Type 1 interferon aggravates lipopolysaccharide-induced sepsis through upregulating Caspase-11 and Gasdermin D.

Abstract

This study aimed to investigate the mechanism of type I interferon (IFN) in aggravating sepsis in bacterial infection, focusing on the roles of Caspase-11 (Casp11) and Gasdermin D (Gsdmd) in this process. Type I interferons, including IFNα and IFNβ, were used to treat peritoneal macrophage harvested from wild-type or IFNα/βR1 knockout (KO) mice, of which the levels of Casp11 and Gsdmd were monitored using real-time polymerase chain reaction (RT-PCR) and Western blot, the exposure to phosphatidylserine was monitored by flow cytometry, and tissue factor (TF) activation was assessed by RT-PCR and TF chromogenic assay. Endotoxemia in wild-type mice led to upregulation of Casp11 and Gsdmd in myeloid cells, which in contrast was attenuated in IFNα/βR1 KO mice. IFNα or IFNβ treatment led to dose-dependent upregulation of Casp11 and Gsdmd in peritoneal macrophages harvested from wild-type mice, but induced negligible changes in IFNα/βR1 KO mice. Type I IFN promoted phosphatidylserine exposure in peritoneal macrophage from wild-type mice but not IFNα/βR1 KO mice. Type I IFN induced insignificant changes of TF expression levels in both wild-type mice and IFNα/βR1 KO mice, but the TF activity was markedly increased in wild-type mice after type I IFN treatment. Our data suggested that the upregulation of Casp11 and Gsdmd in myeloid cells and macrophages induced by endotoxemia was reliant on the expression of IFNα/βR1. IFNα or IFNβ treatment efficiently upregulated Casp11 and Gsdmd, phosphatidylserine exposure, and TF activity of macrophages. Therefore, type I IFN could aggravate sepsis through upregulating Casp11 and Gsdmd.

• Authors: Yan Wang, Xiaolei Zhang, Yujie Guo, Xiao Li, Guanyi Guo, Zhiyun Niu, Jingyu Zhang
• Journal: Journal of physiology and biochemistry (J Physiol Biochem) Vol. 77 Issue 1 Pg. 85-92 (Feb 2021) ISSN: 1877-8755 [Electronic] Spain
• PMID: 33515436 (Publication Type: Journal Article)

Chemical References

• Gsdmd protein, mouse
• Interferon Type I
• Intracellular Signaling Peptides and Proteins
• Lipopolysaccharides
• Phosphate-Binding Proteins
• Casp4 protein, mouse
• Caspases, Initiator

Topics

• Animals
• Bacteremia (chemically induced, drug therapy)
• Caspases, Initiator (metabolism)
• Cells, Cultured
• Interferon Type I (pharmacology)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Lipopolysaccharides
• Macrophages (cytology, drug effects)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phosphate-Binding Proteins (metabolism)