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Immunity. 2018 Jul 17;49(1):42-55.e6. doi: 10.1016/j.immuni.2018.06.011.

Caspase-8 Collaborates with Caspase-11 to Drive Tissue Damage and Execution of Endotoxic Shock.

Author information

1
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta GA 30322, USA. Electronic address: pmanda2@emory.edu.
2
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta GA 30322, USA.
3
Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA 30322, USA.
4
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA; Host Defense Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
5
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
6
Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA.
7
Department of Biochemistry, Emory University School of Medicine, Atlanta GA 30322, USA.
8
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta GA 30322, USA.
9
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
10
Host Defense Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
11
Lowance Center for Human Immunology, Emory University, Atlanta GA 30322, USA.
12
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta GA 30322, USA. Electronic address: mocarski@emory.edu.

Abstract

The execution of shock following high dose E. coli lipopolysaccharide (LPS) or bacterial sepsis in mice required pro-apoptotic caspase-8 in addition to pro-pyroptotic caspase-11 and gasdermin D. Hematopoietic cells produced MyD88- and TRIF-dependent inflammatory cytokines sufficient to initiate shock without any contribution from caspase-8 or caspase-11. Both proteases had to be present to support tumor necrosis factor- and interferon-β-dependent tissue injury first observed in the small intestine and later in spleen and thymus. Caspase-11 enhanced the activation of caspase-8 and extrinsic cell death machinery within the lower small intestine. Neither caspase-8 nor caspase-11 was individually sufficient for shock. Both caspases collaborated to amplify inflammatory signals associated with tissue damage. Therefore, combined pyroptotic and apoptotic signaling mediated endotoxemia independently of RIPK1 kinase activity and RIPK3 function. These observations bring to light the relevance of tissue compartmentalization to disease processes in vivo where cytokines act in parallel to execute diverse cell death pathways.

KEYWORDS:

Caspase; RIP kinase; TNF; endotoxic shock; extrinsic apoptosis; ileum; interferon; programmed necrosis; pyroptosis

PMID:
30021146
PMCID:
PMC6064639
[Available on 2019-07-17]
DOI:
10.1016/j.immuni.2018.06.011
[Indexed for MEDLINE]

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