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<p>The NLRP3 inflammasome contributes to a wide range of conditions from infections to Alzheimer’s disease. NLRP3 forms an inactive decameric cage, that upon interaction with the trans-Golgi network (TGN) and microtubule organization center (MTOC), leads to inflammasome activation, yet whether non-decamer NLRP3 species form functional inflammasomes remains unclear. Here, we design a NLRP3 exon 3 deletion variant that forms low molecular weight NLRP3 assemblies. Spatially and dynamically highly&#xa0;resolved microscopy in THP-1 and human macrophages shows that nigericin, a K<sup>+</sup>-dependent NLRP3 stimulus, can&#xa0;trigger two distinct activation pathways: (i) the rapidly engaged decameric cage-dependent pathway; and (ii) a decameric cage-independent, TGN/MTOC-distal, and slow-reacting pathway employed by low molecular weight NLRP3 species, that dominates in human neutrophils. Collectively, our results delineate two parallel yet biologically distinct NLRP3 activation pathways, thereby providing a framework to understand NLRP3-driven inflammation across a wide range of pathological context and cell types.</p>

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Non-decameric NLRP3 reveals a TGN/MTOC-distal pathway of inflammasome activation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月30日

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  • María Mateo-Tórtola,
  • Inga V. Hochheiser,
  • Gaopeng Li,
  • Lukas Funk,
  • Atousa Hashemi,
  • Xiao Liu,
  • Jane Torp,
  • Lena Erlebach,
  • András Szolek,
  • Jelena Grga,
  • Francesca Bork,
  • Jana S. Müller,
  • Deborah Kronenberg-Versteeg,
  • Matthias Geyer,
  • Alexander N. R. Weber,
  • Ana Tapia-Abellán

摘要

The NLRP3 inflammasome contributes to a wide range of conditions from infections to Alzheimer’s disease. NLRP3 forms an inactive decameric cage, that upon interaction with the trans-Golgi network (TGN) and microtubule organization center (MTOC), leads to inflammasome activation, yet whether non-decamer NLRP3 species form functional inflammasomes remains unclear. Here, we design a NLRP3 exon 3 deletion variant that forms low molecular weight NLRP3 assemblies. Spatially and dynamically highly resolved microscopy in THP-1 and human macrophages shows that nigericin, a K+-dependent NLRP3 stimulus, can trigger two distinct activation pathways: (i) the rapidly engaged decameric cage-dependent pathway; and (ii) a decameric cage-independent, TGN/MTOC-distal, and slow-reacting pathway employed by low molecular weight NLRP3 species, that dominates in human neutrophils. Collectively, our results delineate two parallel yet biologically distinct NLRP3 activation pathways, thereby providing a framework to understand NLRP3-driven inflammation across a wide range of pathological context and cell types.