Exosome-Based Delivery of Super-Repressor IκBα Alleviates Alcohol-Associated Liver Injury in Mice.
Hee-Hoon KimYoung-Ri ShimSung Eun ChoiTolulope Esther FalanaJae-Kwang YooSo-Hee AhnMinhye ParkHyangmi SeoChulhee ChoiWon-Il JeongPublished in: Pharmaceutics (2023)
Activation of Kupffer cells (KCs) by gut-derived lipopolysaccharide (LPS) instigates nuclear factor-κB (NF-κB)-mediated inflammatory responses in alcohol-associated liver diseases (ALD). Here, we utilized a novel optogenetically engineered exosome technology called 'exosomes for protein loading via optically reversible protein-protein interactions (EXPLOR)' to efficiently deliver the super-repressor IκB-loaded exosomes (Exo-srIκB) to the liver and examined its therapeutic potential in acute-on-chronic alcohol-associated liver injury. We detected enhanced uptake of DiI-labeled Exo-srIκB by LPS-treated inflammatory KCs, which suppressed LPS-induced inflammatory gene expression levels. In animal experiments, a single intravenous injection of Exo-srIκB prior to alcohol binge drinking significantly attenuated alcohol-associated hepatic steatosis and infiltration of neutrophils and macrophages but not a liver injury. Notably, three consecutive days of Exo-srIκB injection remarkably reduced alcohol-associated liver injury, steatosis, apoptosis of hepatocytes, fibrosis-related gene expression levels in hepatic stellate cells, infiltration of neutrophils and macrophages, and inflammatory gene expression levels in hepatocytes and KCs. In particular, the above effects occurred with inhibition of nuclear translocation of NF-κB in liver tissues, and these beneficial effects of Exo-srIκB on ALD were shown regardless of doses. Our results suggest an exosome-based modulation of NF-κB activity in KCs by Exo-srIκB as a novel and efficient therapeutic approach in ALD.
Keyphrases
- liver injury
- drug induced
- lps induced
- gene expression
- inflammatory response
- nuclear factor
- oxidative stress
- alcohol consumption
- induced apoptosis
- cell cycle arrest
- toll like receptor
- signaling pathway
- dna methylation
- endoplasmic reticulum stress
- stem cells
- immune response
- high fat diet induced
- skeletal muscle
- low dose
- adipose tissue
- small molecule
- extracorporeal membrane oxygenation
- cell proliferation
- high fat diet
- ultrasound guided
- liver failure
- amino acid
- drug delivery
- pet imaging
- anti inflammatory