Single-cell analysis shows macrophage caspase-1 activation is an all-or-none response
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All cells in which caspase-1 is activated undergo cell death
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The kinetics of caspase-1 activation is independent of stimulus type and intensity
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Only cells with caspase-1 activation exhibit an IL-1β burst.
Summary
Inflammasome-mediated caspase-1 activation is involved in cell death and the secretion of the proinflammatory cytokine interleukin-1β (IL-1β). Although the dynamics of caspase-1 activation, IL-1β secretion, and cell death have been examined with bulk assays in population-level studies, they remain poorly understood at the single-cell level. In this study, we conducted single-cell imaging using a genetic fluorescence resonance energy transfer sensor that detects caspase-1 activation. We determined that caspase-1 exhibits all-or-none (digital) activation at the single-cell level, with similar activation kinetics irrespective of the type of inflammasome or the intensity of the stimulus. Real-time concurrent detection of caspase-1 activation and IL-1β release demonstrated that dead macrophages containing activated caspase-1 release a local burst of IL-1β in a digital manner, which identified these macrophages as the main source of IL-1β within cell populations. Our results highlight the value of single-cell analysis in enhancing understanding of the inflammasome system and chronic inflammatory diseases.
Present address: Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Wakayama 641-8509, Japan