The pore forming protein gasdermin D regulates interleukin-1 secretion from living macrophages

By Charles L. Evavold, J. Ruan, Yunhao Tan, S. Xia, Hao Wu, Jonathan C. Kagan. Immunity, 2017

981 citations recorded by the source corpus.

Summary The 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‐1&bgr; 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‐1&bgr; 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 Abstract Figure. No Caption available. HighlightsMultiple 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 cells &NA; Inflammasomes 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.

Subfields: Hematology, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f5594dcb54c15e5413c76e796fa0a2c05cf90989

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Citations in the corpus

Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances (2025, positive): “203,204 Recently, researchers have further uncovered that GSDMD also mediates mitochondrial damage during the activation of macrophages.”
Caspases in Cell Death, Inflammation, and Gasdermin-Induced Pyroptosis (2020, background): “, before pyroptosis execution) in living cells (91) (Figures 2 and 3).”
TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling (2020, background): “Caspase-1 also catalyzes the proteolysis of gasdermin D which binds to the inner surface of the plasma membrane and forms pores which can lead to cell death via pyroptosis or release of IL-1β from living cells [109].”
Caspases in cell death, inflammation and disease (2019, background): “Although several mechanisms of IL-1β secretion from viable cells have recently been reported (Evavold et al., 2018; Gaidt et al., 2016), pyroptosis and necroptosis are rapidly emerging as the prime mechanisms for secretion of IL-1β and IL-18, as well as DAMPs such as ATP, HMGB1, S100 proteins and IL”
Pattern Recognition Receptors and the Host Cell Death Molecular Machinery (2018, methodology): “Moreover, the assessment of cell death by the detection of lactate dehydrogenase release (LDH), used in several studies as the only viability assay, might be insufficient to discriminate viable cells from dying cells since both viable and unviable cells can release LDH to the cell culture (170, 173,”