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Immunoglobulin A (IgA) is a major immunoglobulin isotype in the gut and plays a role in maintenance of gut homeostasis. Secretory IgA (SIgA) has multiple functions in the gut, such as to regulate microbiota composition, to protect intestinal epithelium from pathogenic microorganisms, and to help for immune-system development. The liver is the front-line organ that receives gut-derived products through the portal vein, implying that the liver could be severely affected by a disrupted intestinal homeostasis. Indeed, some liver diseases like alcoholic liver disease are associated with an altered composition of gut microbiota and increased blood endotoxin levels. Therefore, deficiency of SIgA function appears as a significant factor for the pathogenesis of liver diseases associated with altered gut microbiome. In this review, we describe SIgA functions on the gut microbiome and discuss the role of IgA for liver diseases, especially alcoholic liver disease and non-alcoholic fatty liver disease/non-alcoholic steatohepatitis.

Hepatic macrophages are key components of the liver immunity and consist of two main populations. Liver resident macrophages, known as Kupffer cells in mammals, are crucial for maintaining normal liver homeostasis. Upon injury, they become activated to release proinflammatory cytokines and chemokines and recruit a large population of inflammatory monocyte-derived macrophages to the liver. During the progression of liver diseases, macrophages are highly plastic and have opposing functions depending on the signaling cues that they receive from the microenvironment. A comprehensive understanding of liver macrophages is essential for developing therapeutic interventions that target these cells in acute and chronic liver diseases. Mouse studies have provided the bulk of our current knowledge of liver macrophages. The emergence of various liver disease models and availability of transgenic tools to visualize and manipulate macrophages have made the teleost zebrafish ( ) an attractive new vertebrate model to study liver macrophages. In this review, we summarize the origin and behaviors of macrophages in healthy and injured livers in zebrafish. We highlight the roles of macrophages in zebrafish models of alcoholic and non-alcoholic liver diseases, hepatocellular carcinoma, and liver regeneration, and how they compare with the roles that have been described in mammals. We also discuss the advantages and challenges of using zebrafish to study liver macrophages.

ᅟ Oral administration of anti-CD3 antibodies induced regulatory T cells (Tregs) alleviating the insulin resistance and liver damage in animal models. Objective To determine the safety and biological effects of oral OKT3 monoclonal antibody (Balashov et al. Neurology 55:192–8, 2000 ) in patients with NASH. Design In this Phase-IIa trial, four groups of patients with biopsy-proven NASH ( n  = 9/group) received placebo (group A) or oral OKT3 (group B: 0.2; C: 1.0; D: 5.0 mg/day) for 30 days. Patients were followed for safety, liver enzymes, glucose, lipid profile, oral glucose tolerance test (OGTT), serum cytokines and Tregs. Results Oral OKT3 was well tolerated without treatment-related adverse events. OKT3 induced Tregs: with significant increases of CD4 + LAP + (Latency associated peptide) and CD4 + CD25 + LAP + cells in Group D, and a significant increase in TGF-β in Groups C and D. AST decreased significantly in group D and a trend in Groups B and C. Fasting plasma glucose decreased significantly in all treatment groups compared with placebo. OGTT decreased significantly in Group D. Correlations were observed between the changes in several immune-modulatory effects and clinical biomarkers. While serum anti-CD3 levels where undetectable increases in human anti-mouse antibody levels were observed in Groups C and D. Conclusion Oral administration of anti-CD3 MAb to patients with NASH was safe and well tolerated. Positive biological effects were noted in several hepatic, metabolic and immunologic parameters. These findings provide the basis for future trials to investigate the effect of oral anti-CD3 MAb immunotherapy in patients with NASH.

The liver is known to be a classical immunoprivileged site with a relatively high resistance against immune responses. Here we demonstrate that highly activated liver-specific effector CD8+ T cells alone were not sufficient to trigger immune destruction of the liver in mice. Only additional innate immune signals orchestrated by TLR3 provoked liver damage. While TLR3 activation did not directly alter liver-specific CD8+ T cell function, it induced IFN-alpha and TNF-alpha release. These cytokines generated expression of the chemokine CXCL9 in the liver, thereby enhancing CD8+ T cell infiltration and liver disease in mice. Thus, nonspecific activation of innate immunity can drastically enhance susceptibility to immune destruction of a solid organ.

In sterile liver inflammation, danger signals are released in response to tissue injury to alert the immune system; e.g., by activation of the NLRP3 inflammasome. Recently, IL-33 has been identified as a novel type of danger signal or “alarmin”, which is released from damaged and necrotic cells. IL-33 is a pleiotropic cytokine that targets a broad range of immune cells and exhibits pro- and anti-inflammatory properties dependent on the disease. This review summarizes the immunomodulatory roles of the NLRP3 inflammasome and IL-33 in sterile liver inflammation and highlights potential therapeutic strategies targeting these pathways in liver disease.

Mucosal-associated invariant T cells (MAIT cells) are a new population of innate immune cells, which are abundant in the liver and play complex roles in various liver diseases. In this review, we summarize MAIT cells in the liver diseases in recent studies, figure out the role of MAIT cells in various liver disease, including Alcoholic liver disease, Non-alcoholic liver disease, Autoimmune liver diseases, Viral hepatitis and Liver Cancer. Briefly, MAIT cells are involved in anti-bacteria responses in the alcoholic liver diseases. Besides, the activated MAIT cells promote the liver inflammation by secreting inflammatory cytokines and produce regulatory cytokines, which induces anti-inflammatory macrophage polarization. MAIT cells participate in the liver fibrosis via enhancing hepatic stellate cell activation. In viral hepatitis, MAIT cells exhibit a flawed and exhausted phenotype, which results in little effect on controlling the virus and bacteria. In liver cancer, MAIT cells indicate the disease progression and the outcome of therapy. In summary, MAIT cells are attractive biomarkers and therapeutic targets for liver disease.

The microbiome has received increasing attention over the last 15 years. Although gut microbes have been explored for several decades, investigations of the role of microorganisms that reside in the human gut has attracted much attention beyond classical infectious diseases. For example, numerous studies have reported changes in the gut microbiota during not only obesity, diabetes, and liver diseases but also cancer and even neurodegenerative diseases. The human gut microbiota is viewed as a potential source of novel therapeutics. Between 2013 and 2017, the number of publications focusing on the gut microbiota was, remarkably, 12 900, which represents four-fifths of the total number of publications over the last 40 years that investigated this topic. This review discusses recent evidence of the impact of the gut microbiota on metabolic disorders and focus on selected key mechanisms. This review also aims to provide a critical analysis of the current knowledge in this field, identify putative key issues or problems and discuss misinterpretations. The abundance of metagenomic data generated on comparing diseased and healthy subjects can lead to the erroneous claim that a bacterium is causally linked with the protection or the onset of a disease. In fact, environmental factors such as dietary habits, drug treatments, intestinal motility and stool frequency and consistency are all factors that influence the composition of the microbiota and should be considered. The cases of the bacteria Prevotella copri and Akkermansia muciniphila will be discussed as key examples.

Non-alcoholic fatty liver disease (NAFLD) and Alcoholic Liver Disease (ALD) are major causes of liver-related morbidity and mortality and constitute important causes of liver transplantation. The spectrum of the liver disease is wide and includes isolated steatosis, steatohepatitis, and cirrhosis. The treatment of NAFLD and ALD remains, however, an unmet need, and therefore it is a public health priority to develop effective treatments for these diseases. Alcoholic and non-alcoholic liver disease share common complex pathogenetic pathways that involve different organs and systems beyond the liver, including the gut, the adipose tissue, and the immune system, which cross-talk to generate damage. Myeloid-derived cells have been widely studied in the setting of NAFLD and ALD and are implicated at different levels in the onset and progression of this disease. Among these cells, monocytes and macrophages have been found to be involved in the induction of inflammation and in the progression to fibrosis, both in animal models and clinical studies and they have become interesting potential targets for the treatment of both NAFLD and ALD. The different mechanisms by which these cells can be targeted include modulation of Kupffer cell activation, monocyte recruitment in the liver and macrophage polarization and differentiation. Evidence from preclinical studies and clinical trials (some of them already in phase II and III) have shown encouraging results in ameliorating steatohepatitis, fibrosis, and the metabolic profile, individuating promising candidates for the pharmacological treatment of these diseases. The currently available results of myeloid-derived cells targeted treatments in NAFLD and ALD are covered in this review.

Many types of innate (natural killer cells, natural killer T cells, and Kupffer cells/macrophages) and adaptive (T cells and B cells) immune cells are enriched within the liver and function in liver physiology and pathology. Liver pathology is generally induced by two types of immunologic insults: failure to eliminate antigens derived from the gastrointestinal tract which are important for host defense and an impaired tissue protective tolerance mechanism that helps reduce the negative outcomes of immunopathology. Accumulating evidence from the last several decades suggests that hepatic immune cells play an important role in the pathogenesis of alcoholic and nonalcoholic liver injury and inflammation in humans and mice. Here, we focus on the roles of innate and adaptive immune cells in the development and maintenance of alcoholic liver disease and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Additionally, the pathogenesis of liver disease and new therapeutic targets for preventing and treating alcoholic liver disease and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis are discussed.

Macrophages, which are key cellular components of the liver, have emerged as essential players in the maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver diseases. Upon liver injury, resident Kupffer cells (KCs) sense disturbances in homeostasis, interact with hepatic cell populations and release chemokines to recruit circulating leukocytes, including monocytes, which subsequently differentiate into monocyte-derived macrophages (MoMϕs) in the liver. Both KCs and MoMϕs contribute to both the progression and resolution of tissue inflammation and injury in various liver diseases. The diversity of hepatic macrophage subsets and their plasticity explain their different functional responses in distinct liver diseases. In this review, we highlight novel findings regarding the origins and functions of hepatic macrophages and discuss the potential of targeting macrophages as a therapeutic strategy for liver disease.