake and affecting IFN-γR2 internalization through TFR1 cleavage, indicating that TMPRSS11E plays an important role in iron homeostasis and the innate immune response.