Z Gastroenterol 2015; 53 - A1_21
DOI: 10.1055/s-0035-1567951

FPR1 might play a relevant role in prevention of liver fibrosis

A Giebeler 1, LO Brandenburg 2, JM Wang 3, U Neumann 1
  • 1RWTH Aachen University Hospital, Department of Surgery, Aachen, Germany
  • 2RWTH Aachen University Hospital, Department of Anatomy and Cell Anatomy, Aachen, Germany
  • 3Center for Cancer Research, National Cancer Institute, National Institute of Health, Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Fredericks, United States of America

Introduction:

Formylpeptide receptors (FPR) are mainly studied as chemotactic receptors during sterile and pathogen associated inflammation. They are expressed on immune cells but also non-hematopoietic tissues. Theirs ligand fMLF is represented on bacteria or is secreted by mitochondria after apoptosis. Together they can induce a strong chemotactic movement. The role of FPRs in during hepatitis and liver fibrosis is so far poorly understood. Besides, immunoregulation and maintainance of immunehomeostasis is important to prevent hepatitis and to avoid the establishment of liver fibrosis.

Material and Methods:

We investigated the deficiency of FPR1 and FPR2 under the condition of the liver fibrosis inducing CCl4-model. Three groups of mice, Wildtype (WT), FPR1-knockout (F1KO) and FPR-2 knockout (F2KO) were treated with CCl4 for a period of 8 weeks. Afterwards serum and liver tissue was analyzed in more detail by qPCR and IHC.

Results:

After finalization of the CCl4 treatment WT and F2KO-mice displayed a higher gain of weight after 8 weeks compared to F1KO-mice. Analysis of transaminases in the serum of the diverse mice strains revealed no detectable differences in the ALT-levels after CCl4 treatment. The histological analysis displayed a clear fibrotic conversion in the livers of all genotypes. Investigation of collagen deposition in the liver by Sirius Red staining revealed a significant higher amount of collagen fibers detectable in the liver of F1KO-mice compared to WT- and F2KO-mice. Interestingly the expression of the Col1A1-gene was significantly higher in both FPR-KO-mice strains compared to WT-mice. The gene expression of collagen degrading enzymes such as MMP13 was highly altered. MMP13 was higher expressed in WT and F2KO compared to F1KO. Quantitative PCR analysis for the gene expression of pro-inflammatory cytokines such as IL-6 and TNF-α displayed a significant reduction of these two genes in F1KO mice in comparison to the other groups. Contradictory to this, CD45+-cells were stronger represented in livers of FPR1-KO mice compared to WT and F2KO-mice. Also the liver regeneration, detected by PCNA-IHC, was impaired in F1KO-mice compared to wildtype and F2KO-mice.

Discussion:

The deficiency of Formylpeptide receptors leads to various effects in the liver of the knockout mice. Whereas lack of FPR2 seems to have a relatively mild effect on liver fibrogenesis and liver inflammation, FPR1 appears to be more relevant in the regulation of liver inflammation and liver regeneration. Loss of FPR1 was associated with an increased hepatitis and decreased liver regeneration compared to WT-mice. However, the mechanism behind the observed phenomenon remains to be further investigated and deciphered.

Corresponding author: Giebeler, Arne

E-Mail: agiebeler@ukaachen.de