Date on Master's Thesis/Doctoral Dissertation

12-2018

Document Type

Master's Thesis

Degree Name

M.S.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, MS

Committee Chair

Feng, Wenke

Committee Member

McClain, Craig J.

Committee Member

Gobejishvili, Leila

Committee Member

Matoba, Nobuyuki

Committee Member

Deng, Zhongbin

Author's Keywords

ALD; AMPs; cathelicidin; gut microbiota; inflammasome

Abstract

Alcoholic liver disease (ALD) is characterized by gut dysbiosis and hepatic and intestinal inflammation. Gut microbiota is critically maintained by antimicrobial peptides (AMPs) expressed in the epithelial and immune cells. AMPs are also identified as immune-regulators in various diseases. Previous studies demonstrated that deficiency of AMPs REG3 lectins exacerbated alcoholic steatohepatitis. LL-37 is the sole member of human cathelicidin AMP family, named CRAMP in mouse. Despite of the extensive studies in infectious diseases and in gut-microbiota-related inflammatory bowel disease, the role of LL-37/CRAMP in ALD is yet unknown. Our previous studies showed a decreased intestinal CRAMP in a mouse model of ALD, suggesting an AMP dysfunction in ALD associated with CRAMP. In this thesis, CRAMP KO (Camp-/-) mice were used to dissect the role and mechanisms of function of CRAMP in ALD. Camp-/- mice and their wild type controls (WT) were given a 24-day alcohol liquid diet feeding plus one binge alcohol gavage (24C+1B model), and the effects of CRAMP deficiency were examined. Camp-/-mice had exacerbated liver injury, hepatic steatosis and inflammation compared to WT mice by alcohol. Microbiota analysis by 16S rRNA sequencing in mouse feces revealed dramatic shifts of specific bacteria abundance in Camp-/- and WT mice by alcohol, indicating a potential role of CRAMP in maintaining gut microbiota homeostasis. Additionally, we showed in in vitro studies that synthetic CRAMP peptide can inhibit LPS-induced NLRP3 inflammasome activation in macrophages and hepatocytes. In summary, CRAMP exhibited a protective activity against alcohol-induced liver damage, which is possibly through the regulation of gut microbiota and inflammasome activation.

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