Highlight report: Role of the ATP-releasing Panx channels in liver fibrosis
Daniela Fernanda González Leiva11IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, GERMANY
EXCLI J 2019;18:Doc8
Recently Sara Crespo Yanguas and colleagues from the University of Brussel published a study about the role of pannexin1 in the pathogenesis of liver fibrosis (Crespo Yanguas et al., 2018). Panx channels are known as mediators of ATP release (Dahl, 2015). After injury cells may release ATP and uridine-5'-triphosphate into the extracellular space. The released ATP attracts immune cells to the area of damage (Davalos et al., 2005; Chekeni et al., 2010). In cardiac fibrosis cardiomyocytes have been shown to release ATP via pannexin1 which contributes to activation of fibroblasts (Dolmatova et al., 2012). However, in liver the role of pannexin1 in liver fibrosis remains unknown. Therefore, the authors compared pannexin1 knockout and wild-type mice after CCl4 treatment for 8 weeks and after bile duct ligation (Crespo Yanguas et al., 2018).
Interestingly, pannexin1 knockout mice showed reduced collagen content, stellate cell activation, and inflammation compared to wild-type mice. Therefore, the release of ATP seems to contribute to myofibroblast activation also in the liver. In contrast to the CCl4- fibrosis model, bile duct ligation led to more hepatocellular injury and a stronger immune response in the pannexin1 knockout than in wild-type mice.
It is not surprising that different consequences are observed in the CCl4 and the bile duct ligation models. CCl4 is a model of pericentral liver damage where a fraction of approximately 40 % of hepatocytes in the centre of the lobule are killed (Hoehme et al., 2010; Hammad et al., 2017; Bartl et al., 2015). It seems plausible that the ATP released from these damaged hepatocytes activates stellate cells (Leist et al., 2017). In contrast, bile duct ligation leads to a ductular response with proliferation of cholangiocytes, branching and looping of bile ducts, leading to a denser mesh of interlobular bile ducts around portal veins (Vartak et al., 2016; Jansen et al., 2017). Simultaneously, periportal fibrosis occurs (Ghallab et al., 2018). It is interesting that this phenomenon is enhanced by the pannexin1 knockout, although the responsible mechanism still has to be elucidated.
Currently, hepatotoxicity in vivo (Stöber, 2016; Du et al., 2017; Reif et al., 2017; Hammad et al., 2018; Ghallab et al., 2016) as well as mechanistic studies in hepatocyte in vitro systems represent very active research areas (Ghallab, 2017; Godoy et al., 2013, 2015, 2016). In this rapidly progressing field Sara Crespo Yanguas and colleagues made an important contribution by revealing the role of ATP-release channels in the pathogenesis of liver fibrosis.
1. Bartl M, Pfaff M, Ghallab A, Driesch D, Henkel SG, Hengstler JG, et al. Optimality in the zonation of ammonia detoxification in rodent liver. Arch Toxicol. 2015;89:2069-78.
2. Chekeni FB, Elliott MR, Sandilos JK, Walk SF, Kinchen JM, Lazarowski ER, et al. Pannexin 1 channels mediate 'find-me' signal release and membrane permeability during apoptosis. Nature. 2010;467(7317):863-7.
3. Crespo Yanguas S, da Silva TC, Pereira IVA, Maes M, Willebrords J, Shestopalov VI, et al. Genetic ablation of pannexin1 counteracts liver fibrosis in a chemical, but not in a surgical mouse model. Arch Toxicol. 2018;92:2607-27.
4. Dahl G. ATP release through pannexon channels. Philos Trans R Soc Lond B Biol Sci. 2015;370(1672).
5. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, et al.. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci. 2005;8:752-8.
6. Dolmatova E, Spagnol G, Boassa D, Baum JR, Keith K, Ambrosi C, et al. Cardiomyocyte ATP release through pannexin 1 aids in early fibroblast activation. Am J Physiol Heart Circ Physiol. 2012;303:H1208-18.
7. Du K, Farhood A, Jaeschke H. Mitochondria-targeted antioxidant Mito-Tempo protects against acetaminophen hepatotoxicity. Arch Toxicol. 2017;91:761-73.
8. Ghallab A. Highlight report: Metabolomics in hepatotoxicity testing. EXCLI J. 2017;16:1323-5.
9. Ghallab A, Cellière G, Henkel SG, Driesch D, Hoehme S, Hofmann U, et al. Model-guided identification of a therapeutic strategy to reduce hyperammonemia in liver diseases. J Hepatol. 2016;64:860-71.
10. Ghallab A, Hofmann U, Sezgin S, Vartak N, Hassan R, Zaza A, et al. Bile micro-infarcts in cholestasis are initiated by rupture of the apical hepatocyte membrane and cause shunting of bile to sinusoidal blood. Hepatology. 2018 Aug 13. doi: 10.1002/hep.30213. [Epub ahead of print].
11. Godoy P, Hewitt NJ, Albrecht U, Andersen ME, Ansari N, Bhattacharya S, et al. Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Arch Toxicol. 2013;87:1315-530.
12. Godoy P, Schmidt-Heck W, Natarajan K, Lucendo-Villarin B, Szkolnicka D, Asplund A, et al. Gene networks and transcription factor motifs defining the differentiation of stem cells into hepatocyte-like cells. J Hepatol. 2015;63:934-42.
13. Godoy P, Widera A, Schmidt-Heck W, Campos G, Meyer C, Cadenas C, et al. Gene network activity in cultivated primary hepatocytes is highly similar to diseased mammalian liver tissue. Arch Toxicol. 2016;90:2513-29.
14. Hammad S, Braeuning A, Meyer C, Mohamed FEZA, Hengstler JG, Dooley S. A frequent misinterpretation in current research on liver fibrosis: the vessel in the center of CCl4-induced pseudolobules is a portal vein. Arch Toxicol. 2017;91:3689-92.
15. Hammad S, Ellethy T, Othman A, Mahmoud HYAH. Highlight report: hepatotoxicity prediction with Hep3B cells. Arch Toxicol. 2018;92:2403.
16. Hoehme S, Brulport M, Bauer A, Bedawy E, Schormann W, Hermes M, et al. Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration. Proc Natl Acad Sci U S A. 2010;107:10371-6.
17. Jansen PL, Ghallab A, Vartak N, Reif R, Schaap FG, Hampe J, et al. The ascending pathophysiology of cholestatic liver disease. Hepatology. 2017;65:722-38.
18. Leist M, Ghallab A, Graepel R, Marchan R, Hassan R, Bennekou SH, et al. Adverse outcome pathways: opportunities, limitations and open questions. Arch Toxicol. 2017;91:3477-505.
19. Reif R, Ghallab A, Beattie L, Günther G, Kuepfer L, Kaye PM, et al. In vivo imaging of systemic transport and elimination of xenobiotics and endogenous mol-ecules in mice. Arch Toxicol. 2017;91:1335-52.
20. Stöber R. Pathophysiology of cholestatic liver disease and its relevance for in vitro tests of hepatotoxicity. EXCLI J. 2016;15:870-1.
21. Vartak N, Damle-Vartak A, Richter B, Dirsch O, Dahmen U, Hammad S, et al. Cholestasis-induced adaptive remodeling of interlobular bile ducts. Hepatology. 2016;63:951-64.