The liver is the center of complex metabolic processes in the body. As a result, under healthy conditions, the liver is constantly exposed to diverse proteins, substances, or chemicals with the ability to trigger inflammatory reactions. To balance this out, the liver maintains an inherent ability to regulate physiologic inflammatory responses while staying on high alert against toxic products capable of doing real damage.
Normal Vs Injured Liver Credit: Alessio Gerussi
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We know that inflammatory processes in the liver are tightly regulated. This is essential to tissue regeneration and the normal functioning of the liver. Macrophages have a major role to play in the physiologic and pathologic inflammatory processes in the liver, and as such they are key players in the development of several chronic liver diseases. In a healthy liver, they actively regulate homeostasis, promote inflammation, trigger the resolution of inflammatory processes, and stimulate cell proliferation and restoration of damaged tissues. These processes are so effective that even if most of the liver were to be removed, the remaining portion could regenerate an entire liver with some time.
Abnormalities in macrophage activation and functions can impair tissue healing and restoration, especially in organs like the liver. The degree of injury to the liver, as well as how long the liver is exposed to injurious agents, is associated with interference in the tissue regeneration process. It is self-evident that if we have a clearer understanding of the role of macrophages in liver fibrosis or cirrhosis, we will be able to better manage chronic liver diseases.
Macrophage Populations Credit: Alessio Gerussi
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New Regulatory Protein Identified
A recent study has discovered a new protein, RNF41, that is found in macrophages This protein is involved in the production of cell messengers that act to upregulate inflammation.
In the study, the researchers were able to demonstrate a reduction in RNF41 in mice with liver fibrosis. The results of the study show that reduction of the RNF41 protein results in a vicious release of inflammatory cytokines This then proceeds to subsequent fibrosis, liver damage, and in some cases death of the mice. The process was reversible, however. In cases where the protein function was restored, there was a recorded increase in liver regeneration.
Clinical Significance
This discovery highlights some aspects of the involvement of RNF41 in the pathogenesis of chronic liver diseases It also provides a new therapeutic target in their treatment as well as other diseases primarily triggered or worsened by fibrosis and inflammation. The fact that plasmids are involved in the induction of RNF41 expression also indicates that genetic engineering will most likely have a role to play.
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Conclusion
The livelihood of the liver depends on a delicate dance between forces that seek to preserve it and forces that seek to destroy it. When the destructive forces win, fibrosis happens which ends up leading to end-stage liver disease. Luckily, the day may be upon us when the definitive treatment for end-stage liver disease isn’t transplantation. We could be able to flip liver fibrosis on and off like a switch. We could even reverse the process entirely. But for that day to arrive, further research is necessary to reveal mechanisms responsible for regulating the production of RNF41 and treatment options that target this protein in the treatment of chronic liver diseases.
References
Binatti E, Gerussi A, Barisani D, Invernizzi P. The Role of Macrophages in Liver Fibrosis: New Therapeutic Opportunities. International Journal of Molecular Sciences. 2022; 23(12):6649. https://doi.org/10.3390/ijms23126649
