C5aR deficiency rescues hepatic fibrosis but hampers fibrotic resolution

Background Complement factor C5 contributes to hepatic fibrogenesis as C5-deficient mice display less fibrosis after challenge with CCl4 (Hillebrandt et al. 2005). During inflammation C5 is cleaved and the small chemoattractive peptide C5a binds to the receptors C5aR and C5L2. Our aim was to assess the specific roles of the C5 receptors during CCl4-induced liver damage and regeneration.

Methods C5aR- and C5L2-deficient mice and wild-type (WT) controls were treated with CCl4 for 6 weeks. In addition, mice were challenged with CCl4 for 6 weeks and left untreated for another 6 weeks (regression model). Expression of Th1 and Th2 cytokines was determined by qRT-PCR, and hepatic collagen contents were measured via hydroxyproline. Mice were also objected to bile duct ligation (BDL) and unilateral ureteral obstruction (UUO) to compare fibrosis progression in liver and kidney.

Results Chronic fibrosis in liver and kidney was least pronounced in C5aR-deficient mice in comparison to the other lines. Of note, 6 weeks after the last injection C5aR-deficient mice developed highest hepatic collagen levels, indicating response and ongoing damage after cessation of fibrotic stimuli. This is resembled by cytokine profiles, with IL6, IL10, IL12, IL23 and IL27 being reduced in mice deficient for C5 receptors in the chronic model but elevated in C5aR-/- mice during fibrosis regression in the liver.

Conclusions C5aR is critical during chronic fibrogenesis. The novel observation of fibrosis progression in C5aR-deficient mice the after removal of the fibrotic stimulus points to its critical role during wound healing and fibrosis regression.

 

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Publication History

Article published online:
26 January 2022