The Pore-Forming Protein Gasdermin D Regulates Interleukin-1 Secretion from Living Macrophages

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SummaryThe interleukin-1 (IL-1) family cytokines are cytosolic proteins that exhibit inflammatory activity upon release into the extracellular space. These factors are released following various cell death processes, with pyroptosis being a common mechanism. Recently, it was recognized that phagocytes can achieve a state of hyperactivation, which is defined by their ability to secrete IL-1 while retaining viability, yet it is unclear how IL-1 can be secreted from living cells. Herein, we report that the pyroptosis regulator gasdermin D (GSDMD) was necessary for IL-1β secretion from living macrophages that have been exposed to inflammasome activators, such as bacteria and their products or host-derived oxidized lipids. Cell- and liposome-based assays demonstrated that GSDMD pores were required for IL-1β transport across an intact lipid bilayer. These findings identify a non-pyroptotic function for GSDMD, and raise the possibility that GSDMD pores represent conduits for the secretion of cytosolic cytokines under conditions of cell hyperactivation.Graphical AbstractHighlightsMultiple microbial and self-derived stimuli induce IL-1 release from living macrophagesInflammasomes can be detected within cells that display multiple signs of viabilityLiving macrophages require gasdermin D to induce pore formation and IL-1 releaseGasdermin D pores facilitate the release of IL-1 from liposomes and intact cellsInflammasomes elicit pyroptosis or cell hyperactivation, with the latter defined as living cells that release IL-1. Evavold et al report that the pore-forming protein gasdermin D regulates IL-1 release from hyperactive macrophages. Cell- and liposome-based assays revealed that gasdermin D pores permit IL-1 passage across intact lipid bilayers.

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