The Anti-Microbial Peptide LL-37/CRAMP Is Elevated in Patients With Liver Diseases and Acts as a Protective Factor During Mouse Liver Injury

Digestion. 2015;91(4):307-17. doi: 10.1159/000368304. Epub 2015 May 13.

Abstract

Background: Antimicrobial peptides (AMP) are an important defense mechanism of the innate immune system and can modulate the course of various diseases. However, their significance during liver pathogenesis is currently not well defined.

Methods: Patients with liver diseases were analyzed for LL-37/CRAMP, human beta-defensin-2 (hBD2), and complement 5a (C5a) serum levels. Mice deficient in CRAMP (Cathelicidin-related Antimicrobial Peptide), the mouse homolog for human LL-37, were fed with a methionine- and choline-deficient diet (MCD) and underwent bile-duct ligation (BDL).

Results: First, serum samples from patients with chronic liver diseases were investigated. Therefore, significantly enhanced levels for LL-37, hBD2, and complement C5a were detected, all of which comprise antimicrobial properties. Next, CRAMP-knockout (CRAMP-KO) mice were investigated, to better define a functional role of LL-37/CRAMP in animal models of liver diseases. MCD feeding and bile-duct ligation of CRAMP-KO mice resulted in an enhanced degree of liver injury during the early treatment phase. MCD feeding in CRAMP-KO mice led to stronger intrahepatic fat accumulation and significantly enhanced matrix remodeling, whereas BDL caused more extensive liver necrosis. At the late 28 days time point, MCD-fed CRAMP-KO mice displayed a higher intrahepatic fat load. Long-term changes in bile-duct-ligated mice included higher collagen content as a sign of enhanced fibrosis progression if CRAMP was absent.

Conclusion: The study shows a clear correlation of antimicrobial peptide serum levels in patients with chronic liver diseases. Furthermore, we were able to demonstrate protective functions of LL-37/CRAMP in two independent mouse models of chronic liver injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides
  • Bile Ducts / surgery
  • Cathelicidins / blood*
  • Cathelicidins / immunology*
  • Choline Deficiency
  • Complement C5a / analysis
  • Diet Therapy / adverse effects
  • Diet Therapy / methods
  • Humans
  • Immunologic Factors / blood
  • Ligation / adverse effects
  • Liver / immunology*
  • Liver / injuries*
  • Liver Diseases / blood*
  • Liver Diseases / immunology
  • Methionine / deficiency
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • beta-Defensins / blood

Substances

  • Antimicrobial Cationic Peptides
  • Cathelicidins
  • DEFB4A protein, human
  • Immunologic Factors
  • beta-Defensins
  • CAP18 lipopolysaccharide-binding protein
  • Complement C5a
  • Methionine