The Pore-Forming Protein Gasdermin D Regulates Interleukin-1 Secretion from Living Macrophages
Open accessAbstract
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-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.
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Inflammasome activation can lead to pyroptosis, although sublethal inflammasome activation can also occur.
“Inflammasome activation can lead to a form of cell death called pyroptosis, although sublethal inflammasome activation can also occur [64, 65].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [64]
During sublethal inflammasome activation, activated caspase-1 cleaves gasdermin D to generate N-terminal GSDMD fragment, which inserts into and forms pores in the plasma membrane, resulting in release of inflammatory cytokines into the extracellular environment.
“During sublethal inflammasome activation, activated caspase-1 cleaves gasdermin D (GSDMD) to generate N-terminal GSDMD fragment (GSDMD-N), which inserts into and forms pores in the plasma membrane, resulting in the release of inflammatory cytokines into the extracellular environment [64, 66]”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [64]
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- Authors
- Evavold, C. L., Ruan, J., Tan, Y., Xia, S., Wu, H., & Kagan, J. C.
- Affiliations
- Boston Children's Hospital (US)
- Corresponding author
- Kagan, Jonathan C.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 48
- Issue
- 1
- Pages
- 35-44.e6
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC5773350
- OpenAlex
- W2768102094
- Cited by
- 1,115
- References
- 5
- Citations by year
- 2026: 111 · 2025: 112 · 2024: 128 · 2023: 147 · 2022: 171 · 2021: 158 · 2020: 131 · 2019: 95 · 2018: 58 · 2017: 1
- FWCI
- 31.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Massachusetts
- Cedars-Sinai Medical Center
- National Institute of Allergy and Infectious Diseases (R01AI116550, R01AI093589, R56AI093589, R37AI116550, R01AI124491)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (DP1HD087988)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- gasdermin D, interleukin-1β secretion, macrophages, pyroptosis, inflammasome, oxidized lipids, bacterial lipopolysaccharide
- MeSH terms
- Pyroptosis, Gasdermins, Animals, Cell Line, Cell Membrane, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Humans, Macrophages, Neoplasm Proteins, Protein Transport, Phosphate-Binding Proteins, Intracellular Signaling Peptides and Proteins, Interleukin-1beta, Inflammasomes
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