CCR2 and CD44 Promote Inflammatory Cell Recruitment during Fatty Liver Formation in a Lithogenic Diet Fed Mouse Model

Non-alcoholic fatty liver disease (NAFLD) is a common disease with a spectrum of presentations. The current study utilized a lithogenic diet model of NAFLD. The diet was fed to mice that are either resistant (AKR) or susceptible (BALB/c and C57BL/6) to hepatitis followed by molecular and flow cytometric analysis. Following this, a similar approach was taken in congenic mice with specific mutations in immunological genes. The initial study identified a significant and profound increase in multiple ligands for the chemokine receptor CCR2 and an increase in CD44 expression in susceptible C57BL/6 (B6) but not resistant AKR mice. Ccr2(-/-) mice were completely protected from hepatitis and Cd44(-/-) mice were partially protected. Despite protection from inflammation, both strains displayed similar histological steatosis scores and significant increases in serum liver enzymes. CD45(+)CD44(+) cells bound to hyaluronic acid (HA) in diet fed B6 mice but not Cd44(-/-) or Ccr2(-/-) mice. Ccr2(-/-) mice displayed a diminished HA binding phenotype most notably in monocytes, and CD8(+) T-cells. In conclusion, this study demonstrates that absence of CCR2 completely and CD44 partially reduces hepatic leukocyte recruitment. These data also provide evidence that there are multiple redundant CCR2 ligands produced during hepatic lipid accumulation and describes the induction of a strong HA binding phenotype in response to LD feeding in some subsets of leukocytes from susceptible strains.