The good and the bad about separation anxiety: roles of IL-22 and IL-22BP in liver pathologies

Abstract

The human liver fulfills several vital tasks daily and possesses an impressive ability to self-regenerate. However, the capacity of this self-healing process can be exhausted by a variety of different liver diseases, such as alcoholic liver damage, viral hepatitis, or hepatocellular carcinoma. Over time, all these diseases generally lead to progressive liver failure that can become fatal if left untreated. Thus, a great effort has been directed towards the development of innovative therapies. The most recently discovered therapies often involve modifying the patient’s immune system to enhance a beneficial immune response. Current data suggest that, among others, the cytokine IL-22 might be a promising therapeutical candidate. IL-22 and its endogenous antagonist, IL-22BP, have been under thorough scientific investigation for nearly 20 years. While IL-22 is mainly produced by TH22 cells, ILC3s, NKT cells, or γδ T cells, sources of IL-22BP include dendritic cells, eosinophils, and CD4+ cells. In many settings, IL-22 was shown to promote regenerative potential and, thus, could protect tissues from pathogens and damage. However, the effects of IL-22 during carcinogenesis are more ambiguous and depend on the tumor entity and microenvironment. In line with its capabilities of neutralizing IL-22 in vivo, IL-22BP possesses often, but not always, an inverse expression pattern compared to its ligand. In this comprehensive review, we will summarize past and current findings regarding the roles of IL-22 and IL-22BP in liver diseases with a particular focus on the leading causes of advanced liver failure, namely, liver infections, liver damage, and liver malignancies.

Sex-Dependent Hepatoprotective Role of IL-22 Receptor Signaling in Non-Alcoholic Fatty Liver Disease-Related Fibrosis

“…35 These different observations highlight the dual nature of IL22 that likely is dictated by multiple factors including the tissue involved, pathologic environment, endogenous vs exogenous IL22 level, and the time of exposure. 24,25,32,33,36 IL22 activity is regulated by the IL22 binding protein (IL22BP or IL22RA2), which is a soluble decoy IL22 receptor that acts as an endogenous high-affinity inhibitor of IL22. 11,15 Indeed, a proinflammatory role of IL22 has been observed in ischemia-reperfusion and acetaminopheninduced liver injury models using IL22BP-deficient mice (IL22BP -/-).…”

“… 35 These different observations highlight the dual nature of IL22 that likely is dictated by multiple factors including the tissue involved, pathologic environment, endogenous vs exogenous IL22 level, and the time of exposure. 24 , 25 , 32 , 33 , 36 …”

Mediators of liver inflammation and carcinogenesis

“…The lymphocyte-derived cytokine IL-22 is a major regulator of tissue regeneration. Lücke et al [13] provide an overview on the regulation of IL-22 in liver regeneration and carcinogenesis, which depends much on its endogenous antagonist, IL-22BP. The authors elucidate the contributions of the IL-22/IL-22BP system to various liver diseases, fibrosis and cancer.…”

A Critical Role of the IL-22–IL-22 Binding Protein Axis in Hepatocellular Carcinoma

“…In the liver, IL-22 is capable of protecting from both invasion of pathogens, as well as tissue harm through toxic damage [ 27 ]. Furthermore, IL-22 can enhance liver regeneration by reducing the expression of apoptotic genes and increasing the expression of proliferative genes in hepatocytes [ 28 ].…”