International immunopharmacology · 2025
STING knockdown blocks disease progression and inflammation in mice with alcoholic liver disease by relieving pyroptosis via suppressing NLRP3.
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Song Yuxuan, Liu Mengsi, Zhou Mingying, Ren Xueyi, Feng Bo, Xie Yandi
Аннотация
PURPOSE: This study investigated the influence of STING on alcoholic liver disease (ALD) progression, elucidating underlying mechanism.
METHODS: Mice were transfected with adenovirus-based STING shRNA and administered a diet containing 5 % alcohol. The effect of knocking down STING on ALD was determined. The NLRP3 inhibitor MCC950 was administered to ALD mice to assess the effect of NLRP3 on ALD. To investigate whether STING regulated the progression of ALD by modulating NLRP3, adenovirus-based STING shRNA transfection and NLRP3 agonist BMS-986299 treatment were performed on ALD mice. Mouse hepatocyte AML12 cells were used to elucidate the mechanism by which STING regulates the progression of ALD.
RESULTS: In ALD mice, knocking down STING improved liver function, relieved liver inflammation, fiber deposition, and fat accumulation, and decreased GSDMD-N/GSDMD-F, NLRP3, C-caspase1/Pro-caspase1, IL-1β, and p-p65/p65 proteins. The effects of NLRP3 deficiency on ALD mice were similar to those observed after knocking out STING. In the alcohol-induced AML12 cells and the lipopolysaccharide-adenosine triphosphate-induced pyroptosis AML12 cells, knocking down STING enhanced cell viability, attenuated apoptosis, pyroptosis, and ROS production, and decreased NLRP3, GSDMD-N/GSDMD-F, IL-1β, C-caspase1/Pro-caspase1, and p-p65/p65 protein levels. STING knockdown reduced the co-immunoprecipitation of NLRP3 protein. Treatment of ALD mice with MCC950 showed an effect similar to that observed after STING was knocked down. BMS-986299 abrogated the mitigating effect of STING knockdown on ALD mice.
CONCLUSION: Knocking down STING might block the progression of ALD by mitigating pyroptosis via downregulating NLRP3. Therefore, it might be a potential target for ALD treatment.
METHODS: Mice were transfected with adenovirus-based STING shRNA and administered a diet containing 5 % alcohol. The effect of knocking down STING on ALD was determined. The NLRP3 inhibitor MCC950 was administered to ALD mice to assess the effect of NLRP3 on ALD. To investigate whether STING regulated the progression of ALD by modulating NLRP3, adenovirus-based STING shRNA transfection and NLRP3 agonist BMS-986299 treatment were performed on ALD mice. Mouse hepatocyte AML12 cells were used to elucidate the mechanism by which STING regulates the progression of ALD.
RESULTS: In ALD mice, knocking down STING improved liver function, relieved liver inflammation, fiber deposition, and fat accumulation, and decreased GSDMD-N/GSDMD-F, NLRP3, C-caspase1/Pro-caspase1, IL-1β, and p-p65/p65 proteins. The effects of NLRP3 deficiency on ALD mice were similar to those observed after knocking out STING. In the alcohol-induced AML12 cells and the lipopolysaccharide-adenosine triphosphate-induced pyroptosis AML12 cells, knocking down STING enhanced cell viability, attenuated apoptosis, pyroptosis, and ROS production, and decreased NLRP3, GSDMD-N/GSDMD-F, IL-1β, C-caspase1/Pro-caspase1, and p-p65/p65 protein levels. STING knockdown reduced the co-immunoprecipitation of NLRP3 protein. Treatment of ALD mice with MCC950 showed an effect similar to that observed after STING was knocked down. BMS-986299 abrogated the mitigating effect of STING knockdown on ALD mice.
CONCLUSION: Knocking down STING might block the progression of ALD by mitigating pyroptosis via downregulating NLRP3. Therefore, it might be a potential target for ALD treatment.