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2دورية أكاديمية
المؤلفون: Kojima, Hidenobu, Hirao, Hirofumi, Kadono, Kentaro, Ito, Takahiro, Yao, Siyuan, Torgerson, Taylor, Kitajima, Hiroaki, Ogawa, Takahiro, Kaldas, Fady, Farmer, Douglas, Kupiec-Weglinski, Jerzy, Dery, Kenneth
المصدر: JCI insight. 9(3)
مصطلحات موضوعية: Apoptosis pathways, Immunology, Transplantation, Mice, Humans, Animals, Liver Transplantation, Endothelial Cells, Ferroptosis, NF-E2-Related Factor 2, Cold-Shock Response, Liver, Calcium-Binding Proteins, Mitochondrial Membrane Transport Proteins, Cyclohexylamines, Phenylenediamines
الوصف: Although cold preservation remains the gold standard in organ transplantation, cold stress-induced cellular injury is a significant problem in clinical orthotopic liver transplantation (OLT). Because a recent study showed that cold stress activates ferroptosis, a form of regulated cell death, we investigated whether and how ferroptosis determines OLT outcomes in mice and humans. Treatment with ferroptosis inhibitor (ferrostatin-1) during cold preservation reduced lipid peroxidation (malondialdehyde; MDA), primarily in liver sinusoidal endothelial cells (LSECs), and alleviated ischemia/reperfusion injury in mouse OLT. Similarly, ferrostatin-1 reduced cell death in cold-stressed LSEC cultures. LSECs deficient in nuclear factor erythroid 2-related factor 2 (NRF2), a critical regulator of ferroptosis, were susceptible to cold stress-induced cell death, concomitant with enhanced endoplasmic reticulum (ER) stress and expression of mitochondrial Ca2+ uptake regulator (MICU1). Indeed, supplementing MICU1 inhibitor reduced ER stress, MDA expression, and cell death in NRF2-deficient but not WT LSECs, suggesting NRF2 is a critical regulator of MICU1-mediated ferroptosis. Consistent with murine data, enhanced liver NRF2 expression reduced MDA levels, hepatocellular damage, and incidence of early allograft dysfunction in human OLT recipients. This translational study provides a clinically applicable strategy in which inhibition of ferroptosis during liver cold preservation mitigates OLT injury by protecting LSECs from peritransplant stress via an NRF2-regulatory mechanism.
وصف الملف: application/pdf
URL الوصول: https://escholarship.org/uc/item/421706ks
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3دورية أكاديمية
المؤلفون: Sosa, Rebecca A, Ahn, Richard, Li, Fang, Terry, Allyson Q, Qian, Zach, Bhat, Adil, Sen, Subha, Naini, Bita V, Ito, Takahiro, Kaldas, Fady M, Hoffmann, Alexander, Busuttil, Ronald W, Kupiec-Weglinski, Jerzy W, Gjertson, David W, Reed, Elaine F
المصدر: Hepatology Communications. 8(1)
مصطلحات موضوعية: Biomedical and Clinical Sciences, Immunology, Genetics, Liver Disease, Organ Transplantation, Transplantation, Digestive Diseases, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Humans, Liver Transplantation, Reperfusion Injury, Leukocytes, Adaptive Immunity, Biopsy, Inflammation, Clinical sciences
الوصف: BackgroundIschemia-reperfusion injury (IRI) is a significant clinical concern in liver transplantation, with a key influence on short-term and long-term allograft and patient survival. Myeloid cells trigger and sustain tissue inflammation and damage associated with IRI, but the mechanisms regulating these activities are unknown. To address this, we investigated the molecular characteristics of intragraft myeloid cells present in biopsy-proven IRI- and IRI+ liver transplants.MethodsRNA-sequencing was performed on 80 pre-reperfusion and post-reperfusion biopsies from 40 human recipients of liver transplantation (23 IRI+, 17 IRI-). We used transcriptional profiling and computational approaches to identify specific gene coexpression network modules correlated with functional subsets of MPO+, lysozyme+, and CD68+ myeloid cells quantified by immunohistochemistry on sequential sections from the same patient biopsies.ResultsA global molecular map showed gene signatures related to myeloid activation in all patients regardless of IRI status; however, myeloid cell subsets differed dramatically in their spatial morphology and associated gene signatures. IRI- recipients were found to have a natural corticosteroid production and response profile from pre-reperfusion to post-reperfusion, particularly among monocytes/macrophages. The pre-reperfusion signature of IRI+ recipients included acute inflammatory responses in neutrophils and increased translation of adaptive immune-related genes in monocytes/macrophages coupled with decreased glucocorticoid responses. Subsequent lymphocyte activation at post-reperfusion identified transcriptional programs associated with the transition to adaptive immunity found only among IRI+ recipients.ConclusionsMyeloid subset-specific genes and related signaling pathways provide targets for the development of therapeutic strategies aimed at limiting IRI in the clinical setting of liver transplantation.
وصف الملف: application/pdf
URL الوصول: https://escholarship.org/uc/item/3fm2f62g
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4دورية أكاديمية
المؤلفون: Terry, Allyson, Kojima, Hidenobu, Sosa, Rebecca, Kaldas, Fady, Chin, Jackson, Zheng, Ying, Naini, Bita, Noguchi, Daisuke, Nevarez-Mejia, Jessica, Jin, Yi-Ping, Kupiec-Weglinski, Jerzy, Busuttil, Ronald, Reed, Elaine, Meyer, Aaron, Gjertson, David
المصدر: American Journal of Transplantation. 23(12)
مصطلحات موضوعية: TLR activation, alloimmunity, disulfide-HMGB1, ischemia-reperfusion injury, pro-inflammatory macrophage, Humans, Mice, Animals, Liver Transplantation, Toll-Like Receptor 9, HMGB1 Protein, Toll-Like Receptor 4, Reactive Oxygen Species, Liver, Reperfusion Injury, Macrophages, Cytokines, Apoptosis, Mice, Inbred C57BL
الوصف: Ischemia-reperfusion injury (IRI) during orthotopic liver transplantation (OLT) contributes to graft rejection and poor clinical outcomes. The disulfide form of high mobility group box 1 (diS-HMGB1), an intracellular protein released during OLT-IRI, induces pro-inflammatory macrophages. How diS-HMGB1 differentiates human monocytes into macrophages capable of activating adaptive immunity remains unknown. We investigated if diS-HMGB1 binds toll-like receptor (TLR) 4 and TLR9 to differentiate monocytes into pro-inflammatory macrophages that activate adaptive immunity and promote graft injury and dysfunction. Assessment of 106 clinical liver tissue and longitudinal blood samples revealed that OLT recipients were more likely to experience IRI and graft dysfunction with increased diS-HMGB1 released during reperfusion. Increased diS-HMGB1 concentration also correlated with TLR4/TLR9 activation, polarization of monocytes into pro-inflammatory macrophages, and production of anti-donor antibodies. In vitro, healthy volunteer monocytes stimulated with purified diS-HMGB1 had increased inflammatory cytokine secretion, antigen presentation machinery, and reactive oxygen species production. TLR4 inhibition primarily impeded cytokine/chemokine and costimulatory molecule programs, whereas TLR9 inhibition decreased HLA-DR and reactive oxygen species production. diS-HMGB1-polarized macrophages also showed increased capacity to present antigens and activate T memory cells. In murine OLT, diS-HMGB1 treatment potentiated ischemia-reperfusion-mediated hepatocellular injury, accompanied by increased serum alanine transaminase levels. This translational study identifies the diS-HMGB1/TLR4/TLR9 axis as potential therapeutic targets in OLT-IRI recipients.
وصف الملف: application/pdf
URL الوصول: https://escholarship.org/uc/item/1nc6q6wg
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5دورية أكاديمية
المؤلفون: Kadono, Kentaro, Kojima, Hidenobu, Yao, Siyuan, Kageyama, Shoichi, Nakamura, Kojiro, Hirao, Hirofumi, Ito, Takahiro, Kaldas, Fady, Li, Xiaoling, Kupiec-Weglinski, Jerzy, Farmer, Douglas, Dery, Kenneth
المصدر: Cell Death & Disease. 14(11)
مصطلحات موضوعية: Humans, Mice, Animals, Liver Transplantation, Sirtuin 1, Interleukin-18, Liver, Hepatocytes, Apoptosis, Reperfusion Injury, Proto-Oncogene Proteins c-bcl-2
الوصف: Sirtuin 1 (SIRT1) is a histone/protein deacetylase in the cellular response to inflammatory, metabolic, and oxidative stressors. We previously reported that myeloid SIRT1 regulates the inflamed livers canonical pyroptosis cell death pathway. However, whether/how hepatocyte SIRT1 is engaged in programmed cell death in the cold-stressed liver remains uncertain. Here, we undertook translational studies in human and mouse orthotopic liver transplantation (OLT) to interrogate the significance of hepatocyte-specific SIRT1 in cold-stored donor livers and liver grafts after reperfusion. In the clinical arm of sixty human OLT patients, hepatic SIRT1 levels in cold-preserved donor livers correlated with the anti-apoptotic Bcl-2 expression. After reperfusion, improved OLT function was accompanied by hepatic SIRT1 levels negatively associated with cleaved caspase-3 expression. In the experimental arm, we compared FLOX-control with hepatocyte-specific SIRT1-KO livers after orthotopic transplantation into WT mouse recipients, parallel with primary murine hepatocyte cultures subjected to cold activation with/without knockdown of SIRT1, GSDME, and IL18Rβ. Indeed, hepatocyte SIRT1 deficiency upregulated apoptosis and GSDME-mediated programmed cell death, deteriorating hepatocellular function and shortening OLT survival. Augmented GSDME processing, accompanied by increased secretion of IL18 by stressed hepatocytes, was prominent in SIRT1-deficient, cold-stored livers. Hepatocyte SIRT1 expression regulated anti-apoptotic Bcl-2/XIAP proteins, suppressed cold stress-triggered apoptosis, and mitigated GSDME licensing to release IL18. Notably, consistent with the ability of IL18 to depress hepatocyte SIRT1 and Bcl-2/XIAP in vitro, IL18 neutralization in vivo prevented hepatocellular damage and restored the anti-apoptotic phenotype in otherwise injury-prone SIRT1-deficient OLTs. In conclusion, this translational study identifies a novel hepatocyte SIRT1-IL18 molecular circuit as a therapeutic target in the mechanism underpinning hepatocyte death pathways in human and mouse liver transplantation.
وصف الملف: application/pdf
URL الوصول: https://escholarship.org/uc/item/6jc467w0
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6دورية أكاديمية
المؤلفون: Sosa, Rebecca, Terry, Allyson, Ito, Takahiro, Naini, Bita, Zheng, Ying, Pickering, Harry, Nevarez-Mejia, Jessica, Busuttil, Ronald, Gjertson, David, Kupiec-Weglinski, Jerzy, Kaldas, Fady, Reed, Elaine
المصدر: Transplantation Direct. 9(11)
الوصف: BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a severe immune-mediated stage of nonalcoholic fatty liver disease that is rapidly becoming the most common etiology requiring liver transplantation (LT), with Hispanics bearing a disproportionate burden. This study aimed to uncover the underlying immune mechanisms of the disparities experienced by Hispanic patients undergoing LT for NASH. METHODS: We enrolled 164 LT recipients in our institutional review board-approved study, 33 of whom presented with NASH as the primary etiology of LT (20%), with 16 self-reported as Hispanic (48%). We investigated the histopathology of prereperfusion and postreperfusion biopsies, clinical liver function tests, longitudinal soluble cytokines via 38-plex Luminex, and immune cell phenotypes generated by prereperfusion and postreperfusion blood using 14-color flow cytometry and enzyme-linked immunosorbent assay. RESULTS: Hispanic LT recipients transplanted for NASH were disproportionately female (81%) and disproportionately suffered poor outcomes in the first year posttransplant, including rejection (26%) and death (38%). Clinically, we observed increased pro-inflammatory and apoptotic histopathological features in biopsies, increased AST/international normalized ratio early posttransplantation, and a higher incidence of presensitization to mismatched HLA antigens expressed by the donor allograft. Experimental investigations revealed that blood from female Hispanic NASH patients showed significantly increased levels of leukocyte-attracting chemokines, innate-to-adaptive switching cytokines and growth factors, HMGB1 release, and TLR4/TLR8/TLR9/NOD1 activation, and produced a pro-inflammatory, pro-apoptotic macrophage phenotype with reduced CD14/CD68/CD66a/TIM-3 and increased CD16/CD11b/HLA-DR/CD80. CONCLUSIONS: A personalized approach to reducing immunological risk factors is urgently needed for this endotype in Hispanics with NASH requiring LT, particularly in females.
وصف الملف: application/pdf
URL الوصول: https://escholarship.org/uc/item/0wj836t7
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7دورية أكاديمية
المؤلفون: Kojima, Hidenobu, Kadono, Kentaro, Hirao, Hirofumi, Kupiec-Weglinski, Jerzy, Dery, Kenneth
المصدر: Antioxidants and Redox Signaling. 38(7-9)
مصطلحات موضوعية: NRF2, T cell differentiation, liver ischemia–reperfusion injury, liver transplantation, translational research, Humans, Mice, Animals, Liver Transplantation, NF-E2-Related Factor 2, T-Lymphocytes, Living Donors, Liver, Liver Diseases, CD4-Positive T-Lymphocytes, Cell Differentiation, Reperfusion Injury, Mice, Inbred C57BL
الوصف: Aims: Innate and adaptive immune responses regulate hepatic ischemia-reperfusion injury (IRI) in orthotopic liver transplantation (OLT). While the mechanism of how nuclear factor erythroid 2-related factor 2 (NRF2) plays a role in liver IRI has been studied, the contribution of T cell-specific NRF2 in OLT remains unknown. In the current translational study, we investigated whether and how CD4+ T cell-specific NRF2 signaling affects liver transplant outcomes in mice and humans. Results: In the experimental arm, cold-stored (4°C/18 h) wild-type (WT) mouse livers transplanted to NRF2-deficient (NRF2-knockout [NRF2-KO]) recipients experienced greater hepatocellular damage than those in Nrf2-proficient (WT) counterparts, evidenced by Suzukis histological scores, frequency of TdT-mediated dUTP nick end labeling (TUNEL)+ cells, and elevated serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels. In vitro studies showed that NRF2 signaling suppressed CD4+ T cell differentiation to a proinflammatory phenotype (Th1, Th17) while promoting the regulatory (Foxp3+) T cell lineage. Furthermore, OLT injury deteriorated in immune-compromised RAG2-KO test recipients repopulated with CD4+ T cells from NRF2-KO compared with WT donor mice. In the clinical arm of 45 human liver transplant patients, the perioperative increase of NRF2 expression in donor livers negatively regulated innate and adaptive immune activation, resulting in reduced hepatocellular injury in NRF2-proficient OLT. Innovation and Conclusion: CD4+ T cell population expressing NRF2 attenuated ischemia and reperfusion (IR)-triggered hepatocellular damage in a clinically relevant mouse model of extended donor liver cold storage, followed by OLT, whereas the perioperative increase of NRF2 expression reduced hepatic injury in human liver transplant recipients. Thus, CD4+ T cell NRF2 may be a novel cytoprotective sentinel against IR stress in OLT recipients. Antioxid. Redox Signal. 38, 670-683.
وصف الملف: application/pdf
URL الوصول: https://escholarship.org/uc/item/7pr3j4wh
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8دورية أكاديمية
المؤلفون: Hirao, Hirofumi, Kojima, Hidenobu, Dery, Kenneth J, Nakamura, Kojiro, Kadono, Kentaro, Zhai, Yuan, Farmer, Douglas G, Kaldas, Fady M, Kupiec-Weglinski, Jerzy W
المصدر: The Journal of clinical investigation. 133(3)
مصطلحات موضوعية: Liver, Neutrophils, Animals, Humans, Mice, Reperfusion Injury, Cell Adhesion Molecules, Carcinoembryonic Antigen, Transcription Factors, Liver Transplantation, Sphingosine-1-Phosphate Receptors, Hypoxia, Organ transplantation, Transplantation, Digestive Diseases, Liver Disease, Chronic Liver Disease and Cirrhosis, Organ Transplantation, 1.1 Normal biological development and functioning, Underpinning research, Inflammatory and immune system, Medical and Health Sciences, Immunology
الوصف: Neutrophils, the largest innate immune cell population in humans, are the primary proinflammatory sentinel in the ischemia-reperfusion injury (IRI) mechanism in orthotopic liver transplantation (OLT). Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, CC1, or CD66a) is essential in neutrophil activation and serves as a checkpoint regulator of innate immune-driven IRI cascade in OLT. Although CC1 alternative splicing generates two functionally distinct short and long cytoplasmic isoforms, their role in neutrophil activation remains unknown. Here, we undertook molecular and functional studies to interrogate the significance of neutrophil CC1 signaling in mouse and human OLT recipients. In the experimental arm, we employed a mouse OLT model to document that ablation of recipient-derived neutrophil CC1-long (CC1-L) isotype aggravated hepatic IRI by promoting neutrophil extracellular traps (NETs). Notably, by regulating the S1P-S1PR2/S1PR3 axis, neutrophil CC1-L determined susceptibility to NET formation via autophagy signaling. In the clinical arm, liver grafts from 55 transplant patients selectively enriched for neutrophil CC1-L showed relative resistance to ischemia-reperfusion (IR) stress/tissue damage, improved hepatocellular function, and clinical outcomes. In conclusion, despite neutrophils being considered a principal villain in peritransplant tissue injury, their CC1-L isoform may serve as a regulator of IR stress resistance/NETosis in human and mouse OLT recipients.
وصف الملف: application/pdf
URL الوصول: https://escholarship.org/uc/item/38b1p131
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9دورية أكاديمية
المؤلفون: Zhang, Hanwen, Ni, Ming, Wang, Han, Zhang, Jing, Jin, Dan, Busuttil, Ronald W, Kupiec-Weglinski, Jerzy W, Li, Wei, Wang, Xuehao, Zhai, Yuan
المصدر: JCI Insight. 8(1)
مصطلحات موضوعية: Biomedical and Clinical Sciences, Chronic Liver Disease and Cirrhosis, Liver Disease, Digestive Diseases, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Animals, Mice, c-Mer Tyrosine Kinase, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Inflammation, Ischemia, Liver, Reperfusion Injury, Hepatology, Immunology, Innate immunity, Macrophages, Biomedical and clinical sciences, Health sciences
الوصف: Although glycogen synthase kinase β (Gsk3β) has been shown to regulate tissue inflammation, whether and how it regulates inflammation resolution versus inflammation activation is unclear. In a murine liver, partial warm ischemia/reperfusion injury (IRI) model, we found that Gsk3β inhibitory phosphorylation increased at both the early-activation and late-resolution stages of the disease. Myeloid Gsk3β deficiency not only alleviated liver injuries, it also facilitated the restoration of liver homeostasis. Depletion of Kupffer cells prior to the onset of liver ischemia diminished the differences between the WT and Gsk3β-KO mice in the activation of liver IRI. However, the resolution of liver IRI remained accelerated in Gsk3β-KO mice. In CD11b-DTR mice, Gsk3β-deficient BM-derived macrophages (BMMs) facilitated the resolution of liver IRI as compared with WT cells. Furthermore, Gsk3β deficiency promoted the reparative phenotype differentiation in vivo in liver-infiltrating macrophages and in vitro in BMMs. Gsk3 pharmacological inhibition promoted the resolution of liver IRI in WT, but not myeloid MerTK-deficient, mice. Thus, Gsk3β regulates liver IRI at both activation and resolution stages of the disease. Gsk3 inactivation enhances the proresolving function of liver-infiltrating macrophages in an MerTK-dependent manner.
وصف الملف: application/pdf
URL الوصول: https://escholarship.org/uc/item/0496s88c
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المصدر: IMDiK PAN, sygn. ZS46
Repozytorium Cyfrowe Instytutów Naukowych
http://katalog.pan.pl/webpac-bin/219bicmdikPL/wgbroker.exe?new+-access+top+search+open+NR+kg2004000115
http://katalog.pan.pl/webpac-bin/219bicmdikEN/wgbroker.exe?new+-access+top+search+open+NR+kg2004000115
