image: IL-33 is primarily released through NINJ1-mediated membrane rupture, whereas the timing of NINJ1 activation induced by Gasdermins and other factors differs between individual cells.
Credit: Takumi Kanokogi and Hiroyasu Nakano
Researchers at Toho University have uncovered a previously unrecognized mechanism controlling how dying cells release the inflammatory cytokine IL-33, a key driver of allergy, asthma, tissue inflammation, and cancer progression. The findings reveal that cells do not release IL-33 uniformly; instead, individual cells exhibit striking differences in release timing controlled by the membrane rupture protein NINJ1.
Using a high-resolution live-cell imaging platform capable of visualizing cytokine release in real time at single-cell resolution, the research team discovered that IL-33 release frequently occurs only after catastrophic plasma membrane rupture mediated by NINJ1, rather than directly through Gasdermin pores as previously thought.
The study further demonstrated that the timing of IL-33 release differs dramatically depending on the type of cell death. During necroptosis, IL-33 is released almost instantaneously when membrane integrity collapses. In contrast, during apoptosis and pyroptosis, some cells released IL-33 immediately, whereas others waited tens of minutes before release. “This study reveals that inflammatory signal release is not a simple on/off event,” said corresponding author Hiroyasu Nakano. “Even cells dying under the same conditions can release IL-33 with very different timing. We found that temporal regulation of NINJ1 activation is a key determinant of this heterogeneity.”
The researchers also showed that deleting NINJ1 strongly suppressed IL-33 release across multiple cell types and cell death pathways. This highlights NINJ1 as a central executor of the release of damage-associated molecular patterns (DAMPs)—molecules released from dying cells that alert the immune system. Because IL-33 plays critical roles in allergic disease, fibrosis, cancer, and immune activation, the findings may open new therapeutic avenues for controlling excessive inflammation by targeting membrane rupture mechanisms rather than upstream cytokine production alone.
The work additionally showcases the power of real-time single-cell secretion imaging (LCI-S), a technology that allows researchers to directly visualize the dynamics of inflammatory molecule release from living cells.
The study appears in Communications Biology.
Commun Biol. 2026 May 21. doi: 10.1038/s42003-026-10300-1. Online ahead of print.PMID: 42168568
Journal
Communications Biology
Method of Research
Experimental study
Subject of Research
Cells
Article Title
Temporal control of Ninj1 activation determines cell-to-cell heterogeneity in IL-33 release
Article Publication Date
21-May-2026
COI Statement
Mai Yamagishi, one of the authors of the original research article, is the founder and shareholder of Live Cell Diagnosis. Yoshitaka Shirasaki is a family member of Mai Yamagishi. All the other authors declare that they have no competing interests.