Charles L Evavold1, Jianbin Ruan2, Yunhao Tan3, Shiyu Xia2, Hao Wu2, Jonathan C Kagan4. 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.
The pan class="Gene">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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