Inflammatory and Non-Inflammatory Mechanisms Controlling Cirrhosis Development

Abstract

Because the liver is considered to be one of the most important metabolic organs in the body, it is continuously exposed to damaging environmental agents. Upon damage, several complex cellular and molecular mechanisms in charge of liver recovery and regeneration are activated to prevent the failure of the organ. When liver injury becomes chronic, the regenerative response goes awry and impairs the liver function, consequently leading to cirrhosis, a liver disorder that can cause patient death. Cirrhosis has a disrupted liver architecture and zonation, along with the presence of fibrosis and parenchymal nodules, known as regenerative nodules (RNs). Inflammatory cues contribute to the cirrhotic process in response to chronic damaging agents. Cirrhosis can progress to HCC, the most common and one of the most lethal liver cancers with unmet medical needs. Considering the essential role of inflammatory pathways in the development of cirrhosis, further understanding of the relationship between immune cells and the activation of RNs and fibrosis would guide the design of innovative therapeutic strategies to ameliorate the survival of cirrhotic and HCC patients. In this review, we will summarize the inflammatory mechanisms implicated in the development of cirrhosis.

Keywords: cirrhosis; extracellular matrix; fibrosis; hepatic progenitor cells; hepatic stellate cells; immune factors; inflammation; myofibroblasts; regenerative nodules.

Figure 1

The chronic liver injury leads to cirrhosis and consists of the activation of a complex regenerative response that involves two different processes: (i) the activation and expansion of HPCs leading to the formation of the regenerative nodules and (ii) the activation of HSCs that transdifferentiate into myofibroblasts which secrete and deposit several components of ECM, forming fibrotic bands. The continuous and awry activation of both cellular processes leads to liver cirrhosis. Around 2–13% of cirrhotic patients finally develop HCC. This image was created with BioRender (https://biorender.com/ accessed on 10 September 2021).

Figure 2

Different immune factors are responsible for the activation of HPCs and HSCs during the cirrhotic process. (i) Macrophages secrete TWEAK and IFNγ that activate HPCs and HSCs, respectively. (ii) Damaged and dysfunctional hepatocytes are responsible for the secretion of galectin-3 and Hh ligands involved in HPC expansion. Moreover, dead hepatocytes secrete DAMPS that can act directly on HSCs leading to their activation. (iii) Several cytokines activate HSCs, including TNFα, IL1β, TGFβ1, IL22 (macrophages), IL-17A (Th17 cells), TGFβ1, PDGFβ (platelets) and IFNγ (NK). (iv) HSCs could control HPC expansion by the secretion of FGF7 and Hh ligands. Vice versa, HPCs could regulate HSC activation through CCL2 and Hh ligands. (vi) HSCs secrete TGFβ1 leading to their own activation. The activation of both cell types leads to the formation of regenerative nodules and deposition of extracellular matrix, part of the cirrhotic process. This image was created with BioRender (https://biorender.com/ accessed on 10 September 2021).