Genetic ablation of pannexin1 counteracts liver fibrosis in a chemical, but not in a surgical mouse model
Liver fibrosis is the final common pathway for almost all causes of chronic liver injury. This chronic disease is characterized by excessive deposition of extracellular matrix components mainly due to transdifferentiation of quiescent hepatic stellate cell into myofibroblasts-like cells, which in turn is driven by cell death and inflammation. In the last few years, paracrine signaling through pannexin1 channels has emerged as a key player in the latter processes. The current study was set up to investigate the role of pannexin1 signaling in liver fibrosis. Wild-type and whole body pannexin1 knock-out mice were treated with carbon tetrachloride or subjected to bile duct ligation. Evaluation of the effects of pannexin1 deletion was based on a number of clinically relevant read-outs, including markers of liver damage, histopathological analysis, oxidative stress, inflammation and regenerative capacity. In parallel, to elucidate the molecular pathways affected by pannexin1 deletion as well as to mechanistically anchor the clinical observations, whole transcriptome analysis of liver tissue was performed. While pannexin1 knock-out mice treated with carbon tetrachloride displayed reduced collagen content, hepatic stellate cell activation, inflammation and hepatic regeneration, bile duct ligated counterparts showed increased hepatocellular injury and antioxidant enzyme activity with a predominant immune response. Gene expression profiling revealed a downregulation of fibrotic and immune responses in pannexin1 knock-out mice treated with carbon tetrachloride, whereas bile duct ligated pannexin1-deficient animals showed a pronounced inflammatory profile. This study shows for the first time an etiology-dependent role for pannexin1 signaling in experimental liver fibrosis.
KeywordsPannexin1 Liver fibrosis Inflammation Stellate cells
Alpha smooth muscle actin
Analysis of variance
Apoptosis-associated speck-like protein containing a C-terminal caspase-recruitment domain
Bile duct ligation
Collagen type 1 alpha 1
Chemokine ligand 14
Hepatic stellate cells
Lysyl oxidase-like 2
Lymphocyte antigen 96
Monocyte chemoattractant protein 1
Macrophage protein 1 gamma
NACHT, LRR, and pyrin domain-containing protein 3
Number or repeats
Nuclear factor kappa B
Reverse transcription quantitative real-time polymerase chain reaction
S100 calcium-binding protein A9
Standard error of mean
Soluble TNF receptor 1/2
T-cell activation protein 3
Tumor necrosis factor alpha
This work was supported by the grants of the “Fundação de Auxílio à Pesquisa do Estado de São Paulo” (FAPESP Grants 14/23890-4; 14/23887-3 and SPEC 13/50420-6), the European Research Council (ERC Starting Grant 335476), the Fund for Scientific Research-Flanders (FWO Grants G009514N and G010214N) and the University Hospital of the Vrije Universiteit Brussel-Belgium (“Willy Gepts Fonds” UZ-VUB). The authors thank Miss Tineke Vanhalewyn, Miss Dinja De Win and Mr Steven Branson for their dedicated technical assistance.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
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