Abstract
Interleukin-7 (IL-7) is an important cytokine with pivotal pro-survival functions in the adaptive immune system. However, the role of IL-7 in innate immunity is not fully understood. In the present study, the impact of hepatic IL-7 on innate immune cells was assessed by functional experiments as well as in patients with different stages of liver cirrhosis or acute-on-chronic liver failure (ACLF). Human hepatocytes and liver sinusoidal endothelial cells secreted IL-7 in response to stimulation with interferons (IFNs) of type I and II, yet not type III. De novo translation of interferon-response factor-1 (IRF-1) restricted IL-7 production to stimulation with type I and II IFNs. LPS-primed human macrophages were identified as innate immune target cells responding to IL-7 signaling by inactivation of Glycogen synthase kinase-3 (GSK3). IL-7-mediated GSK3 inactivation augmented LPS-induced secretion of pro-inflammatory cytokines and blunted LPS tolerance of macrophages. The IFN-IRF-1-IL-7 axis was present in liver cirrhosis patients. However, liver cirrhosis patients with or without ACLF had significantly lower concentrations of IL-7 in serum compared to healthy controls, which might contribute to LPS-tolerance in these patients. In conclusion, we propose the presence of an inflammatory cascade where IFNs of type I/II induce hepatocellular IL-7 in an IRF-1-restriced way. Beyond its role in adaptive immune responses, IL-7 appears to augment the response of macrophages to LPS and to ameliorate LPS tolerance, which may improve innate immune responses against invading pathogens.
Highlights
The liver is a highly specialized immunological organ [1]
IL-7 is a non-redundant key player required for important adaptive immune cells to proliferate and to be maintained
In a multiple sclerosis animal model, hepatocellular IL-7, which was induced by toll-like receptor (TLR) signaling, was described as an important source of IL-7, which enables survival of CD8+ and CD4+ T cells [4]
Summary
The liver is a highly specialized immunological organ [1]. On the one hand, the liver plays an important role in defending the host from pathogens invading via the blood stream or via the biliary tract. It is highly important that the liver maintains immune tolerance against the large number of harmless foreign substrates (e.g. food components or drugs), which are Interferons and Hepatocellular IL-7 continuously metabolized by the hepatic excretion machinery [1]. This dichotomic function of the liver demands a tight regulation of hepatic immunity, including an appropriate termination of inflammatory responses [1]. Chronic activation of the hepatic immune system with the consequence of low-grade systemic inflammation is a hallmark of liver cirrhosis [2]. The occurrence of organ failures in combination with decompensation of liver cirrhosis is defined as acute-onchronic liver failure (ACLF), which can be considered as the end stage of liver cirrhosis and is burdened with high short-term mortality [2]
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