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      Inflammation in Alcohol-Associated Hepatitis: Pathogenesis and Therapeutic Targets

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          Abstract

          Alcohol-associated hepatitis (AH) is an acute-on-chronic liver injury that occurs in patients with chronic alcohol-associated liver disease (ALD). Patients with severe AH have high short-term mortality and lack effective pharmacologic therapies. Inflammation is believed to be one of the key factors promoting AH progression and has been actively investigated as therapeutic targets over the last several decades, but no effective inflammatory targets have been identified so far. In this review, we discuss how inflammatory cells and the inflammatory mediators produced by these cells contribute to the development and progression of AH, with focus on neutrophils and macrophages. The crosstalk between inflammatory cells and liver nonparenchymal cells in the pathogenesis of AH is elaborated. We also deliberate the application of recent cutting-edge technologies in characterizing liver inflammation in AH. Finally, the potential therapeutic targets of inflammatory mediators for AH are briefly summarized.

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          Landscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma

          Qiming Zhang, Yao He, Nan Luo … (2019)
          The immune microenvironment of hepatocellular carcinoma (HCC) is poorly characterized. Combining two single-cell RNA sequencing technologies, we produced transcriptomes of CD45+ immune cells for HCC patients from five immune-relevant sites: tumor, adjacent liver, hepatic lymph node (LN), blood, and ascites. A cluster of LAMP3+ dendritic cells (DCs) appeared to be the mature form of conventional DCs and possessed the potential to migrate from tumors to LNs. LAMP3+ DCs also expressed diverse immune-relevant ligands and exhibited potential to regulate multiple subtypes of lymphocytes. Of the macrophages in tumors that exhibited distinct transcriptional states, tumor-associated macrophages (TAMs) were associated with poor prognosis, and we established the inflammatory role of SLC40A1 and GPNMB in these cells. Further, myeloid and lymphoid cells in ascites were predominantly linked to tumor and blood origins, respectively. The dynamic properties of diverse CD45+ cell types revealed by this study add new dimensions to the immune landscape of HCC.
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            The gut-liver axis in liver disease: pathophysiological basis for therapy

            Agustin Albillos, Andrea De Gottardi, Maria Rescigno (2019)
            The gut-liver axis refers to the bidirectional relationship between the gut and its microbiota, and the liver, resulting from the integration of signals generated by dietary, genetic and environmental factors. This reciprocal interaction is established by the portal vein which enables transport of gut-derived products directly to the liver, and the liver feedback route of bile and antibody secretion to the intestine. The intestinal mucosal and vascular barrier is the functional and anatomical structure that serves as a playground for the interactions between the gut and the liver, limiting the systemic dissemination of microbes and toxins while allowing nutrients to access the circulation and to reach the liver. The control of microbial communities is critical to maintaining homeostasis of the gut-liver axis, and as part of this bidirectional communication the liver shapes intestinal microbial communities. Alcohol disrupts the gut-liver axis at multiple interconnected levels, including the gut microbiome, mucus barrier, epithelial barrier and at the level of antimicrobial peptide production, which increases microbial exposure and the proinflammatory environment of the liver. Growing evidence indicates the pathogenetic role of microbe-derived metabolites, such as trimethylamine, secondary bile acids, short-chain fatty acids and ethanol, in the pathogenesis of non-alcoholic fatty liver disease. Cirrhosis by itself is associated with profound alterations in gut microbiota and damage at the different levels of defence of the intestinal barrier, including the epithelial, vascular and immune barriers. The relevance of the severe disturbance of the intestinal barrier in cirrhosis has been linked to translocation of live bacteria, bacterial infections and disease progression. The identification of the elements of the gut-liver axis primarily damaged in each chronic liver disease offers possibilities for intervention. Beyond antibiotics, upcoming therapies centred on the gut include new generations of probiotics, bacterial metabolites (postbiotics), faecal microbial transplantation, and carbon nanoparticles. FXR-agonists target both the gut and the liver and are currently being tested in different liver diseases. Finally, synthetic biotic medicines, phages that target specific bacteria or therapies that create physical barriers between the gut and the liver offer new therapeutic approaches.
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              Sterile inflammation: sensing and reacting to damage.

              Grace Chen, Gabriel Nuñez (2010)
              Over the past several decades, much has been revealed about the nature of the host innate immune response to microorganisms, with the identification of pattern recognition receptors (PRRs) and pathogen-associated molecular patterns, which are the conserved microbial motifs sensed by these receptors. It is now apparent that these same PRRs can also be activated by non-microbial signals, many of which are considered as damage-associated molecular patterns. The sterile inflammation that ensues either resolves the initial insult or leads to disease. Here, we review the triggers and receptor pathways that result in sterile inflammation and its impact on human health.
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                Author and article information

                Contributors
                Dechun Feng
                Bin Gao
                Journal
                Journal ID (nlm-ta): Cell Mol Gastroenterol Hepatol
                Journal ID (iso-abbrev): Cell Mol Gastroenterol Hepatol
                Title: Cellular and Molecular Gastroenterology and Hepatology
                Publisher: Elsevier
                ISSN (Electronic): 2352-345X
                Publication date PMC-release: 01 May 2024
                Publication date Collection: 2024
                Publication date (Electronic): 01 May 2024
                Volume: 18
                Issue: 3
                Electronic Location Identifier: 101352
                Affiliations
                [1 ]Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
                [2 ]College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
                [3 ]Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
                Author notes
                [∗ ] Correspondence Address correspondence to: Dechun Feng, PhD, Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Room 2S-30, 5625 Fishers Lane, Bethesda, Maryland 20892. dechun.feng@ 123456nih.gov
                [∗ ]Bin Gao, MD, PhD, Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Room 2S-33, 5625 Fishers Lane, Bethesda, Maryland 20892. bgao@ 123456mail.nih.gov
                Article
                Publisher Item ID: S2352-345X(24)00106-1 Publisher ID: 101352
                DOI: 10.1016/j.jcmgh.2024.04.009
                PMC ID: 11234022
                PubMed ID: 38697358
                SO-VID: 5697545e-5a04-437a-8f53-0455cd8b63db
                Copyright © © 2024 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 9 January 2024
                Date accepted : 25 April 2024
                Categories
                Subject: Reviews

                Keywords: alcohol-associated hepatitis,alcohol-associated liver diseases,inflammation,single-cell rna sequencing
                Data availability:
                Keywords: alcohol-associated hepatitis, alcohol-associated liver diseases, inflammation, single-cell rna sequencing

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