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Published on: February 9, 2014
Disruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis
Dongdong Wang1,2,3, Yanxia Li1,4, Hao Yang5
1Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China.
Abstract:
Macrophage-orchestrated inflammation contributes to multiple diseases including sepsis. However, the underlying mechanisms remain to be defined clearly. Here, we show that macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is up-regulated in murine sepsis models. When myeloid Tigar is ablated, sepsis induced by either lipopolysaccharide treatment or cecal ligation puncture in male mice is attenuated via inflammation inhibition. Mechanistic characterizations indicate that TIGAR directly binds to transforming growth factor β-activated kinase (TAK1) and promotes tumor necrosis factor receptor-associated factor 6-mediated ubiquitination and auto-phosphorylation of TAK1, in which residues 152-161 of TIGAR constitute crucial motif independent of its phosphatase activity. Interference with the binding of TIGAR to TAK1 by 5Z-7-oxozeaenol exhibits therapeutic effects in male murine model of sepsis. These findings demonstrate a non-canonical function of macrophage TIGAR in promoting inflammation, and confer a potential therapeutic target for sepsis by disruption of TIGAR-TAK1 interaction.
Insights
Macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) promotes sepsis inflammation. Inhibiting TIGAR-TAK1 interaction offers a potential therapeutic strategy for sepsis by reducing inflammation.
Area of Science:
- Immunology
- Molecular Biology
- Pathophysiology
Background:
- Macrophage-driven inflammation is central to diseases like sepsis.
- The precise molecular mechanisms underlying this inflammation require further elucidation.
Purpose of the Study:
- To investigate the role of TP53-induced glycolysis and apoptosis regulator (TIGAR) in macrophage-mediated inflammation during sepsis.
- To identify TIGAR as a potential therapeutic target for sepsis.
Main Methods:
- Utilized murine sepsis models (lipopolysaccharide and cecal ligation puncture) with myeloid Tigar ablation.
- Performed mechanistic studies involving TIGAR-TAK1 interaction and ubiquitination assays.
- Evaluated therapeutic effects of disrupting TIGAR-TAK1 binding using 5Z-7-oxozeaenol.
Main Results:
- Macrophage TIGAR expression is upregulated in murine sepsis models.
- Ablation of myeloid Tigar attenuated sepsis and reduced inflammation.
- TIGAR directly binds to TAK1, promoting its activation via TRAF6-mediated ubiquitination.
- A specific TIGAR motif (residues 152-161) is critical for TAK1 interaction, independent of phosphatase activity.
- Disrupting TIGAR-TAK1 interaction demonstrated therapeutic benefits in a male murine sepsis model.
Conclusions:
- Macrophage TIGAR plays a non-canonical role in promoting inflammation during sepsis.
- The TIGAR-TAK1 interaction is a key pathway in sepsis-induced inflammation.
- Targeting the TIGAR-TAK1 interaction presents a novel therapeutic avenue for sepsis treatment.
