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The Endogenous Metabolite TDCA Ameliorates LPS-Driven Liver Injury via Modulation of Caspase-11/GSDMD-Mediated
Deqing Ruan1,2, Xing Yan3, Yanmei Tang1,2
1Yunnan Key Laboratory of Southern Medicine Utilization, Yunnan University of Chinese Medicine, 1076 Yuhua Road, Kunming 650500, China.
Abstract:
The liver is a central immunometabolic organ during endotoxemia and a major target of sepsis-related injury. Intriguingly, the liver exhibits a notable resilience to endotoxemia or septic insults, suggesting the activation of endogenous protective mechanisms. The bile acid taurodeoxycholic acid (TDCA) demonstrates hepatoprotective properties; nonetheless, its role and mechanism in lipopolysaccharide (LPS)-driven inflammatory liver injury remain elusive. This study reveals that LPS challenge induces significant reprogramming of hepatic bile acid metabolism, with TDCA being markedly elevated in LPS-challenged mice. In vitro, TDCA dose-dependently attenuated pyroptosis in bone marrow-derived macrophages, as evidenced by reduced lactate dehydrogenase (LDH) release, decreased interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) secretion, and suppressed dye Oxazole yellow uptake. Consistent with reduced non-canonical inflammasome signaling, TDCA treatment was associated with decreased activation of caspase-11 and its downstream targets Gasdermin D (GSDMD) and IL-1β. In a lethal D-Galactosamine (D-GalN)/LPS-induced toxin-sensitized inflammatory liver injury model, therapeutic administration of TDCA (3, 6 mg/kg) profoundly improved survival rates (40% and 80%, respectively), attenuated liver injury, reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST), suppressed systemic inflammation (IL-1β and IL-18), and ameliorated histopathological damage. Crucially, TDCA treatment reduced the activation of the caspase-11/GSDMD pathway in the septic liver. Our findings demonstrate that TDCA is an endogenously mobilized bile acid that confers protection against LPS-driven inflammatory liver injury, with effects supporting a role for modulation of the Caspase-11/GSDMD pyroptotic pathway. These observations provide hypothesis-generating implications for sepsis-associated liver injury that warrant further validation in clinically relevant sepsis models and pathway-necessity studies.
Insights
Taurodeoxycholic acid (TDCA) protects against inflammatory liver injury by reducing pyroptosis. This bile acid is elevated during endotoxemia and therapeutic TDCA improves survival and liver health in sepsis models.
Area of Science:
- Immunology
- Hepatology
- Metabolism
Background:
- The liver is a key immunometabolic organ vulnerable to sepsis-induced injury.
- Endotoxemia triggers endogenous protective mechanisms, including bile acid alterations.
- The role of taurodeoxycholic acid (TDCA) in lipopolysaccharide (LPS)-induced liver injury is unclear.
Purpose of the Study:
- To investigate the protective role and mechanism of TDCA in LPS-driven inflammatory liver injury.
- To determine TDCA's effect on pyroptosis and inflammasome signaling.
- To evaluate TDCA's therapeutic potential in a murine model of sepsis-induced liver injury.
Main Methods:
- Assessed hepatic bile acid metabolism changes in LPS-challenged mice.
- Evaluated TDCA's effect on pyroptosis in bone marrow-derived macrophages in vitro.
- Utilized a D-Galactosamine (D-GalN)/LPS mouse model to test therapeutic TDCA administration.
- Measured survival rates, liver enzymes (ALT, AST), inflammatory cytokines (IL-1β, IL-18), and inflammasome pathway activation (caspase-11, GSDMD).
Main Results:
- LPS challenge significantly elevated endogenous TDCA levels.
- TDCA dose-dependently attenuated macrophage pyroptosis, reducing LDH release and IL-1β/IL-18 secretion.
- TDCA suppressed caspase-11/GSDMD activation in vitro and in septic livers.
- Therapeutic TDCA administration improved survival rates (up to 80%) and attenuated liver injury in the D-GalN/LPS model.
- TDCA reduced liver enzymes and systemic inflammation markers.
Conclusions:
- TDCA is an endogenously produced bile acid offering protection against LPS-induced liver injury.
- TDCA exerts its hepatoprotective effects by modulating the caspase-11/GSDMD-mediated pyroptosis pathway.
- TDCA represents a potential therapeutic target for sepsis-associated liver injury.
