Human but not mouse hepatocytes respond to interferon-lambda in vivo

Area of Science:

• Immunology
• Hepatology
• Cell Biology

Background:

• Type III interferon (IFN-λ) receptor (IFNLR1) is expressed by epithelial cells.
• Human hepatocytes express IFNLR1 and respond to IFN-λ, unlike mouse hepatocytes.
• Mouse liver IFN-λ response is weak, with low IFNLR1 expression.

Purpose of the Study:

• Investigate the cellular IFN-λ response in the mouse liver.
• Determine if human and mouse hepatocytes differ in IFN-λ responsiveness.
• Clarify the basis of differential IFN-λ response in hepatocytes.

Main Methods:

• Immunohistofluorescence to monitor IFN-responsive Mx gene expression in mouse livers.
• Experimental infection of mice with influenza A virus to induce local IFN-λ production.
• Analysis of chimeric mice with transplanted human hepatocytes in a murine environment.

Main Results:

• IFN-λ response in mouse livers was confined to cholangiocytes, not hepatocytes.
• Mouse hepatocytes showed no IFN-λ responsiveness, even during influenza A virus infection.
• Human hepatocytes in chimeric mice readily responded to IFN-λ in vivo.

Conclusions:

• Human hepatocytes are responsive to IFN-λ in vivo, while mouse hepatocytes are not.
• The non-responsiveness of mouse hepatocytes to IFN-λ is an intrinsic cellular property.
• The mouse liver micro-environment does not cause the lack of hepatocyte response to IFN-λ.