Feedback Loops Shape Oxidative and Immune Interactions in Hepatic Ischemia-Reperfusion Injury.

Reactive oxygen species (ROS) play a dual role as both essential signaling molecules and harmful mediators of damage. Imbalances in the redox state of the liver can overwhelm antioxidant defenses and promote mitochondrial dysfunction, oxidative damage, and inflammation. Complex feedback loops between ROS and immune signaling pathways are a hallmark of pathological liver conditions, such as hepatic ischemia-reperfusion injury (IRI).

Pregnancy after orthotopic liver transplantation: a comprehensive review.

Background: Medical innovations and advancements, such as orthotopic liver transplantation (OLT) allow thousands of patients worldwide to live comfortably, despite previously life-threatening conditions. Procreation, one of the most powerful human instincts, drives the force behind the increasing popularity of pregnancies after OLT, with their numbers rising since the first documented case in 1976. Pregnancy post OLT remains a high-risk event, requiring careful management by a multidisciplinary team of hepatologists, obstetricians, transplant surgeons, and neonatologists.

Mouse orthotopic liver transplantation: Challenges, achievements, and applications.

The surgically challenging mouse orthotopic liver transplant model has provided numerous insights into liver immunobiology, cellular and molecular regulation of liver transplant ischemia-reperfusion injury, liver regeneration, the influence of major histocompatibility complex antigens on transplant outcome, spontaneous transplant tolerance, and regulation of allograft immunity. Nonarterialized and arterialized models have been established. Reduced-size liver transplant models have also been developed and used to determine critical mass and factors that determine tissue injury and regeneration.

Tensor-Based Integration of Time-Series Measurements Reveals Relationships Between Underlying Disease, Early Injury, and CD4+ Polarization in Liver Transplantation.

For patients with end-stage liver failure, liver transplantation (LT) remains the standard-of-care, though five-year allograft survival rates remain below 80%. Liver ischemia reperfusion injuries (LIRI) arise during transplant and contribute to allograft dysfunction. While many drivers of LIRI have been well-characterized, the relationships between LIRI and later immunological signatures remain poorly understood, possibly because of limited integrated studies examining immunological signatures across the LT process.

Ronald W. Busuttil, M.D., Ph.D.- TTS 2024 Medawar Prize Laureate.

The Transplantation Society (TTS) has been presenting the Medawar Prize at its biennial Congresses since 1990 in recognition of Sir Peter Medawar's seminal contributions to organ transplantation. This prestigious award acknowledges individuals for their outstanding accomplishments in experimental and clinical transplantation. On September 25, 2024, I was honored to introduce Ronald W.

Group 1 innate lymphoid cells protect liver transplants from ischemia-reperfusion injury via an interferon gamma-mediated pathway.

As important immune regulatory cells, whether innate lymphoid cells (ILCs) are involved in liver transplantation (LT) remains unclear. In a murine orthotopic LT model, we dissected roles of ILCs in liver ischemia-reperfusion injury (IRI). Wild-type (WT) grafts suffered significantly higher IRI in Rag2-γc double knockout (DKO) than Rag2 knockout (KO) recipients, in association with downregulation of group 1 ILCs genes, including interferon gamma.

Mechanism and function of CEACAM1 splice isoforms.

Background: Alternative splicing is a fundamental mechanism in the post-transcriptional regulation of genes. The multifunctional transmembrane glycoprotein receptor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) undergoes extensive alternative splicing to allow for tunable functions in cell signalling, adhesion and modulation of immune and metabolic responses. Splice isoforms that differ in their ectodomain and short or long cytoplasmic tail (CEACAM1-S/CEACAM1-L) have distinct functional roles.

The Coming Age of Antisense Oligos for the Treatment of Hepatic Ischemia/Reperfusion (IRI) and Other Liver Disorders: Role of Oxidative Stress and Potential Antioxidant Effect.

Imbalances in the redox state of the liver arise during metabolic processes, inflammatory injuries, and proliferative liver disorders. Acute exposure to intracellular reactive oxygen species (ROS) results from high levels of oxidative stress (OxS) that occur in response to hepatic ischemia/reperfusion injury (IRI) and metabolic diseases of the liver. Antisense oligonucleotides (ASOs) are an emerging class of gene expression modulators that target RNA molecules by Watson-Crick binding specificity, leading to RNA degradation, splicing modulation, and/or translation interference.

Cold stress-induced ferroptosis in liver sinusoidal endothelial cells determines liver transplant injury and outcomes.

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.

Myeloid spatial and transcriptional molecular signature of ischemia-reperfusion injury in human liver transplantation.

Background: Ischemia-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.

SIRT1 regulates hepatocyte programmed cell death via GSDME - IL18 axis in human and mouse liver transplantation.

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 liver's canonical pyroptosis cell death pathway. However, whether/how hepatocyte SIRT1 is engaged in programmed cell death in the cold-stressed liver remains uncertain.

Immune Features of Disparate Liver Transplant Outcomes in Female Hispanics With Nonalcoholic Steatohepatitis.

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%).

Mechanistic Insights into Alternative Gene Splicing in Oxidative Stress and Tissue Injury.

Oxidative stress (OS) and inflammation are inducers of tissue injury. Alternative splicing (AS) is an essential regulatory step for diversifying the eukaryotic proteome. Human diseases link AS to OS; however, the underlying mechanisms must be better understood.

Alternative splicing of CEACAM1 by hypoxia-inducible factor-1α enhances tolerance to hepatic ischemia in mice and humans.

Although alternative splicing (AS) drives transcriptional responses and cellular adaptation to environmental stresses, its contributions in organ transplantation have not been appreciated. We have shown that carcinoembryonic antigen-related cell adhesion molecule (Ceacam1; ), a transmembrane biliary glycoprotein expressed in epithelial, endothelial, and immune cells, determines donor liver transplant quality. Here, we studied how AS of affects ischemia-reperfusion injury (IRI) in mouse and human livers.

NRF2: New Mechanistic Insights and Therapeutic Perspectives.

Targeted modulation of a dynamic interplay between transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) and its negative regulator, Kelch-like ECH-associated protein 1 (KEAP1), is of paramount importance in maintaining redox, metabolic, and protein homeostasis and regulating inflammation responses. Indeed, inducible NRF2 activation promotes cytoprotective mechanisms against many immune, neurodegenerative, and metabolic disorders with oxidative stress and inflammation as underlying pathological features. In this ARS Forum, five state-of-the-art reviews and two original research communications report on canonical and newly discovered molecular mechanisms by which the NRF2-KEAP1 axis controls fundamental cell life or death decisions and exerts biological functions under environmental and endogenous stress conditions.

New therapeutic concepts against ischemia-reperfusion injury in organ transplantation.

Introduction: Ischemia-reperfusion injury (IRI) involves a positive amplification feedback loop that stimulates innate immune-driven tissue damage associated with organ procurement from deceased donors and during transplantation surgery. As our appreciation of its basic immune mechanisms has improved in recent years, translating putative biomarkers into therapeutic interventions in clinical transplantation remains challenging.

Areas Covered: This review presents advances in translational/clinical studies targeting immune responses to reactive oxygen species in IRI-stressed solid organ transplants, especially livers.

T Cell CEACAM1-TIM-3 Crosstalk Alleviates Liver Transplant Injury in Mice and Humans.

Background & Aims: Carcinoembryonic antigen-related cell adhesion molecule 1 (CC1) acts through homophilic and heterophilic interactions with T cell immunoglobulin domain and mucin domain-containing protein 3 (TIM-3), which regulates innate immune activation in orthotopic liver transplantation (OLT). We investigated whether cluster of differentiation (CD) 4 T cell-dependent CC1-TIM-3 crosstalk may affect OLT outcomes in mice and humans.

Methods: Wild-type (WT) and CC1-deficient (CC1 knock-out [KO]) mouse livers were transplanted into WT, CC1KO, or T-cell TIM-3 transgenic (TIM-3Tg)/CC1KO double-mutant recipients.

Recipient signaling regulates ischemia reperfusion-induced ER stress and metabolic responses in liver transplantation: from mouse-to-human.

T-cell immunoglobulin and mucin ()4 is expressed on APCs, including macrophages, as one of the main amplifiers in the mechanism of liver ischemia-reperfusion injury (IRI) following orthotopic liver transplantation (OLT). Though donor selectively expressed on Kupffer cells serves as a checkpoint regulator of innate immune-driven IRI cascades, its role on cells outside the OLT remains unclear. To dissect the role of donor vs.

Neutrophil CEACAM1 determines susceptibility to NETosis by regulating the S1PR2/S1PR3 axis in liver transplantation.

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.

Gsk3β regulates the resolution of liver ischemia/reperfusion injury via MerTK.

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.

CD4 T Cell NRF2 Signaling Improves Liver Transplantation Outcomes by Modulating T Cell Activation and Differentiation.

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.

New insights into ischemia-reperfusion injury signaling pathways in organ transplantation.

Purpose Of Review: Ischemia-reperfusion injury (IRI) leading to allograft rejection in solid organ transplant recipients is a devastating event that compromises graft and patient survival. As our clinical knowledge regarding its definition and presentation has significantly improved over the last years, adequate biomarkers translating to important therapeutic intervention remains a challenge. This review will summarize recent findings in this area.