Gasdermin D mediates the pathogenesis of neonatal-onset multisystem inflammatory disease in mice.

Abstract

Mutated NLRP3 assembles a hyperactive inflammasome, which causes excessive secretion of interleukin (IL)-1β and IL-18 and, ultimately, a spectrum of autoinflammatory disorders known as cryopyrinopathies of which neonatal-onset multisystem inflammatory disease (NOMID) is the most severe phenotype. NOMID mice phenocopy several features of the human disease as they develop severe systemic inflammation driven by IL-1β and IL-18 overproduction associated with damage to multiple organs, including spleen, skin, liver, and skeleton. Secretion of IL-1β and IL-18 requires gasdermin D (GSDMD), which-upon activation by the inflammasomes-translocates to the plasma membrane where it forms pores through which these cytokines are released. However, excessive pore formation resulting from sustained activation of GSDMD compromises membrane integrity and ultimately causes a pro-inflammatory form of cell death, termed pyroptosis. In this study, we first established a strong correlation between NLRP3 inflammasome activation and GSDMD processing and pyroptosis in vitro. Next, we used NOMID mice to determine the extent to which GSDMD-driven pyroptosis influences the pathogenesis of this disorder. Remarkably, all NOMID-associated inflammatory symptoms are prevented upon ablation of GSDMD. Thus, GSDMD-dependent actions are required for the pathogenesis of NOMID in mice.

• Authors: Jianqiu Xiao, Chun Wang, Juo-Chin Yao, Yael Alippe, Canxin Xu, Dustin Kress, Roberto Civitelli, Yousef Abu-Amer, Thirumala-Devi Kanneganti, Daniel C Link, Gabriel Mbalaviele
• Journal: PLoS biology (PLoS Biol) Vol. 16 Issue 11 Pg. e3000047 (11 2018) ISSN: 1545-7885 [Electronic] United States
• PMID: 30388107 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• Gsdmd protein, mouse
• Inflammasomes
• Interleukin-18
• Interleukin-1beta
• Intracellular Signaling Peptides and Proteins
• NLR Family, Pyrin Domain-Containing 3 Protein
• Neoplasm Proteins
• Phosphate-Binding Proteins

Topics

• Animals
• Animals, Newborn
• Apoptosis Regulatory Proteins (metabolism, physiology)
• Cell Membrane (metabolism)
• Cryopyrin-Associated Periodic Syndromes (genetics, metabolism, physiopathology)
• Inflammasomes (metabolism)
• Inflammation
• Interleukin-18 (metabolism)
• Interleukin-1beta (metabolism)
• Intracellular Signaling Peptides and Proteins
• Mice
• Mice, Inbred C57BL
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Neoplasm Proteins (genetics)
• Phosphate-Binding Proteins
• Pyroptosis (physiology)