IRF3/7 Double knockout enhanced progressive steatosis and inflammation during overexpression of Hepatitis B surface proteins in mice

Chronic hepatitis B infection is serious global health problem. Experimental investigations have suggested that HBV infection is a potential trigger of liver steatosis. Interferon regulatory factors (IRFs) are transcription factors involved in innate immunity but also having a regulatory role in metabolism. IRF3 and IRF7 are considered master regulators of type I interferon (IFN) and IFN stimulated gene (ISG) expression, which is induced in HBs transgenic mice. However, little is known about the role of type I interferon (IFN) signaling in metabolic diseases. Our present aim is to investigate the effect of global double knock out (DKO) of IRF3 and IRF7 on liver pathology in HBs transgenic mice.

Results & Methods:

IRF3/7 DKO (double knock out) and IRF3^-/-/7^-/-/HBs^/- (triple transgenic) mice on BLAB/c background developed downregulation of ISGs expression and progressive steatosis and inflammation in comparison to wild type and HBs transgenic mice Hepatic triglycerides (TG) accumulation was demonstrated by TLC (thin layer chromatography). Quantitative assessment as well as H&E and Oil red staining supported the same findings. Microarray and qRT PCR analysis revealed increased in proinflammatory genes markers such as Cxcl9, Cxcl5, Il1β, Tnfα, Caspase 1, Caspase4 in IRF3/7DKO, IRF3^-/-/7^-/-/HBs^/- mice. Histological studies showed increased deposition of Type I collagen in the IRF3/7 DKO and IRF3/7/HBs (triple transgenic) mice compare to wild type and HBs transgenic mice.

In conclusion our present study shows that IRF3and IRF7 double knockout causes progressive steatosis, inflammation and fibrosis in HBs transgenic mice. Thus, our data demonstrate that type I interferon signaling might have a protective role against hepatic damage induced by expression of HBV surface proteins.