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<p>Interleukin-33 (IL-33), an IL-1 family cytokine, is released during cell damage. However, the mechanism underlying IL-33 release is not fully understood. Here, we generate IL-33–mCherry-expressing mouse cell lines to monitor IL-33 release at single cell resolution. During necroptosis, SYTOX uptake that represents loss of membrane integrity, and IL-33–mCherry release occur simultaneously, indicating that Mlkl-mediated damage causes immediate membrane rupture. In contrast, some apoptotic and pyroptotic cells exhibit delayed IL-33–mCherry release relative to SYTOX uptake, whereas in other cells, both events occur simultaneously. IL-33–mCherry release is only modestly affected by loss of Gsdmd or Gsdme but is markedly reduced in Ninjurin-1 (Ninj1) knockout cells. These findings indicate that Gasdermins act upstream, whereas Ninj1-mediated membrane rupture represents the principal mechanism of IL-33 release. The delay in IL-33–mCherry release in some cells implies that the activation of Ninj1 occurs with variable timing, thus contributing to cell-to-cell heterogeneity.</p><p></p>

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Temporal control of Ninj1 activation determines cell-to-cell heterogeneity in IL-33 release

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月21日

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  • Takumi Kanokogi,
  • Sachiko Komazawa-Sakon,
  • Shin Murai,
  • Kenta Moriwaki,
  • Yoshitaka Shirasaki,
  • Mai Yamagishi,
  • Kenta Sumiyama,
  • Kazuma Kishi,
  • Hiroyasu Nakano

摘要

Interleukin-33 (IL-33), an IL-1 family cytokine, is released during cell damage. However, the mechanism underlying IL-33 release is not fully understood. Here, we generate IL-33–mCherry-expressing mouse cell lines to monitor IL-33 release at single cell resolution. During necroptosis, SYTOX uptake that represents loss of membrane integrity, and IL-33–mCherry release occur simultaneously, indicating that Mlkl-mediated damage causes immediate membrane rupture. In contrast, some apoptotic and pyroptotic cells exhibit delayed IL-33–mCherry release relative to SYTOX uptake, whereas in other cells, both events occur simultaneously. IL-33–mCherry release is only modestly affected by loss of Gsdmd or Gsdme but is markedly reduced in Ninjurin-1 (Ninj1) knockout cells. These findings indicate that Gasdermins act upstream, whereas Ninj1-mediated membrane rupture represents the principal mechanism of IL-33 release. The delay in IL-33–mCherry release in some cells implies that the activation of Ninj1 occurs with variable timing, thus contributing to cell-to-cell heterogeneity.