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Immunity. 2018 Jan 16;48(1):35-44.e6. doi: 10.1016/j.immuni.2017.11.013. Epub 2017 Nov 28.

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

Author information

1
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA; Program in Immunology, Harvard Medical School, Boston, MA, USA.
2
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
3
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA.
4
Harvard Medical School and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA; Program in Immunology, Harvard Medical School, Boston, MA, USA. Electronic address: jonathan.kagan@childrens.harvard.edu.

Abstract

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.

PMID:
29195811
PMCID:
PMC5773350
DOI:
10.1016/j.immuni.2017.11.013
[Indexed for MEDLINE]
Free PMC Article

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