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      Is Open Access

      Inhibition of Triggering Receptor Expressed on Myeloid Cells 1 Ameliorates Inflammation and Macrophage and Neutrophil Activation in Alcoholic Liver Disease in Mice

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          Alcoholic liver disease (ALD) is characterized by macrophage and neutrophil leukocyte recruitment and activation in the liver. Damage‐ and pathogen‐associated molecular patterns contribute to a self‐perpetuating proinflammatory state in ALD. Triggering receptor expressed on myeloid cells 1 (TREM‐1) is a surface receptor that amplifies inflammation induced by toll‐like receptors (TLRs) and is expressed on neutrophils and monocytes/macrophages. We hypothesized that TREM‐1 signaling contributes to proinflammatory pathway activation in ALD. Using an in vivo ALD model in mice, we tested the effects of ligand‐independent TREM‐1 inhibitory peptides that were formulated into human high‐density lipoprotein (HDL)‐mimicking complexes GF9‐HDL and GA/E31‐HDL. As revealed in vitro, macrophages endocytosed these rationally designed complexes through scavenger receptors. A 5‐week alcohol feeding with the Lieber‐DeCarli diet in mice resulted in increased serum alanine aminotransferase (ALT), liver steatosis, and increased proinflammatory cytokines in the liver. TREM‐1 messenger RNA (mRNA) expression was significantly increased in alcohol‐fed mice, and TREM‐1 inhibitors significantly reduced this increase. TREM‐1 inhibition significantly attenuated alcohol‐induced spleen tyrosine kinase (SYK) activation, an early event in both TLR4 and TREM‐1 signaling. The TREM‐1 inhibitors significantly inhibited macrophage (epidermal growth factor‐like module‐containing mucin‐like hormone receptor‐like 1 [F4/80], clusters of differentiation [CD]68) and neutrophil (lymphocyte antigen 6 complex, locus G [Ly6G] and myeloperoxidase [MPO]) markers and proinflammatory cytokines (monocyte chemoattractant protein 1 [MCP‐1], tumor necrosis factor α [TNF‐α], interleukin‐1β [IL‐1β], macrophage inflammatory protein 1α [MIP‐1α]) at the mRNA level compared to the HDL vehicle. Administration of TREM‐1 inhibitors ameliorated liver steatosis and early fibrosis markers (α‐smooth muscle actin [αSMA] and procollagen1α [Pro‐Col1α]) at the mRNA level in alcohol‐fed mice. However, the HDL vehicle also reduced serum ALT and some cytokine protein levels in alcohol‐fed mice, indicating HDL‐related effects. Conclusion: HDL‐delivered novel TREM‐1 peptide inhibitors ameliorate early phases of inflammation and neutrophil and macrophage recruitment and activation in the liver and attenuate hepatocyte damage and liver steatosis. TREM‐1 inhibition represents a promising therapeutic approach for further investigations in ALD.

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          TREM-1 amplifies inflammation and is a crucial mediator of septic shock.

          Host innate responses to bacterial infections are primarily mediated by neutrophils and monocytes/macrophages. These cells express pattern recognition receptors (PRRs) that bind conserved molecular structures shared by groups of microorganisms. Stimulation of PRR signalling pathways initiates secretion of proinflammatory mediators, which promote the elimination of infectious agents and the induction of tissue repair. Excessive inflammation owing to bacterial infections can lead to tissue damage and septic shock. Here we show that inflammatory responses to microbial products are amplified by a pathway mediated by triggering receptor expressed on myeloid cells (TREM)-1. TREM-1 is an activating receptor expressed at high levels on neutrophils and monocytes that infiltrate human tissues infected with bacteria. Furthermore, it is upregulated on peritoneal neutrophils of patients with microbial sepsis and mice with experimental lipopolysaccaride (LPS)-induced shock. Notably, blockade of TREM-1 protects mice against LPS-induced shock, as well as microbial sepsis caused by live Escherichia coli or caecal ligation and puncture. These results demonstrate a critical function of TREM-1 in acute inflammatory responses to bacteria and implicate TREM-1 as a potential therapeutic target for septic shock.
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            Mouse model of chronic and binge ethanol feeding (the NIAAA model).

            Chronic alcohol consumption is a leading cause of chronic liver disease worldwide, leading to cirrhosis and hepatocellular carcinoma. Currently, the most widely used model for alcoholic liver injury is ad libitum feeding with the Lieber-DeCarli liquid diet containing ethanol for 4-6 weeks; however, this model, without the addition of a secondary insult, only induces mild steatosis, slight elevation of serum alanine transaminase (ALT) and little or no inflammation. Here we describe a simple mouse model of alcoholic liver injury by chronic ethanol feeding (10-d ad libitum oral feeding with the Lieber-DeCarli ethanol liquid diet) plus a single binge ethanol feeding. This protocol for chronic-plus-single-binge ethanol feeding synergistically induces liver injury, inflammation and fatty liver, which mimics acute-on-chronic alcoholic liver injury in patients. This feeding protocol can also be extended to chronic feeding for longer periods of time up to 8 weeks plus single or multiple binges. Chronic-binge ethanol feeding leads to high blood alcohol levels; thus, this simple model will be very useful for the study of alcoholic liver disease (ALD) and of other organs damaged by alcohol consumption.
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              The TREM receptor family and signal integration.

              TREM proteins are a family of cell surface receptors that participate in diverse cell processes, including inflammation, bone homeostasis, neurological development and coagulation. TREM-1, the first to be identified, acts to amplify inflammation. Other TREM proteins regulate the differentiation and function of macrophages, microglia, dendritic cells, osteoclasts and platelets. Here we discuss the state of the field, putative ligands of TREM proteins and the challenges that remain in understanding TREM biology.

                Author and article information

                Hepatol Commun
                Hepatol Commun
                Hepatology Communications
                John Wiley and Sons Inc. (Hoboken )
                29 October 2018
                January 2019
                : 3
                : 1 ( doiID: 10.1002/hep4.v3.1 )
                : 99-115
                [ 1 ] Department of Medicine University of Massachusetts Medical School Worcester MA
                [ 2 ] SignaBlok, Inc. Shrewsbury MA
                Author notes
                [* ] Address Correspondence and Reprint Requests To:

                Gyongyi Szabo, M.D., Ph.D., Department of Medicine, University of Massachusetts Medical School, LRB208, 364 Plantation Street, Worcester, MA 01605, E‐mail: Gyongyi.Szabo@ , Tel.: +1‐508‐856‐5275; Alexander B. Sigalov, Ph.D., SignaBlok, Inc., P.O. Box 4064, Shrewsbury, MA 01545, E‐mail: Sigalov@ , Tel.: +1‐203‐505‐3807

                © 2018 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.

                This is an open access article under the terms of the License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                Page count
                Figures: 7, Tables: 1, Pages: 17, Words: 15160
                Funded by: National Institute on Alcohol Abuse and Alcoholism
                Award ID: R43AA024355
                Award ID: U01 AA021907
                Original Article
                Original Articles
                Custom metadata
                January 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.4 mode:remove_FC converted:01.01.2019


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