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  1. Article: Emerging Roles for Lymphatics in Chronic Liver Disease.

    Burchill, Matthew A / Goldberg, Alyssa R / Tamburini, Beth A Jirón

    Frontiers in physiology

    2020  Volume 10, Page(s) 1579

    Abstract: Chronic liver disease (CLD) is a global health epidemic causing ∼2 million deaths annually worldwide. As the incidence of CLD is expected to rise over the next decade, understanding the cellular and molecular mediators of CLD is critical for developing ... ...

    Abstract Chronic liver disease (CLD) is a global health epidemic causing ∼2 million deaths annually worldwide. As the incidence of CLD is expected to rise over the next decade, understanding the cellular and molecular mediators of CLD is critical for developing novel therapeutics. Common characteristics of CLD include steatosis, inflammation, and cholesterol accumulation in the liver. While the lymphatic system in the liver has largely been overlooked, the liver lymphatics, as in other organs, are thought to play a critical role in maintaining normal hepatic function by assisting in the removal of protein, cholesterol, and immune infiltrate. Lymphatic growth, permeability, and/or hyperplasia in non-liver organs has been demonstrated to be caused by obesity or hypercholesterolemia in humans and animal models. While it is still unclear if changes in permeability occur in liver lymphatics, the lymphatics do expand in number and size in all disease etiologies tested. This is consistent with the lymphatic endothelial cells (LEC) upregulating proliferation specific genes, however, other transcriptional changes occur in liver LECs that are dependent on the inflammatory mediators that are specific to the disease etiology. Whether these changes induce lymphatic dysfunction or if they impact liver function has yet to be directly addressed. Here, we will review what is known about liver lymphatics in health and disease, what can be learned from recent work on the influence of obesity and hypercholesterolemia on the lymphatics in other organs, changes that occur in LECs in the liver during disease and outstanding questions in the field.
    Language English
    Publishing date 2020-01-14
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2019.01579
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: NF-κB/NLRP3 Translational Inhibition by Nanoligomer Therapy Mitigates Ethanol and Advanced Age-Related Neuroinflammation.

    Anton, Paige E / Nagpal, Prashant / Moreno, Julie / Burchill, Matthew A / Chatterjee, Anushree / Busquet, Nicolas / Mesches, Michael / Kovacs, Elizabeth J / McCullough, Rebecca L

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Binge alcohol use is increasing among aged adults (>65 years). Alcohol-related toxicity in aged adults is associated with neurodegeneration, yet the molecular underpinnings of age-related sensitivity to alcohol are not well described. Studies utilizing ... ...

    Abstract Binge alcohol use is increasing among aged adults (>65 years). Alcohol-related toxicity in aged adults is associated with neurodegeneration, yet the molecular underpinnings of age-related sensitivity to alcohol are not well described. Studies utilizing rodent models of neurodegenerative disease reveal heightened activation of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Nod like receptor 3 (NLRP3) mediate microglia activation and associated neuronal injury. Our group, and others, have implicated hippocampal-resident microglia as key producers of inflammatory mediators, yet the link between inflammation and neurodegeneration has not been established in models of binge ethanol exposure and advanced age. Here, we report binge ethanol increased the proportion of NLRP3
    Language English
    Publishing date 2024-02-28
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.02.26.582114
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Antigen-driven CD8

    Burtis, Abbigayl E C / DeNicola, Destiny M C / Ferguson, Megan E / Santos, Radleigh G / Pinilla, Clemencia / Kriss, Michael S / Orlicky, David J / Tamburini, Beth A Jirón / Gillen, Austin E / Burchill, Matthew A

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Background and aims: Chronic liver disease due to metabolic dysfunction-associated steatohepatitis (MASH) is a rapidly increasing global epidemic. MASH progression is a consequence of the complex interplay between inflammatory insults and dysregulated ... ...

    Abstract Background and aims: Chronic liver disease due to metabolic dysfunction-associated steatohepatitis (MASH) is a rapidly increasing global epidemic. MASH progression is a consequence of the complex interplay between inflammatory insults and dysregulated hepatic immune responses. T lymphocytes have been shown to accumulate in the liver during MASH, but the cause and consequence of T cell accumulation in the liver remain unclear. Our study aimed to define the phenotype and T cell receptor diversity of T cells from human cirrhotic livers and an animal model of MASH to begin resolving their function in disease.
    Approach and results: In these studies, we evaluated differences in T cell phenotype in the context of liver disease we isolated liver resident T cell populations from individuals with cirrhosis and a murine model of MASH. Using both 5' single cell sequencing and flow cytometry we defined the phenotype and T cell receptor repertoire of liver resident T cells during health and disease.
    Conclusions: MASH-induced cirrhosis and diet-induced MASH in mice resulted in the accumulation of activated and clonally expanded T cells in the liver. The clonally expanded T cells in the liver expressed markers of chronic antigenic stimulation, including
    Language English
    Publishing date 2024-03-22
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.03.20.583964
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Digestion of the Murine Liver for a Flow Cytometric Analysis of Lymphatic Endothelial Cells.

    Finlon, Jeffrey M / Burchill, Matthew A / Tamburini, Beth A Jirón

    Journal of visualized experiments : JoVE

    2019  , Issue 143

    Abstract: Within the liver, lymphatic vessels are found within the portal triad, and their described function is to remove interstitial fluid from the liver to the lymph nodes where cellular debris and antigens can be surveyed. We are very interested in ... ...

    Abstract Within the liver, lymphatic vessels are found within the portal triad, and their described function is to remove interstitial fluid from the liver to the lymph nodes where cellular debris and antigens can be surveyed. We are very interested in understanding how the lymphatic vasculature might be involved in inflammation and immune cell function within the liver. However, very little has been published establishing digestion protocols for the isolation of lymphatic endothelial cells (LECs) from the liver or specific markers that can be used to evaluate liver LECs on a per cell basis. Therefore, we optimized a method for the digestion and staining of the liver in order to evaluate the LEC population in the liver. We are confident that the method outlined here will be useful for the identification and isolation of LECs from the liver and will strengthen our understanding of how LECs respond to the liver microenvironment.
    MeSH term(s) Animals ; Biomarkers/metabolism ; Endothelial Cells/pathology ; Flow Cytometry/methods ; Humans ; Liver/pathology ; Lymphatic Vessels/physiopathology ; Mice
    Chemical Substances Biomarkers
    Language English
    Publishing date 2019-01-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Video-Audio Media
    ZDB-ID 2259946-0
    ISSN 1940-087X ; 1940-087X
    ISSN (online) 1940-087X
    ISSN 1940-087X
    DOI 10.3791/58621
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Biomimetic Synthesis Enables the Structure Revision of Furoerioaustralasine.

    Coleman, Matthew A / Burchill, Laura / Sumby, Christopher J / George, Jonathan H

    Organic letters

    2019  Volume 21, Issue 21, Page(s) 8776–8778

    Abstract: The structure of furoerioaustralasine, a unique Australian alkaloid, has been revised based on a concise, biomimetic synthesis. The key step is a stereospecific, intramolecular ring opening of an epoxide to form a central dihydrofuran fused to a ... ...

    Abstract The structure of furoerioaustralasine, a unique Australian alkaloid, has been revised based on a concise, biomimetic synthesis. The key step is a stereospecific, intramolecular ring opening of an epoxide to form a central dihydrofuran fused to a quinoline ring system.
    MeSH term(s) Alkaloids/chemical synthesis ; Alkaloids/chemistry ; Biomimetics ; Chemistry Techniques, Synthetic ; Cyclization
    Chemical Substances Alkaloids
    Language English
    Publishing date 2019-10-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1523-7052
    ISSN (online) 1523-7052
    DOI 10.1021/acs.orglett.9b03392
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Single-cell transcriptomic analyses of T cells in chronic HCV-infected patients dominated by DAA-induced interferon signaling changes.

    Burchill, Matthew A / Salomon, Matthew P / Golden-Mason, Lucy / Wieland, Amanda / Maretti-Mira, Ana C / Gale, Michael / Rosen, Hugo R

    PLoS pathogens

    2021  Volume 17, Issue 8, Page(s) e1009799

    Abstract: Chronic infection with HCV is manifested by dysregulation of innate immune responses and impaired T cell function at multiple levels. These changes may impact susceptibility to other infections, responsiveness to antiviral therapies, vaccine ... ...

    Abstract Chronic infection with HCV is manifested by dysregulation of innate immune responses and impaired T cell function at multiple levels. These changes may impact susceptibility to other infections, responsiveness to antiviral therapies, vaccine responsiveness, and development of complications such as hepatocellular carcinoma. Highly effective direct-acting antiviral (DAA) therapy has revolutionized the management of chronic HCV, with expected cure rates exceeding 95%. DAA treatment represents a unique opportunity to investigate to what extent elimination of viral replication and chronic antigen stimulation can restore immunologic phenotype. In this study we interrogated the global transcriptional profile of isolated peripheral blood T cells before, during and after IFN-free DAA therapy using single-cell mRNA sequencing. Our results demonstrate that T cells mapped at single-cell resolution have dramatic transcriptomic changes early after initiation of DAA and many of these changes are sustained after completion of DAA therapy. Specifically, we see a significant reduction in transcripts associated with innate immune activation and interferon signaling such as ISG15, ISG20, IFIT3, OAS and MX1 in many different T cell subsets. Furthermore, we find an early upregulation of a gene involved in suppression of immune activation, DUSP1, in circulating T cells. Conclusion: This study provides the first in-depth transcriptomic analysis at the single-cell level of patients undergoing DAA therapy, demonstrating that IFN-free antiviral therapy in chronic HCV infection induces hitherto unrecognized shifts in innate immune and interferon signaling within T cell populations early, during, and long-term after treatment. The present study provides a rich data source to explore the effects of DAA treatment on bulk T cells.
    MeSH term(s) Antiviral Agents/therapeutic use ; Biomarkers/blood ; Gene Expression Regulation/drug effects ; Hepacivirus/drug effects ; Hepacivirus/physiology ; Hepatitis C, Chronic/drug therapy ; Hepatitis C, Chronic/genetics ; Hepatitis C, Chronic/virology ; Humans ; Interferons/genetics ; Interferons/metabolism ; Male ; Prospective Studies ; Single-Cell Analysis/methods ; T-Lymphocyte Subsets/drug effects ; T-Lymphocyte Subsets/metabolism ; Transcriptome/drug effects
    Chemical Substances Antiviral Agents ; Biomarkers ; Interferons (9008-11-1)
    Language English
    Publishing date 2021-08-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1009799
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Tumor NLRP3-Derived IL-1β Drives the IL-6/STAT3 Axis Resulting in Sustained MDSC-Mediated Immunosuppression.

    Tengesdal, Isak W / Dinarello, Alberto / Powers, Nicholas E / Burchill, Matthew A / Joosten, Leo A B / Marchetti, Carlo / Dinarello, Charles A

    Frontiers in immunology

    2021  Volume 12, Page(s) 661323

    Abstract: Tumors evade the immune system by inducing inflammation. In melanoma, tumor-derived IL-1β drives inflammation and the expansion of highly immunosuppressive myeloid-derived suppressor cells (MDSCs). Similar in many tumors, melanoma is also linked to the ... ...

    Abstract Tumors evade the immune system by inducing inflammation. In melanoma, tumor-derived IL-1β drives inflammation and the expansion of highly immunosuppressive myeloid-derived suppressor cells (MDSCs). Similar in many tumors, melanoma is also linked to the downstream IL-6/STAT3 axis. In this study, we observed that both recombinant and tumor-derived IL-1β specifically induce pSTAT3(Y705), creating a tumor-autoinflammatory loop, which amplifies IL-6 signaling in the human melanoma cell line 1205Lu. To disrupt IL-1β/IL-6/STAT3 axis, we suppressed IL-1β-mediated inflammation by inhibiting the NOD-like receptor protein 3 (NLRP3) using OLT1177, a safe-in-humans specific NLRP3 oral inhibitor.
    MeSH term(s) Animals ; Cell Line, Tumor ; Humans ; Immune Tolerance/drug effects ; Immune Tolerance/immunology ; Interleukin-1beta/immunology ; Interleukin-1beta/metabolism ; Interleukin-6/immunology ; Interleukin-6/metabolism ; Melanoma/immunology ; Melanoma/metabolism ; Melanoma/pathology ; Melanoma, Experimental/drug therapy ; Melanoma, Experimental/immunology ; Melanoma, Experimental/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Models, Immunological ; Myeloid-Derived Suppressor Cells/immunology ; Myeloid-Derived Suppressor Cells/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/immunology ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Nitriles/pharmacology ; Pyrazoles/pharmacology ; Pyrimidines/pharmacology ; STAT3 Transcription Factor/immunology ; STAT3 Transcription Factor/metabolism ; Signal Transduction/drug effects ; Signal Transduction/immunology ; Tumor Burden/drug effects ; Tumor Burden/immunology ; Mice
    Chemical Substances AZD 1480 ; Interleukin-1beta ; Interleukin-6 ; NLR Family, Pyrin Domain-Containing 3 Protein ; Nitriles ; Pyrazoles ; Pyrimidines ; STAT3 Transcription Factor ; STAT3 protein, human ; dapansutrile (2Z03364G96)
    Language English
    Publishing date 2021-08-31
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2021.661323
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Single-cell transcriptomic analyses of T cells in chronic HCV-infected patients dominated by DAA-induced interferon signaling changes.

    Matthew A Burchill / Matthew P Salomon / Lucy Golden-Mason / Amanda Wieland / Ana C Maretti-Mira / Michael Gale / Hugo R Rosen

    PLoS Pathogens, Vol 17, Iss 8, p e

    2021  Volume 1009799

    Abstract: Chronic infection with HCV is manifested by dysregulation of innate immune responses and impaired T cell function at multiple levels. These changes may impact susceptibility to other infections, responsiveness to antiviral therapies, vaccine ... ...

    Abstract Chronic infection with HCV is manifested by dysregulation of innate immune responses and impaired T cell function at multiple levels. These changes may impact susceptibility to other infections, responsiveness to antiviral therapies, vaccine responsiveness, and development of complications such as hepatocellular carcinoma. Highly effective direct-acting antiviral (DAA) therapy has revolutionized the management of chronic HCV, with expected cure rates exceeding 95%. DAA treatment represents a unique opportunity to investigate to what extent elimination of viral replication and chronic antigen stimulation can restore immunologic phenotype. In this study we interrogated the global transcriptional profile of isolated peripheral blood T cells before, during and after IFN-free DAA therapy using single-cell mRNA sequencing. Our results demonstrate that T cells mapped at single-cell resolution have dramatic transcriptomic changes early after initiation of DAA and many of these changes are sustained after completion of DAA therapy. Specifically, we see a significant reduction in transcripts associated with innate immune activation and interferon signaling such as ISG15, ISG20, IFIT3, OAS and MX1 in many different T cell subsets. Furthermore, we find an early upregulation of a gene involved in suppression of immune activation, DUSP1, in circulating T cells. Conclusion: This study provides the first in-depth transcriptomic analysis at the single-cell level of patients undergoing DAA therapy, demonstrating that IFN-free antiviral therapy in chronic HCV infection induces hitherto unrecognized shifts in innate immune and interferon signaling within T cell populations early, during, and long-term after treatment. The present study provides a rich data source to explore the effects of DAA treatment on bulk T cells.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article: Oxidized low density lipoprotein in the liver causes decreased permeability of liver lymphatic- but not liver sinusoidal-endothelial cells

    Goldberg, Alyssa R / Ferguson, Megan / Pal, Sarit / Cohen, Rachel / Orlicky, David J / McCullough, Rebecca L / Rutkowski, Joseph M / Burchill, Matthew A / Tamburini, Beth A Jirón

    Frontiers in physiology

    2022  Volume 13, Page(s) 1021038

    Abstract: The lymphatic vasculature of the liver is vital for liver function as it maintains fluid and protein homeostasis and is important for immune cell transport to the lymph node. Chronic liver disease is associated with increased expression of inflammatory ... ...

    Abstract The lymphatic vasculature of the liver is vital for liver function as it maintains fluid and protein homeostasis and is important for immune cell transport to the lymph node. Chronic liver disease is associated with increased expression of inflammatory mediators including oxidized low-density lipoprotein (oxLDL). Intrahepatic levels of oxLDL are elevated in nonalcoholic fatty liver disease (NAFLD), chronic hepatitis C infection (HCV), alcohol-associated liver disease (ALD), and cholestatic liver diseases. To determine if liver lymphatic function is impaired in chronic liver diseases, in which increased oxLDL has been documented, we measured liver lymphatic function in murine models of NAFLD, ALD and primary sclerosing cholangitis (PSC). We found that
    Language English
    Publishing date 2022-10-19
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2022.1021038
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: HCV and nonhepatic malignancy: Is pre-emptive direct-acting antiviral therapy indicated prior to treatment?

    Kriss, Michael / Burchill, Matthew

    Hepatology (Baltimore, Md.)

    2017  Volume 67, Issue 1, Page(s) 4–6

    MeSH term(s) Antiviral Agents ; Hepatitis C ; Humans ; Immunocompromised Host ; Neoplasms
    Chemical Substances Antiviral Agents
    Language English
    Publishing date 2017-11-24
    Publishing country United States
    Document type Editorial ; Comment
    ZDB-ID 604603-4
    ISSN 1527-3350 ; 0270-9139
    ISSN (online) 1527-3350
    ISSN 0270-9139
    DOI 10.1002/hep.29414
    Database MEDical Literature Analysis and Retrieval System OnLINE

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