Abstract
The liver commonly self-regenerates by a proliferation of mature cell types. Nevertheless, in case of severe or protracted damage, the organ renewal is mediated by the hepatic progenitor cells (HPCs), adult progenitors capable of differentiating toward the biliary and the hepatocyte lineages. This regeneration process is determined by the formation of a stereotypical niche surrounding the emerging progenitors. The organization of the HPC niche microenvironment is crucial to drive biliary or hepatocyte regeneration. Furthermore, this is the site of a complex immunological activity mediated by several immune and non-immune cells. Indeed, several cytokines produced by monocytes, macrophages and T-lymphocytes may promote the activation of HPCs in the niche. On the other side, HPCs may produce pro-inflammatory cytokines induced by liver inflammation. The inflamed liver is characterized by high generation of reactive oxygen and nitrogen species, which in turn lead to the oxidation of macromolecules and the alteration of signaling pathways. Reactive species and redox signaling are involved in both the immunological and the adult stem cell regeneration processes. It is then conceivable that redox balance may finely regulate the immune response in the HPC niche, modulating the regeneration process and the immune activity of HPCs. In this perspective article, we summarize the current knowledge on the role of reactive species in the regulation of hepatic immunity, suggesting future research directions for the study of redox signaling on the immunomodulatory properties of HPCs.
Highlights
The liver is provided of exclusive regenerative capacity after consistent damage of various origin
An impairment in redox balance is described in non-alcoholic fatty liver disease (NAFLD), where free fatty acid excess causes overproduction of reactive species mostly by mitochondria and cytochrome P450 (Serviddio et al, 2011a,b, 2013b; Bellanti et al, 2017, 2018), which lead to a pro-oxidative environment triggering the release of pro-inflammatory cytokines, which in turn activate hepatic stellate cells to produce connective
A classic example of liver redox balance impairment by a toxic compound is provided by acetaminophen, whose hepatic metabolism is mediated by UDP-glucuronosyltransferases, sulfotransferases, and other cytochrome P450 enzymes which produce a reactive intermediate that can bind to sulfhydryl groups, deplete liver glutathione (GSH), and modify cellular proteins, leading to oxidative stress and mitochondrial damage (McGill and Jaeschke, 2013)
Summary
The liver is provided of exclusive regenerative capacity after consistent damage of various origin (viral, toxic, metabolic, genetic, or immunologic). Since regenerative niches are characterized by a hypoxic environment, cells stabilize HIF-1α which can modulate specific effectors, such as Notch, Wnt and Oct that control proliferation, differentiation and pluripotency (Mazumdar et al, 2009) Another stress-responsive transcription factor, the Nuclear factor erythroid 2-related factor 2 (NRF2), is a pivotal regulator of both pluripotent and adult stem cell biology in response to various environmental signals (Dai et al, 2020). After a basic introduction on redox biology, the present perspective article will focus on redox-dependent pathways involved in immune regulation in liver diseases, providing support for redox signaling as a key factor in the immunemediated processes of HPCs in the niche
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