Vector‐mediated microRNA‐21 silencing ameliorates granulomatous liver fibrosis in Schistosoma japonicum infection
Authors: Martina Sombetzki, Micha Loebermann, Emil C. Reisinger
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report See Article on Page 2008 The liver is a solid immune regulatory organ and, more than other organs, able to manage persistent damage by wound healing and tissue repair with a unique self‐regenerative capacity. As a consequence of sustained liver damage, hepatic wound healing results in fibrosis, which involves effector cell–coordinated and gene‐regulated processes. The main causes for hepatic fibrosis in industrialized countries include viral hepatitis (hepatitis B and C viruses), alcohol abuse, nonalcoholic steatohepatitis, autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis,1 whereas Schistosoma spp. infection, which results in granulomatous liver fibrosis, is most prevalent in developing countries.2 Fibrotic scarring (production of extracellular matrix) has been shown to protect hepatocytes from toxic insults3 but carries the risk of dysregulated excessive matrix deposition in case of persisting hepatic injury. This results in cirrhotic changes and their clinical sequels as well as hepatocellular carcinoma.4 Therefore, there is an urgent need for highly effective antifibrotic drugs that are able to impede fibrosis progression and possibly promote fibrosis regression. However, as manifold as the reasons for liver injury, as diverse are the regulatory responses leading to hepatic fibrosis. It is generally accepted that liver injury (apoptosis or necrosis of hepatocytes and cholangiocytes) leads to secretion of proinflammatory cytokines such as tumor necrosis factor‐α, interleukin (IL)‐6, and IL‐1β and the recruitment of phagocytic leukocytes and hepatic stellate cells (HSCs) as main producers of extracellular matrix. The HSCs are transactivated after phagocytosis of apoptotic hepatocytes or by inflammatory mediators such as platelet‐derived growth factor, transforming growth factor‐β (TGF‐β), and IL‐13 released by activated immune cells.5 Because the progression of fibrosis is generally related to the extent of inflammation and the duration of liver damage, most antifibrotic efforts target the inflammatory response or the removal of pathogenic stimuli. Although several potential substances have been investigated so far,6 only a few of them have provided direct antifibrotic efficacy, like hydrophilic bile acids, such as ursodeoxycholic acid, for the treatment of primary biliary cirrhosis and its side chain–shortened derivative, 24‐nor‐ursodeoxycholic acid, which has been shown to have a beneficial effect in mouse models of primary sclerosing cholangitis and Schistosoma mansoni infection.7 Intestinal schistosomiasis displays a special type of liver fibrosis. Five species of the digenetic trematode Schistosoma are known to infect humans. Of these, S. mansoni, S. japonicum, S. intercalatum, and S. mekongi predominantly affect the gastrointestinal tract. Adult worms reside within the mesenteric veins and produce numerous eggs per day. Eggs are mainly translocated into the gut by penetrating the vessel and the gut wall by local inflammation, but up to one‐third of the eggs are flushed to the liver. Here they become entrapped within the small presinusoids and provoke infiltration with inflammatory cells and granulomatous lesions leading to hepatic fibrosis. In contrast to other chronic liver diseases, liver injury in schistosomiasis displays a delayed type of hypersensitivity reaction and results in relatively higher amounts of matrix deposits but with a comparatively low risk of developing cirrhosis or hepatocellular carcinoma. Tissue‐entrapped parasitic eggs cause sustained liver injury and provoke a vigorous granulomatous response with an early transient Th1 response with secretion of proinflammatory cytokines, such as IL‐1β, IL‐12, tumor necrosis factor‐α, and interferon‐γ. During the chronic stage of infection, the onset of egg deposition is followed by a continuous Th2‐mediated reaction, which is characterized by a profibrotic cytokine profile with the secretion of IL‐4, IL‐5, IL‐10, and IL‐13 and the production of immunoglobulin E.9 In addition, the profibrotic Th2 milieu promotes the alternative activation of macrophages that are able to regulate granulomatous inflammation.10 Antihelminthic treatment (praziquantel) efficiently eradicates adult worms but has no impact on advanced hepatic fibrosis and its clinical sequels.11 In this issue of Hepatology, He et al.12 present a trend‐setting approach to treat lethal Schistosoma japonicum–associated fibrosis in mice. Recombinant adeno‐associated virus 8–mediated silencing of fibro‐regulative murine microRNA‐21 (miRNA‐21) in vivo is shown to have beneficial effects on liver fibrosis, granuloma size, liver damage, and even the promotion of fibrolysis. Using in situ hybridization of liver sections He et al. were able to localize areas of miRNA‐21–expressing cells in the periphery of granulomas and to detect a significant up‐regulation of miRNA‐21 in HCSs and Kupffer cells of infected mice. Furthermore, the up‐regulation of miRNA‐21 in isolated HSCs is shown to be concurrent with the elevation of IL‐13 expression. Both recombinant TGF‐β1 and IL‐13 up‐regulate miRNA‐21 expression in isolated HSCs, in the case of IL‐13 in a dose‐dependent manner. This includes the activation of all mothers against decapentaplegic (SMAD) proteins and therefore triggers up‐regulation of miRNA‐21 in this model of hepatic fibrosis. Moreover, He and colleagues provide a link between anti‐miRNA‐21‐tough decoy–dependent increase of SMAD7 expression, the key inhibitory regulator of SMAD signaling, and a decreased TGF‐β1– and IL‐13–mediated expression of miRNA‐21, accompanied by a reduction of collagens I and III. The study of He et al. impressively demonstrates the strong regulatory impact of miRNA‐21 in a complex inflammatory‐associated fibrotic disease like S. japonicum infection. These results and the steadily growing knowledge about miRNAs as potent posttranscriptional regulators are trailblazers for new treatment opportunities not only for the treatment of schistosomiasis but for a wide range of human diseases. The small (∼22 nucleotides) non–protein‐coding RNAs are able to cleave and degrade messenger RNAs as well as repress messenger RNA translation by targeting the 3′‐untranslated region of target gene messenger RNAs. In doing so they are involved in the regulation of cell proliferation and differentiation, apoptosis, disease progression, antiviral defense, and developmental timing of more simple life forms.13 To date, several miRNAs have been shown to be involved in the progression of hepatic fibrosis in different hepatic disorders, primarily in hepatocellular carcinoma and hepatitis C virus. Promising therapeutic strategies in this regard target oncogenic miRNA by the use of antisense oligonucleotides. An miRNA‐122 inhibitor and a recombinant miR‐34 have been tested already in clinical studies.14 Another interesting target is the miRNA‐29 family, which was shown to be down‐regulated following carbon tetrachloride intoxication in mice and to provide regulatory properties with regard to TGF‐β1/SMAD signaling in HSCs. A comparative analysis of different murine fibrosis models with corresponding human samples15 revealed similar expression patterns of a range of miRNAs in both human and murine specimens, but only for a minor number of miRNAs is the specific function known. So far, it is unclear whether synthetic and drugable miRNAs exert comparable effects to their naturally occurring counterparts. Approaches like the study presented by He et al. reveal innovative applications for miRNAs and take us one step closer to recognizing the importance of miRNAs in the regulation of biological events. Acknowledgment: The authors acknowledge the substantial support obtained by the BMBF Project RESPONSE. Author names in bold designate shared co‐first authorship.