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Deng S, Zhang Y, Shen S, Li C, Qin C. Immunometabolism of Liver Xenotransplantation and Prospective Solutions. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2407610. [PMID: 39912334 DOI: 10.1002/advs.202407610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 10/26/2024] [Indexed: 02/07/2025]
Abstract
End-stage liver diseases, such as hepatocellular carcinoma or acute liver failure, critically necessitate liver transplantation. However, the shortage of available organ donors fails to meet the rapidly growing transplantation demand. Due to the high similarity of liver tissue structure and metabolism between miniature pigs and humans, xenotransplantation of pig livers is considered as a potentially viable solution to organ scarcity. In the 2024, teams from China first time have successfully transplanted a genetically modified Bama miniature pig liver into a clinically brain-dead man lasting for 10 days. This milestone in human xenotransplantation research not only confirms the feasibility of clinical application of xenotransplantation, but also underscores the daunting and protracted nature of this pathway. Despite advanced gene-editing technologies theoretically circumventing the occurrence of most transplant rejection reactions, patients still face challenges such as chronic immune rejection, coagulation disorders, and thrombotic microangiopathy after receiving xenografts. Moreover, prolonged use of immunosuppressive drugs may induce irreversible immune dysfunction, leading to opportunistic infections and metabolic disorders. This article compares the similarities and differences in livers between humans and pigs, summarizes the immunometabolism of xenotransplantation based on current findings, and provides research perspectives on pre-transplantation and post-transplantation strategies for prolonging the survival time of xenografts.
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Affiliation(s)
- Shoulong Deng
- National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, National Health Commission of China (NHC) Key Laboratory of Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, 100021, China
| | - Yi Zhang
- Department of Medicine, Panzhihua University, Sichuan, 61700, China
| | - Shasha Shen
- Department of Medicine, Panzhihua University, Sichuan, 61700, China
| | - Chongyang Li
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Chuan Qin
- National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, National Health Commission of China (NHC) Key Laboratory of Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, 100021, China
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Krishna AA, Abhirami BL, Kumaran A. Pain in rheumatoid arthritis: Emerging role of high mobility group box 1 protein-HMGB1. Life Sci 2025; 362:123361. [PMID: 39761742 DOI: 10.1016/j.lfs.2024.123361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/20/2024] [Accepted: 12/31/2024] [Indexed: 01/11/2025]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease where pain, driven by both inflammatory and non-inflammatory processes, is a major concern for patients. This pain can persist even after joint inflammation subsides. High mobility group box-1 (HMGB1) is a non-histone-DNA binding protein located in the nucleus that plays a key role in processes such as DNA transcription, recombination, and replication. HMGB1 can be released into the extracellular space through both passive and active mechanisms. Extracellular HMGB1 contributes to synovial inflammation, bone degradation, and the production of cytokines in RA by binding to toll-like receptors (TLRs) and receptors for advanced glycation end products (RAGE). It also forms complexes with molecules like lipopolysaccharide (LPS) and IL-1β, amplifying inflammatory responses. Due to its central role in these processes, HMGB1 is considered a promising therapeutic target in RA. It also acts as a nociceptive molecule in mediating pain in diseases such as diabetes and bone cancer. In this review, we explore how HMGB1 contributes to chronic pain in RA, supported by both in vitro and in vivo models. We begin by providing an overview of the mechanisms of pain in RA, the structure of HMGB1, its release mechanisms, and the therapeutic potential of targeting HMGB1 in RA. Following this, we highlight its role in peripheral and central pain sensitization through direct activation of the TLR4/MAPK/NF-κB pathway, as well as indirectly through downstream mediators, underscoring its potential as a target for managing RA pain.
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Affiliation(s)
- Anithakumari Aswathy Krishna
- Agroprocessing and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram 695019, Kerala, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Beena Levakumar Abhirami
- Agroprocessing and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram 695019, Kerala, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Alaganandam Kumaran
- Agroprocessing and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram 695019, Kerala, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Hou Y, Feng Q, Wei C, Cao F, Liu D, Pan S, Shi Y, Liu Z, Liu F. Emerging role of PANoptosis in kidney diseases: molecular mechanisms and therapeutic opportunities. Apoptosis 2025:10.1007/s10495-024-02072-y. [PMID: 39833634 DOI: 10.1007/s10495-024-02072-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/26/2024] [Indexed: 01/22/2025]
Abstract
Kidney diseases represent a significant global public health challenge, characterized by complex pathogenesis, high incidence, low awareness, insufficient early screening, and substantial treatment disparities. Effective therapeutic options remain lacking. Programmed cell death (PCD), including apoptosis, pyroptosis, and necroptosis, play pivotal roles in the pathogenesis of various kidney diseases. In 2019, PANoptosis, a novel form of inflammatory cell death, was introduced, providing new insights into innate immunity and PCD research. Although research on PANoptosis in kidney diseases is still limited, identifying key molecules within PANoptosomes and understanding their regulatory roles is critical for disease prevention and management. This review summarizes the various forms of PCD implicated in kidney diseases, along with PANoptosomes activated by Z-DNA binding protein 1 (ZBP1), absent in melanoma 2 (AIM2), receptor-interacting protein kinase 1 (RIPK1), NOD-like receptor family CARD domain containing 12 (NLRP12), and NOD-like receptor family member C5 (NLRC5). It also reviews the advancements in PANoptosis research in the field of kidney diseases, particularly in renal tumors and acute kidney injuries (AKI). The goal is to establish a foundation for future research into the role of PANoptosis in kidney diseases.
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Affiliation(s)
- Yi Hou
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China
| | - Qi Feng
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P. R. China
| | - Cien Wei
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China
| | - Fengyu Cao
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China
| | - Dongwei Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P. R. China
| | - Shaokang Pan
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P. R. China
| | - Yan Shi
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China
| | - Zhangsuo Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China.
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China.
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, P. R. China.
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China.
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P. R. China.
| | - Fengxun Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China.
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P. R. China.
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, P. R. China.
- Henan Province Research Center for Kidney Disease, Zhengzhou, 450052, P. R. China.
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P. R. China.
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Myette RL, Trentin-Sonoda M, Landry C, Holterman CE, Lin T, Burger D, Kennedy CR. Damage-Associated Molecular Patterns and Pattern Recognition Receptors in the Podocyte. J Am Soc Nephrol 2025; 36:136-143. [PMID: 39331471 PMCID: PMC11706563 DOI: 10.1681/asn.0000000531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 09/24/2024] [Indexed: 09/29/2024] Open
Abstract
Podocytes possess immune system components allowing for a variety of innate responses to endogenous and exogenous stimuli. Recently, several groups have linked inappropriate innate immune signaling to podocyte injury, particularly chronic, sustained injury; however, the immune capabilities of podocytes have not been fully elucidated. Damage-associated molecular patterns (DAMPs) are endogenous danger molecules released from damaged cells, including podocytes, and can elicit an inflammatory response and recruit immune cells to areas of injury. This is performed through binding to pattern recognition receptors. Believed largely to be protective and responsive to injury or infection, recent evidence suggests signaling through DAMP pathways can aggravate and promote chronic diseases already associated with inflammation. The purpose of this narrative review was to highlight current knowledge with respect to specific podocyte DAMPs and pattern recognition receptors and to provide insight into ongoing work and possible future research avenues to advance our understanding of podocyte immune mechanisms.
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Affiliation(s)
- Robert L. Myette
- Division of Pediatric Nephrology, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada
- Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Mayra Trentin-Sonoda
- Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Chloé Landry
- Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Chet E. Holterman
- Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Tony Lin
- Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Dylan Burger
- Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Christopher R.J. Kennedy
- Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
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Steinhauser C, Yakac A, Markgraf W, Kromnik S, Döcke A, Talhofer P, Thiele C, Malberg H, Sommer U, Baretton GB, Füssel S, Thomas C, Putz J. Assessing Biomarkers of Porcine Kidneys under Normothermic Machine Perfusion-Can We Gain Insight into a Marginal Organ? Int J Mol Sci 2024; 25:10280. [PMID: 39408610 PMCID: PMC11476884 DOI: 10.3390/ijms251910280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 09/17/2024] [Accepted: 09/20/2024] [Indexed: 10/20/2024] Open
Abstract
To identify potentially transplantable organs in a pool of marginal kidneys, 33 porcine slaughterhouse kidneys were perfused for 4 h with whole blood. During the normothermic perfusion, plasma, urine, and tissue samples were taken. Several biomarkers for tubule injury, endothelial activation, and inflammatory response were evaluated for a potential correlation with macroscopic appearance, histology, and filtration activity. Generally, biomarker levels increased during perfusion. TLR-4, EDN-1, and NGAL were not associated with any classification. In contrast, a steeper increase in NAG and IL-6 in plasma correlated with a poor macroscopic appearance at 4 h, indicating a higher inflammatory response in the kidneys with worse macroscopy early on, potentially due to more damage at the tubules. Although long-term effects on the graft could not be assessed in this setting, early observation under machine perfusion with whole blood was feasible. It allowed the assessment of kidneys under conditions comparable to reperfusion. This setting could give surgeons further insight into the quality of marginal kidneys and an opportunity to pre-treat them.
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Affiliation(s)
- Carla Steinhauser
- Department of Urology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01309 Dresden, Germany
| | - Abdulbaki Yakac
- Department of Urology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01309 Dresden, Germany
| | - Wenke Markgraf
- Institute of Biomedical Engineering, Technische Universität Dresden, D-01309 Dresden, Germany
| | - Susanne Kromnik
- Institute of Biomedical Engineering, Technische Universität Dresden, D-01309 Dresden, Germany
| | - Andreas Döcke
- Institute of Biomedical Engineering, Technische Universität Dresden, D-01309 Dresden, Germany
| | - Philipp Talhofer
- Institute of Biomedical Engineering, Technische Universität Dresden, D-01309 Dresden, Germany
| | - Christine Thiele
- Institute of Biomedical Engineering, Technische Universität Dresden, D-01309 Dresden, Germany
| | - Hagen Malberg
- Institute of Biomedical Engineering, Technische Universität Dresden, D-01309 Dresden, Germany
| | - Ulrich Sommer
- Institute of Pathology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01309 Dresden, Germany
| | - Gustavo B. Baretton
- Institute of Pathology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01309 Dresden, Germany
| | - Susanne Füssel
- Department of Urology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01309 Dresden, Germany
| | - Christian Thomas
- Department of Urology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01309 Dresden, Germany
| | - Juliane Putz
- Department of Urology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01309 Dresden, Germany
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Vagiotas L, Lioulios G, Panteli M, Ouranos K, Xochelli A, Kasimatis E, Nikolaidou V, Samali M, Daoudaki M, Katsanos G, Antoniadis N, Tsoulfas G, Stangou M, Fylaktou A. Kidney Transplantation and Cellular Immunity Dynamics: Immune Cell Alterations and Association with Clinical and Laboratory Parameters. J Clin Med 2024; 13:5093. [PMID: 39274306 PMCID: PMC11396483 DOI: 10.3390/jcm13175093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 08/23/2024] [Accepted: 08/25/2024] [Indexed: 09/16/2024] Open
Abstract
Background/Objectives: The purpose of this study was to evaluate numerical changes in immune cells after successful kidney transplantation and associate their recovery with clinical and laboratory factors. Methods: In 112 kidney transplant recipients, we performed flow cytometry to evaluate counts of CD4+, CD8+, and regulatory T cells (Tregs), as well as natural killer (NK) cells, before kidney transplantation (T0) and three (T3), six (T6), and twelve (T12) months later. The results were associated with the recipient's age, cold ischemia time (CIT), the type of donor, dialysis method and vintage, and graft function in one year. Results: Total and CD8+ T cell counts increased gradually one year post transplantation in comparison with pre-transplantation levels, whereas the number of CD4+ T cells and Tregs increased, and the number of NK cells decreased in the first three months and remained stable thereafter. The recipient's age was negatively correlated with total, CD4+, and Treg counts at T12, whereas CIT affected only total and CD4+ T cell count. Moreover, recipients receiving kidneys from living donors presented better recovery of all T cell subsets at T12 in comparison with recipients receiving kidneys from cadaveric donors. Patients on peritoneal dialysis had increased numbers of total and CD8+ T cells, as well as NK cells. Finally, estimated glomerular filtration rate was positively correlated with Treg level and potentially CD4+ T cells one-year post transplantation. Conclusions: Successful kidney transplantation results in the recovery of most T cell subsets. Lower recipient age and better graft function contribute to increased T cell counts, whereas donor type and dialysis modality are the most important modifiable factors for optimal immune recovery.
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Affiliation(s)
- Lampros Vagiotas
- Department of Transplant Surgery, General Hospital Hippokratio, 54642 Thessaloniki, Greece
| | - Georgios Lioulios
- Department of Nephrology, 424 General Military Hospital of Thessaloniki, 56429 Thessaloníki, Greece
| | - Manolis Panteli
- 1st Department of Nephrology, General Hospital Hippokratio, 54642 Thessaloniki, Greece
| | - Konstantinos Ouranos
- Department of Medicine, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Aliki Xochelli
- National Peripheral Histocompatibility Center, Department of Immunology, General Hospital Hippokratio, 54642 Thessaloniki, Greece
| | - Efstratios Kasimatis
- 1st Department of Nephrology, General Hospital Hippokratio, 54642 Thessaloniki, Greece
| | - Vasiliki Nikolaidou
- National Peripheral Histocompatibility Center, Department of Immunology, General Hospital Hippokratio, 54642 Thessaloniki, Greece
| | - Margarita Samali
- National Peripheral Histocompatibility Center, Department of Immunology, General Hospital Hippokratio, 54642 Thessaloniki, Greece
| | - Maria Daoudaki
- School of Medicine, Aristotle University of Thessaloniki, 45636 Thessaloniki, Greece
| | - Georgios Katsanos
- Department of Transplant Surgery, General Hospital Hippokratio, 54642 Thessaloniki, Greece
| | - Nikolaos Antoniadis
- Department of Transplant Surgery, General Hospital Hippokratio, 54642 Thessaloniki, Greece
| | - Georgios Tsoulfas
- Department of Transplant Surgery, General Hospital Hippokratio, 54642 Thessaloniki, Greece
| | - Maria Stangou
- 1st Department of Nephrology, General Hospital Hippokratio, 54642 Thessaloniki, Greece
- School of Medicine, Aristotle University of Thessaloniki, 45636 Thessaloniki, Greece
| | - Asimina Fylaktou
- National Peripheral Histocompatibility Center, Department of Immunology, General Hospital Hippokratio, 54642 Thessaloniki, Greece
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Pang Q, Chen L, An C, Zhou J, Xiao H. Single-cell and bulk RNA sequencing highlights the role of M1-like infiltrating macrophages in antibody-mediated rejection after kidney transplantation. Heliyon 2024; 10:e27865. [PMID: 38524599 PMCID: PMC10958716 DOI: 10.1016/j.heliyon.2024.e27865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 03/07/2024] [Indexed: 03/26/2024] Open
Abstract
Background Antibody-mediated rejection (ABMR) significantly affects transplanted kidney survival, yet the macrophage phenotype, ontogeny, and mechanisms in ABMR remain unclear. Method We analyzed post-transplant sequencing and clinical data from GEO and ArrayExpress. Using dimensionality reduction and clustering on scRNA-seq data, we identified macrophage subpopulations and compared their infiltration in ABMR and non-rejection cases. Cibersort quantified these subpopulations in bulk samples. Cellchat, SCENIC, monocle2, and monocle3 helped explore intercellular interactions, predict transcription factors, and simulate differentiation of cell subsets. The Scissor method linked macrophage subgroups with transplant prognosis. Furthermore, hdWGCNA, nichnet, and lasso regression identified key genes associated with core transcription factors in selected macrophages, validated by external datasets. Results Six macrophage subgroups were identified in five post-transplant kidney biopsies. M1-like infiltrating macrophages, prevalent in ABMR, correlated with pathological injury severity. MIF acted as a primary intercellular signal in these macrophages. STAT1 regulated monocyte-to-M1-like phenotype transformation, impacting transplant prognosis via the IFNγ pathway. The prognostic models built on the upstream and downstream genes of STAT1 effectively predicted transplant survival. The TLR4-STAT1-PARP9 axis may regulate the pro-inflammatory phenotype of M1-like infiltrating macrophages, identifying PARP9 as a potential target for mitigating ABMR inflammation. Conclusion Our study delineates the macrophage landscape in ABMR post-kidney transplantation, underscoring the detrimental impact of M1-like infiltrating macrophages on ABMR pathology and prognosis.
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Affiliation(s)
- Qidan Pang
- Department of Nephrology, Bishan Hospital of Chongqing Medical University, Chongqing, 402760, China
| | - Liang Chen
- Department of General Surgery/Gastrointestinal Surgery, Bishan Hospital of Chongqing Medical University, Chongqing, 402760, China
| | - Changyong An
- Department of General Surgery/Gastrointestinal Surgery, Bishan Hospital of Chongqing Medical University, Chongqing, 402760, China
| | - Juan Zhou
- Department of Nephrology, Bishan Hospital of Chongqing Medical University, Chongqing, 402760, China
| | - Hanyu Xiao
- Department of General Surgery/Gastrointestinal Surgery, Bishan Hospital of Chongqing Medical University, Chongqing, 402760, China
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Vezzoli A, Mrakic-Sposta S, Brizzolari A, Balestra C, Camporesi EM, Bosco G. Oxy-Inflammation in Humans during Underwater Activities. Int J Mol Sci 2024; 25:3060. [PMID: 38474303 DOI: 10.3390/ijms25053060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 02/22/2024] [Accepted: 03/01/2024] [Indexed: 03/14/2024] Open
Abstract
Underwater activities are characterized by an imbalance between reactive oxygen/nitrogen species (RONS) and antioxidant mechanisms, which can be associated with an inflammatory response, depending on O2 availability. This review explores the oxidative stress mechanisms and related inflammation status (Oxy-Inflammation) in underwater activities such as breath-hold (BH) diving, Self-Contained Underwater Breathing Apparatus (SCUBA) and Closed-Circuit Rebreather (CCR) diving, and saturation diving. Divers are exposed to hypoxic and hyperoxic conditions, amplified by environmental conditions, hyperbaric pressure, cold water, different types of breathing gases, and air/non-air mixtures. The "diving response", including physiological adaptation, cardiovascular stress, increased arterial blood pressure, peripheral vasoconstriction, altered blood gas values, and risk of bubble formation during decompression, are reported.
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Affiliation(s)
- Alessandra Vezzoli
- Institute of Clinical Physiology-National Research Council (CNR-IFC), 20142 Milano, Italy
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
| | - Simona Mrakic-Sposta
- Institute of Clinical Physiology-National Research Council (CNR-IFC), 20142 Milano, Italy
| | - Andrea Brizzolari
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
| | - Costantino Balestra
- Environmental, Occupational, Aging (Integrative) Physiology Laboratory, Haute Ecole Bruxelles-Brabant (HE2B), 1160 Brussels, Belgium
- Physical Activity Teaching Unit, Motor Sciences Department, Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium
- DAN Europe Research Division (Roseto-Brussels), 1160 Brussels, Belgium
| | | | - Gerardo Bosco
- Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
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Yang M, Zhang C. The role of innate immunity in diabetic nephropathy and their therapeutic consequences. J Pharm Anal 2024; 14:39-51. [PMID: 38352948 PMCID: PMC10859537 DOI: 10.1016/j.jpha.2023.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 07/12/2023] [Accepted: 09/05/2023] [Indexed: 02/16/2024] Open
Abstract
Diabetic nephropathy (DN) is an enduring condition that leads to inflammation and affects a substantial number of individuals with diabetes worldwide. A gradual reduction in glomerular filtration and emergence of proteins in the urine are typical aspects of DN, ultimately resulting in renal failure. Mounting evidence suggests that immunological and inflammatory factors are crucial for the development of DN. Therefore, the activation of innate immunity by resident renal and immune cells is critical for initiating and perpetuating inflammation. Toll-like receptors (TLRs) are an important group of receptors that identify patterns and activate immune responses and inflammation. Meanwhile, inflammatory responses in the liver, pancreatic islets, and kidneys involve inflammasomes and chemokines that generate pro-inflammatory cytokines. Moreover, the activation of the complement cascade can be triggered by glycated proteins. This review highlights recent findings elucidating how the innate immune system contributes to tissue fibrosis and organ dysfunction, ultimately leading to renal failure. This review also discusses innovative approaches that can be utilized to modulate the innate immune responses in DN for therapeutic purposes.
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Affiliation(s)
- Min Yang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
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Bhatia D, Choi ME. Autophagy and mitophagy: physiological implications in kidney inflammation and diseases. Am J Physiol Renal Physiol 2023; 325:F1-F21. [PMID: 37167272 PMCID: PMC10292977 DOI: 10.1152/ajprenal.00012.2023] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 04/25/2023] [Accepted: 05/09/2023] [Indexed: 05/13/2023] Open
Abstract
Autophagy is a ubiquitous intracellular cytoprotective quality control program that maintains cellular homeostasis by recycling superfluous cytoplasmic components (lipid droplets, protein, or glycogen aggregates) and invading pathogens. Mitophagy is a selective form of autophagy that by recycling damaged mitochondrial material, which can extracellularly act as damage-associated molecular patterns, prevents their release. Autophagy and mitophagy are indispensable for the maintenance of kidney homeostasis and exert crucial functions during both physiological and disease conditions. Impaired autophagy and mitophagy can negatively impact the pathophysiological state and promote its progression. Autophagy helps in maintaining structural integrity of the kidney. Mitophagy-mediated mitochondrial quality control is explicitly critical for regulating cellular homeostasis in the kidney. Both autophagy and mitophagy attenuate inflammatory responses in the kidney. An accumulating body of evidence highlights that persistent kidney injury-induced oxidative stress can contribute to dysregulated autophagic and mitophagic responses and cell death. Autophagy and mitophagy also communicate with programmed cell death pathways (apoptosis and necroptosis) and play important roles in cell survival by preventing nutrient deprivation and regulating oxidative stress. Autophagy and mitophagy are activated in the kidney after acute injury. However, their aberrant hyperactivation can be deleterious and cause tissue damage. The findings on the functions of autophagy and mitophagy in various models of chronic kidney disease are heterogeneous and cell type- and context-specific dependent. In this review, we discuss the roles of autophagy and mitophagy in the kidney in regulating inflammatory responses and during various pathological manifestations.
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Affiliation(s)
- Divya Bhatia
- Division of Nephrology and Hypertension, Joan and Sanford I. Weill Department of Medicine, NewYork-Presbyterian Hospital, Weill Cornell Medicine, New York, New York, United States
| | - Mary E Choi
- Division of Nephrology and Hypertension, Joan and Sanford I. Weill Department of Medicine, NewYork-Presbyterian Hospital, Weill Cornell Medicine, New York, New York, United States
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11
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Huang J, Shi L, Xia Y, Zhu J, Zha H, Wu X, Song Z. S100-A8/A9 activated TLR4 in renal tubular cells to promote ischemia-reperfusion injury and fibrosis. Int Immunopharmacol 2023; 118:110110. [PMID: 37028272 DOI: 10.1016/j.intimp.2023.110110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 02/22/2023] [Accepted: 03/26/2023] [Indexed: 04/09/2023]
Abstract
Renal ischemia/reperfusion injury (IRI) is a significant clinical problem without effective therapy. Unbiased omics approaches may reveal key renal mediators to initiate IRI. S100-A8/A9 was identified as the most significantly upregulated gene and protein base on proteomic analysis and RNA sequencing during the early reperfusion stage. S100-A8/A9 levels were significantly increased 1 day after transplantation in patients with donation after brain death (DBD). S100-A8/A9 production was associated with CD11b+Ly6G+ CXCR2+ immunocytes infiltration. Administration of S100-A8/A9 blocker ABR238901 significantly alleviates renal tubular injury, inflammatory cell infiltration, and renal fibrosis after renal IRI. Mechanistically, S100-A8/A9 could promote renal tubular cell injury and profibrotic cytokine production via TLR4. In conclusion, our findings found that early activation of S100-A8/A9 in renal IRI and targeting S100-A8/A9 signaling alleviates tubular injury and inhibits inflammatory response and renal fibrosis, which may provide a novel target for the prevention and treatment of acute kidney injury.
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Affiliation(s)
- Jing Huang
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Lang Shi
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Yao Xia
- Department of Nephrology, The First Clinical Medical College of Three Gorges University, Center People's Hospital of Yichang, Yichang, Hubei 443000, China
| | - Jiefu Zhu
- Department of Organ transplantation, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Hongchu Zha
- Department of Nephrology, The First Clinical Medical College of Three Gorges University, Center People's Hospital of Yichang, Yichang, Hubei 443000, China
| | - Xiongfei Wu
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
| | - Zhixia Song
- Department of Nephrology, The First Clinical Medical College of Three Gorges University, Center People's Hospital of Yichang, Yichang, Hubei 443000, China.
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12
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Yiu W, Lok S, Xue R, Chen J, Lai K, Lan H, Tang S. The long noncoding RNA Meg3 mediates TLR4-induced inflammation in experimental obstructive nephropathy. Clin Sci (Lond) 2023; 137:317-331. [PMID: 36705251 PMCID: PMC9977690 DOI: 10.1042/cs20220537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 01/25/2023] [Accepted: 01/27/2023] [Indexed: 01/28/2023]
Abstract
Kidney inflammation contributes to the progression of chronic kidney disease (CKD). Modulation of Toll-like receptor 4 (TLR4) signaling is a potential therapeutic strategy for this pathology, but the regulatory mechanisms of TLR4 signaling in kidney tubular inflammation remains unclear. Here, we demonstrated that tubule-specific deletion of TLR4 in mice conferred protection against obstruction-induced kidney injury, with reduction in inflammatory cytokine production, macrophage infiltration and kidney fibrosis. Transcriptome analysis revealed a marked down-regulation of long noncoding RNA (lncRNA) Meg3 in the obstructed kidney from tubule-specific TLR4 knockout mice compared with wild-type control. Meg3 was also induced by lipopolysaccharide in tubular epithelial cells via a p53-dependent signaling pathway. Silencing of Meg3 suppressed LPS-induced cytokine production of CCL-2 and CXCL-2 and the activation of p38 MAPK pathway in vitro and ameliorated kidney fibrosis in mice with obstructive nephropathy. Together, these findings identify a proinflammatory role of lncRNA Meg3 in CKD and suggest a novel regulatory pathway in TLR4-driven inflammatory responses in tubular epithelial cells.
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Affiliation(s)
- Wai Han Yiu
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Sarah W.Y. Lok
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Rui Xue
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Jiaoyi Chen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Kar Neng Lai
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Hui Yao Lan
- Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
| | - Sydney C.W. Tang
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
- Correspondence: Sydney C.W. Tang ()
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13
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Huang J, Zhang Y, Lin T, Yin H, Pan Y, Zhu M, Zhang M. A cell-permeable peptide inhibitor of p55PIK signaling alleviates suture-induced corneal neovascularization and inflammation. Heliyon 2023; 9:e14869. [PMID: 37095989 PMCID: PMC10121607 DOI: 10.1016/j.heliyon.2023.e14869] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/17/2023] [Accepted: 03/21/2023] [Indexed: 04/03/2023] Open
Abstract
To prepare an ophthalmic solution with a cell-permeable TAT peptide (TAT-N24) as the main cell-permeable peptide inhibitor of p55PIK signaling and observe its therapeutic effect on suture-induced corneal neovascularization (CNV) in rats. Sprague-Dawley rats were used to establish a corneal suture (CS) model of CNV. The vehicle and 0.9% TAT-N24 ophthalmic solution was topically administered. CNV induction was assessed on the basis of the clinical performance of each group. Hematoxylin-eosin staining was used to observe pathological changes, and immunohistochemical staining and confocal immunofluorescence were used to determine the localization of factors associated with corneal tissue. The mRNA expression levels of hypoxia-inducible factor (HIF-1α), vascular endothelial growth factor (VEGF-A), nuclear transcription factor κB (NF-κB p65), tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and interleukin (IL)-6 were determined using real-time quantitative polymerase chain reaction. Western blotting was performed to detect the protein expression levels of HIF-1α and NF-κB p65. TAT-N24 slowed CNV production and reduced the expression of HIF-1α and inflammatory factors in CS models. The mRNA levels of HIF-1α, VEGF-A, NF-kB, TNF-α, IL-1β, and IL-6 significantly decreased. Moreover, the protein levels of HIF-1α and NF-κB p65 were significantly decreased. TAT-N24 can treat CNV and ocular inflammation by inhibiting the HIF-1α/NF-κB signaling pathway in CS. In the early treatment of corneal foreign body trauma, topical application of TAT-N24 can not only reduce the inflammatory response but also inhibit corneal neovascularization.
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14
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Rao JS, Pruett TL. Immunology of the transplanted cryopreserved kidney. Cryobiology 2023; 110:1-7. [PMID: 36640932 DOI: 10.1016/j.cryobiol.2023.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/28/2022] [Accepted: 01/10/2023] [Indexed: 01/13/2023]
Abstract
Transplantation has substituted dysfunctional organs with healthy organs from donors to significantly lower morbidity and mortality associated with end-stage organ disease. Since the advent of transplantation, the promise of functional replacement has attracted an exponential mismatch between organ supply and demand. Theoretical proposals to counter the increasing needs have either been to create a source through genetic engineering of porcine donors for xenotransplantation (with more potent immunosuppression protocols) or recreate one's organ in a pig using interspecies blastocyst complementation for exogenic organ transplantation (without immunosuppression). Another promising avenue has been organ banking through cryopreservation for transplantation. Although ice free preservation and acceptable early function following rewarming is critical for success in transplantation, the immunological response that predominantly defines short- and long-term graft survival has failed to captivate attention to date. It is well sorted that thermal and metabolic stress incurred at 4 °C during recovery and reperfusion of organs for clinical transplantation has varying impact on graft survival. Considering the magnitude of cellular imbalance and injury at sub-zero/ultralow temperatures in addition to the chemical toxicity of cryoprotective agents (CPA), it is essential to assess and address the immunological response associated following transplantation to maximize the success of cryopreservation.
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Affiliation(s)
- Joseph Sushil Rao
- Division of Solid Organ Transplantation, Department of Surgery, University of Minnesota, Minneapolis, MN, USA; Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
| | - Timothy L Pruett
- Division of Solid Organ Transplantation, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
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15
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Kostyo J, Lallande AT, Sells CA, Shuda MR, Kane RR. Sulfonamide Prodrugs with a Two-Stage Release Mechanism for the Efficient Delivery of the TLR4 Antagonist TAK-242. ACS Med Chem Lett 2023; 14:110-115. [PMID: 36660224 PMCID: PMC9841982 DOI: 10.1021/acsmedchemlett.2c00492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022] Open
Abstract
We previously demonstrated that the potent TLR4 inhibitor TAK-242 could be covalently conjugated to pancreatic islets using a linker that afforded an effective sustained delivery of the active drug after transplant. This drug-eluting tissue achieved local inhibition of TLR4-linked inflammation and proved beneficial to the islet graft survival. Here, we describe a new family of prodrugs with a modular design featuring a self-immolative para-aminobenzyl spacer bonded directly to the TAK-242 sulfonamide nitrogen, a tether for bioconjugation, and a β-eliminative arylsulfone "trigger". The inclusion of the para-aminobenzyl spacer affords a more stable prodrug which exhibits complex drug-release kinetics due to a two-stage release mechanism. This manuscript reports the preparation and characterization of several TAK-242 prodrugs fitted with different triggers and linkers and demonstrates that these second-generation prodrugs effectively release TAK-242 while avoiding nonproductive sulfonamide hydrolysis.
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Affiliation(s)
- Jessica
H. Kostyo
- Department
of Chemistry and Biochemistry, Baylor University, Waco, Texas76798, United States
| | - Avery T. Lallande
- Department
of Chemistry and Biochemistry, Baylor University, Waco, Texas76798, United States
| | - Chloë A. Sells
- Department
of Chemistry and Biochemistry, Baylor University, Waco, Texas76798, United States
| | - Mina R. Shuda
- Department
of Chemistry and Biochemistry, Baylor University, Waco, Texas76798, United States
| | - Robert R. Kane
- Department
of Chemistry and Biochemistry, Baylor University, Waco, Texas76798, United States
- Institute
of Biomedical Studies, Baylor University, Waco, Texas76798, United States
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16
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Vallés PG, Gil Lorenzo AF, Garcia RD, Cacciamani V, Benardon ME, Costantino VV. Toll-like Receptor 4 in Acute Kidney Injury. Int J Mol Sci 2023; 24:ijms24021415. [PMID: 36674930 PMCID: PMC9864062 DOI: 10.3390/ijms24021415] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 12/06/2022] [Accepted: 12/13/2022] [Indexed: 01/13/2023] Open
Abstract
Acute kidney injury (AKI) is a common and devastating pathologic condition, associated with considerable high morbidity and mortality. Although significant breakthroughs have been made in recent years, to this day no effective pharmacological therapies for its treatment exist. AKI is known to be connected with intrarenal and systemic inflammation. The innate immune system plays an important role as the first defense response mechanism to tissue injury. Toll-like receptor 4 (TLR4) is a well-characterized pattern recognition receptor, and increasing evidence has shown that TLR4 mediated inflammatory response, plays a pivotal role in the pathogenesis of acute kidney injury. Pathogen-associated molecular patterns (PAMPS), which are the conserved microbial motifs, are sensed by these receptors. Endogenous molecules generated during tissue injury, and labeled as damage-associated molecular pattern molecules (DAMPs), also activate pattern recognition receptors, thereby offering an understanding of sterile types of inflammation. Excessive, uncontrolled and/or sustained activation of TLR4, may lead to a chronic inflammatory state. In this review we describe the role of TLR4, its endogenous ligands and activation in the inflammatory response to ischemic/reperfusion-induced AKI and sepsis-associated AKI. The potential regeneration signaling patterns of TLR4 in acute kidney injury, are also discussed.
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Affiliation(s)
- Patricia G. Vallés
- Área de Fisiopatología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Centro Universitario, Mendoza 5500, Argentina
- IMBECU-CONICET (Instituto de Medicina y Biología Experimental de Cuyo—Consejo Nacional de Investigaciones Científicas y Técnicas), Mendoza 5500, Argentina
- Correspondence:
| | - Andrea Fernanda Gil Lorenzo
- Área de Fisiopatología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Centro Universitario, Mendoza 5500, Argentina
| | - Rodrigo D. Garcia
- Área de Fisiopatología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Centro Universitario, Mendoza 5500, Argentina
| | - Valeria Cacciamani
- IMBECU-CONICET (Instituto de Medicina y Biología Experimental de Cuyo—Consejo Nacional de Investigaciones Científicas y Técnicas), Mendoza 5500, Argentina
| | - María Eugenia Benardon
- Área de Fisiopatología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Centro Universitario, Mendoza 5500, Argentina
| | - Valeria Victoria Costantino
- IMBECU-CONICET (Instituto de Medicina y Biología Experimental de Cuyo—Consejo Nacional de Investigaciones Científicas y Técnicas), Mendoza 5500, Argentina
- Área de Biología Celular, Departamento de Morfofisiología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Centro Universitario, Mendoza 5500, Argentina
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17
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Toll-like receptors 2 and 4 stress signaling and sodium-glucose cotransporter-2 in kidney disease. Mol Cell Biochem 2022:10.1007/s11010-022-04652-5. [PMID: 36586092 DOI: 10.1007/s11010-022-04652-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 12/23/2022] [Indexed: 01/01/2023]
Abstract
Kidney disease is the 6th fastest-growing cause of death and a serious global health concern that urges effective therapeutic options. The inflammatory response is an initial reaction from immune and parenchymal cells in kidney diseases. Toll-like receptors (TLR) 2 and 4 are highly expressed by various kidney cells and respond to 'signaling danger' proteins, such as high mobility group box binding protein 1 (HMGB1) and prompt the progression of kidney disease by releasing inflammatory mediators. Burgeoning reports suggest that both SGLT2 and ER stress elevates TLR2/4 signaling via different axis. Moreover, SGLT2 signaling aggravates inflammation under the disease condition by promoting the NLR family pyrin domain-containing three inflammasomes and ER stress. Intriguingly, TLR2/4 downstream adaptors activate ER stress regulators. The above-discussed interactions imply that TLR2/4 does more than immune response during kidney disease. Here, we discuss in detail evidence of the roles and regulation of TLR2/4 in the context of a relationship between ER stress and SGLT2. Also, we highlighted different preclinical studies of SGLT2 inhibitors against TLR2/4 signaling in various kidney diseases. Moreover, we discuss the observational and interventional evidence about the relation between TLR2/4, ER stress, and SGLT2, which may represent the TLR2/4 as a potential therapeutic target for kidney disease.
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18
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Chandran S, Tang Q. Impact of interleukin-6 on T cells in kidney transplant recipients. Am J Transplant 2022; 22 Suppl 4:18-27. [PMID: 36453710 DOI: 10.1111/ajt.17209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 09/23/2022] [Indexed: 12/02/2022]
Abstract
Interleukin-6 (IL-6), a multifunctional proinflammatory cytokine, plays a key role in T cell activation, survival, and differentiation. Acting as a switch that induces the differentiation of naïve T cells into Th17 cells and inhibits their development into regulatory T cells, IL-6 promotes rejection and abrogates tolerance. Therapies that target IL-6 signaling include antibodies to IL-6 and the IL-6 receptor and inhibitors of janus kinases; several of these therapeutics have demonstrated robust clinical efficacy in autoimmune and inflammatory diseases. Clinical trials of IL-6 inhibition in kidney transplantation have focused primarily on its effects on B cells, plasma cells, and HLA antibodies. In this review, we summarize the impact of IL-6 on T cells in experimental models of transplant and describe the effects of IL-6 inhibition on the T cell compartment in kidney transplant recipients.
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Affiliation(s)
- Sindhu Chandran
- Department of Medicine, University of California San Francisco, San Francisco, California, USA
| | - Qizhi Tang
- Department of Surgery, Diabetes Center, Gladstone-UCSF Institute of Genome Immunology, University of California San Francisco, San Francisco, California, USA
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19
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Shepherd HM, Gauthier JM, Terada Y, Li W, Krupnick AS, Gelman AE, Kreisel D. Updated Views on Neutrophil Responses in Ischemia-Reperfusion Injury. Transplantation 2022; 106:2314-2324. [PMID: 35749228 PMCID: PMC9712152 DOI: 10.1097/tp.0000000000004221] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Ischemia-reperfusion injury is an inevitable event during organ transplantation and represents a primary risk factor for the development of early graft dysfunction in lung, heart, liver, and kidney transplant recipients. Recent studies have implicated recipient neutrophils as key mediators of this process and also have found that early innate immune responses after transplantation can ultimately augment adaptive alloimmunity and affect late graft outcomes. Here, we discuss signaling pathways involved in neutrophil recruitment and activation after ischemia-mediated graft injury in solid organ transplantation with an emphasis on lung allografts, which have been the focus of recent studies. These findings suggest novel therapeutic interventions that target ischemia-reperfusion injury-mediated graft dysfunction in transplant recipients.
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Affiliation(s)
- Hailey M. Shepherd
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO
| | - Jason M. Gauthier
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO
| | - Yuriko Terada
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO
| | - Wenjun Li
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO
| | | | - Andrew E. Gelman
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO
| | - Daniel Kreisel
- Department of Surgery, Washington University School of Medicine, Saint Louis, MO
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO
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20
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Renoprotective effects of oleanolic acid and its possible mechanisms in rats with diabetic kidney disease. Biochem Biophys Res Commun 2022; 636:1-9. [DOI: 10.1016/j.bbrc.2022.10.074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 10/20/2022] [Accepted: 10/20/2022] [Indexed: 11/19/2022]
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21
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Lu TY, Xu XL, Du XG, Wei JH, Yu JN, Deng SL, Qin C. Advances in Innate Immunity to Overcome Immune Rejection during Xenotransplantation. Cells 2022; 11:cells11233865. [PMID: 36497122 PMCID: PMC9735653 DOI: 10.3390/cells11233865] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/26/2022] [Accepted: 11/28/2022] [Indexed: 12/03/2022] Open
Abstract
Transplantation is an effective approach for treating end-stage organ failure. There has been a long-standing interest in xenotransplantation as a means of increasing the number of available organs. In the past decade, there has been tremendous progress in xenotransplantation accelerated by the development of rapid gene-editing tools and immunosuppressive therapy. Recently, the heart and kidney from pigs were transplanted into the recipients, which suggests that xenotransplantation has entered a new era. The genetic discrepancy and molecular incompatibility between pigs and primates results in barriers to xenotransplantation. An increasing body of evidence suggests that innate immune responses play an important role in all aspects of the xenogeneic rejection. Simultaneously, the role of important cellular components like macrophages, natural killer (NK) cells, and neutrophils, suggests that the innate immune response in the xenogeneic rejection should not be underestimated. Here, we summarize the current knowledge about the innate immune system in xenotransplantation and highlight the key issues for future investigations. A better understanding of the innate immune responses in xenotransplantation may help to control the xenograft rejection and design optimal combination therapies.
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Affiliation(s)
- Tian-Yu Lu
- NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, International Center for Technology and Innovation of animal model, Beijing 100021, China
| | - Xue-Ling Xu
- National Engineering Laboratory of Animal Breeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Xu-Guang Du
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Jin-Hua Wei
- Cardiovascular Surgery Department, Center of Laboratory Medicine, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
| | - Jia-Nan Yu
- NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, International Center for Technology and Innovation of animal model, Beijing 100021, China
| | - Shou-Long Deng
- NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, International Center for Technology and Innovation of animal model, Beijing 100021, China
- Correspondence: (S.-L.D.); (C.Q.)
| | - Chuan Qin
- NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, International Center for Technology and Innovation of animal model, Beijing 100021, China
- Changping National Laboratory (CPNL), Beijing 102206, China
- Correspondence: (S.-L.D.); (C.Q.)
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22
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Immune response associated with ischemia and reperfusion injury during organ transplantation. Inflamm Res 2022; 71:1463-1476. [PMID: 36282292 PMCID: PMC9653341 DOI: 10.1007/s00011-022-01651-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 09/20/2022] [Accepted: 09/21/2022] [Indexed: 12/03/2022] Open
Abstract
Background Ischemia and reperfusion injury (IRI) is an ineluctable immune-related pathophysiological process during organ transplantation, which not only causes a shortage of donor organs, but also has long-term and short-term negative consequences on patients. Severe IRI-induced cell death leads to the release of endogenous substances, which bind specifically to receptors on immune cells to initiate an immune response. Although innate and adaptive immunity have been discovered to play essential roles in IRI in the context of organ transplantation, the pathway and precise involvement of the immune response at various stages has not yet to be elucidated. Methods We combined “IRI” and “organ transplantation” with keywords, respectively such as immune cells, danger signal molecules, macrophages, neutrophils, natural killer cells, complement cascade, T cells or B cells in PubMed and the Web of Science to search for relevant literatures. Conclusion Comprehension of the immune mechanisms involved in organ transplantation is promising for the treatment of IRI, this review summarizes the similarities and differences in both innate and adaptive immunity and advancements in the immune response associated with IRI during diverse organ transplantation.
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23
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Tan Z, Wang L, Li X. Composition and regulation of the immune microenvironment of salivary gland in Sjögren’s syndrome. Front Immunol 2022; 13:967304. [PMID: 36177010 PMCID: PMC9513852 DOI: 10.3389/fimmu.2022.967304] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by exocrine gland dysfunction and inflammation. Patients often have dry mouth and dry eye symptoms, which seriously affect their lives. Improving dry mouth and eye symptoms has become a common demand from patients. For this reason, researchers have conducted many studies on external secretory glands. In this paper, we summarize recent studies on the salivary glands of pSS patients from the perspective of the immune microenvironment. These studies showed that hypoxia, senescence, and chronic inflammation are the essential characteristics of the salivary gland immune microenvironment. In the SG of pSS, genes related to lymphocyte chemotaxis, antigen presentation, and lymphocyte activation are upregulated. Interferon (IFN)-related genes, DNA methylation, sRNA downregulation, and mitochondrial-related differentially expressed genes are also involved in forming the immune microenvironment of pSS, while multiple signaling pathways are involved in regulation. We further elucidated the regulation of the salivary gland immune microenvironment in pSS and relevant, targeted treatments.
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Kynurenine Pathway-An Underestimated Factor Modulating Innate Immunity in Sepsis-Induced Acute Kidney Injury? Cells 2022; 11:cells11162604. [PMID: 36010680 PMCID: PMC9406744 DOI: 10.3390/cells11162604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/17/2022] [Accepted: 08/17/2022] [Indexed: 11/17/2022] Open
Abstract
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, and it accounts for about half of the cases of acute kidney injury (AKI). Although sepsis is the most frequent cause of AKI in critically ill patients, its pathophysiological mechanisms are not well understood. Sepsis has the ability to modulate the function of cells belonging to the innate immune system. Increased activity of indoleamine 2,3-dioxygenase 1 (IDO1) and production of kynurenines are the major metabolic pathways utilized by innate immunity cells to maintain immunological tolerance. The activation of the kynurenine pathway (KP) plays a dual role in sepsis—in the early stage, the induction of IDO1 elicits strong proinflammatory effects that may lead to tissue damage and septic shock. Afterwards, depletion of tryptophan and production of kynurenines contribute to the development of immunosuppression that may cause the inability to overpower opportunistic infections. The presented review provides available data on the various interdependencies between elements of innate immunity and sepsis-induced AKI (SAKI) with particular emphasis on the immunomodulatory significance of KP in the above processes. We believe that KP activation may be one of the crucial, though underestimated, components of a deregulated host response to infection during SAKI.
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25
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Guo M, Ji X, Liu J. Hypoxia and Alpha-Synuclein: Inextricable Link Underlying the Pathologic Progression of Parkinson's Disease. Front Aging Neurosci 2022; 14:919343. [PMID: 35959288 PMCID: PMC9360429 DOI: 10.3389/fnagi.2022.919343] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 06/22/2022] [Indexed: 11/13/2022] Open
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, with typical motor symptoms as the main clinical manifestations. At present, there are about 10 million patients with PD in the world, and its comorbidities and complications are numerous and incurable. Therefore, it is particularly important to explore the pathogenesis of PD and find possible therapeutic targets. Because the etiology of PD is complex, involving genes, environment, and aging, finding common factors is the key to identifying intervention targets. Hypoxia is ubiquitous in the natural environment and disease states, and it is considered to be closely related to the etiology of PD. Despite research showing that hypoxia increases the expression and aggregation of alpha-synuclein (α-syn), the most important pathogenic protein, there is still a lack of systematic studies on the role of hypoxia in α-syn pathology and PD pathogenesis. Considering that hypoxia is inextricably linked with various causes of PD, hypoxia may be a co-participant in many aspects of the PD pathologic process. In this review, we describe the risk factors for PD, and we discuss the possible role of hypoxia in inducing PD pathology by these risk factors. Furthermore, we attribute the pathological changes caused by PD etiology to oxygen uptake disorder and oxygen utilization disorder, thus emphasizing the possibility of hypoxia as a critical link in initiating or promoting α-syn pathology and PD pathogenesis. Our study provides novel insight for exploring the pathogenesis and therapeutic targets of PD.
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Affiliation(s)
- Mengyuan Guo
- Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Beijing Advanced Innovation Center for Big Data-based Precision Medicine, Capital Medical University, Beijing, China
| | - Xunming Ji
- Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Beijing Advanced Innovation Center for Big Data-based Precision Medicine, Capital Medical University, Beijing, China
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Xunming Ji
| | - Jia Liu
- Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Beijing Advanced Innovation Center for Big Data-based Precision Medicine, Capital Medical University, Beijing, China
- *Correspondence: Jia Liu
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26
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Kwong AM, Luke PPW, Bhattacharjee RN. Carbon monoxide mechanism of protection against renal ischemia and reperfusion injury. Biochem Pharmacol 2022; 202:115156. [PMID: 35777450 DOI: 10.1016/j.bcp.2022.115156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 12/20/2022]
Abstract
Carbon monoxide is quickly moving past its historic label as a molecule once feared, to a therapeutic drug that modulates inflammation. The development of carbon monoxide releasing molecules and utilization of heme oxygenase-1 inducers have shown carbon monoxide to be a promising therapy in reducing renal ischemia and reperfusion injury and other inflammatory diseases. In this review, we will discuss the developments and application of carbon monoxide releasing molecules in renal ischemia and reperfusion injury, and transplantation. We will review the anti-inflammatory mechanisms of carbon monoxide in respect to mitigating apoptosis, suppressing dendritic cell maturation and signalling, inhibiting toll-like receptor activation, promoting anti-inflammatory responses, and the effects on renal vasculature.
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Affiliation(s)
- Aaron M Kwong
- Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Patrick P W Luke
- Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Surgery, London Health Sciences Centre, Canada; Matthew Mailing Centre for Translational Transplantation Studies, Canada.
| | - Rabindra N Bhattacharjee
- Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Surgery, London Health Sciences Centre, Canada; Matthew Mailing Centre for Translational Transplantation Studies, Canada.
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27
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Garcés-Lázaro I, Kotzur R, Cerwenka A, Mandelboim O. NK Cells Under Hypoxia: The Two Faces of Vascularization in Tumor and Pregnancy. Front Immunol 2022; 13:924775. [PMID: 35769460 PMCID: PMC9234265 DOI: 10.3389/fimmu.2022.924775] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 05/17/2022] [Indexed: 01/14/2023] Open
Abstract
Environmental conditions greatly shape the phenotype and function of immune cells. Specifically, hypoxic conditions that exist within tissues and organs have been reported to affect both the adaptive and the innate immune system. Natural killer (NK) cells belong to the innate immune system. They are among the first immune cells responding to infections and are involved in tumor surveillance. NK cells produce cytokines that shape other innate and adaptive immune cells, and they produce cytolytic molecules leading to target cell killing. Therefore, they are not only involved in steady state tissue homeostasis, but also in pathogen and tumor clearance. Hence, understanding the role of NK cells in pathological and physiological immune biology is an emerging field. To date, it remains incompletely understood how the tissue microenvironment shapes NK cell phenotype and function. In particular, the impact of low oxygen concentrations in tissues on NK cell reactivity has not been systematically dissected. Here, we present a comprehensive review focusing on two highly compelling hypoxic tissue environments, the tumor microenvironment (pathological) and the decidua (physiological) and compare their impact on NK cell reactivity.
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Affiliation(s)
- Irene Garcés-Lázaro
- Department of Immunobiochemistry, Mannheim Institute of Innate Immunosciences (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Rebecca Kotzur
- The Lautenberg Center for General and Tumor Immunology, Institute for Medical Research Israel-Canada, The Hebrew University Hadassah Medical School, Jerusalem, Israel
| | - Adelheid Cerwenka
- Department of Immunobiochemistry, Mannheim Institute of Innate Immunosciences (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- *Correspondence: Adelheid Cerwenka, ; Ofer Mandelboim,
| | - Ofer Mandelboim
- The Lautenberg Center for General and Tumor Immunology, Institute for Medical Research Israel-Canada, The Hebrew University Hadassah Medical School, Jerusalem, Israel
- *Correspondence: Adelheid Cerwenka, ; Ofer Mandelboim,
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28
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Jia P, Xu SJ, Wang X, Wu X, Ren T, Zou Z, Zeng Q, Shen B, Ding X. Chemokine CCL2 from proximal tubular epithelial cells contributes to sepsis-induced acute kidney injury. Am J Physiol Renal Physiol 2022; 323:F107-F119. [PMID: 35658715 DOI: 10.1152/ajprenal.00037.2022] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Damage-associated molecular patterns secreted from activated kidney cells initiate inflammatory response, a critical step in the development of sepsis-induced acute kidney injury (AKI). However, the underlying mechanism remains to be clarified. Here, we established a mouse model of sepsis-induced AKI through intraperitoneal injection of lipopolysaccharide (LPS), and demonstrated that LPS induced dramatical upregulation of C-C motif chemokine ligand 2 (CCL2) at both the mRNA and the protein levels in kidney, which was mainly expressed by tubular epithelial cells (TECs), especially by proximal TECs. Proximal tubule-specific ablation of CCL2 reduced LPS-induced macrophage infiltration, proinflammatory cytokine expression, and attenuated AKI. In vitro, using transwell migration assay, we found that deficiency of CCL2 in TECs decreased macrophage migration ability. However, myeloid-specific depletion of CCL2 could not protect the kidneys from the aforementioned effects. Mechanistically, LPS activated toll like receptor (TLR) 2 signaling in TECs, which induced activation of its downstream effector nuclear factor (NF)-κB. Blockade of TLR2 signaling or inhibition of NF-κB activation in TECs significantly suppressed LPS-induced CCL2 expression. Furthermore, ChIP analyses confirmed a direct binding of NF-κB p65 in the CCL2 promoter regein, and LPS increased the binding of NF-κB p65 to CCL2 promoter, suggesting that TLR2/NF-κB p65 regulates CCL2 expression in TECs. Together, these results demonstrate that endogenous CCL2 released from PTECs, not from myeloid cells was responsible for sepsis-induced kidney inflammation and AKI. Specificly targeting tubular TLR2/NF-κB/CCL2 signaling may be a potential therapeutic strategy for prevention or attenuation of septic AKI.
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Affiliation(s)
- Ping Jia
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Su-Juan Xu
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaoyan Wang
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaoli Wu
- Traditional Chinese Medicine Pharmacology Laboratory, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ting Ren
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhouping Zou
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qi Zeng
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bo Shen
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaoqiang Ding
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Medical Center of Kidney, Shanghai, China.,Kidney and Dialysis Institute of Shanghai, Shanghai, China.,Kidney and Blood Purification Laboratory of Shanghai, Shanghai, China.,Hemodialysis quality control center of Shanghai, Shanghai, China
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29
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Ackland GL, Abbott TEF. Hypotension as a marker or mediator of perioperative organ injury: a narrative review. Br J Anaesth 2022; 128:915-930. [PMID: 35151462 PMCID: PMC9204667 DOI: 10.1016/j.bja.2022.01.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/16/2021] [Accepted: 01/08/2022] [Indexed: 12/21/2022] Open
Abstract
Perioperative hypotension has been repeatedly associated with organ injury and worse outcome, yet many interventions to reduce morbidity by attempting to avoid or reverse hypotension have floundered. In part, this reflects uncertainty as to what threshold of hypotension is relevant in the perioperative setting. Shifting population-based definitions for hypertension, plus uncertainty regarding individualised norms before surgery, both present major challenges in constructing useful clinical guidelines that may help improve clinical outcomes. Aside from these major pragmatic challenges, a wealth of biological mechanisms that underpin the development of higher blood pressure, particularly with increasing age, suggest that hypotension (however defined) or lower blood pressure per se does not account solely for developing organ injury after major surgery. The mosaic theory of hypertension, first proposed more than 60 yr ago, incorporates multiple, complementary mechanistic pathways through which clinical (macrovascular) attempts to minimise perioperative organ injury may unintentionally subvert protective or adaptive pathways that are fundamental in shaping the integrative host response to injury and inflammation. Consideration of the mosaic framework is critical for a more complete understanding of the perioperative response to acute sterile and infectious inflammation. The largely arbitrary treatment of perioperative blood pressure remains rudimentary in the context of multiple complex adaptive hypertensive endotypes, defined by distinct functional or pathobiological mechanisms, including the regulation of reactive oxygen species, autonomic dysfunction, and inflammation. Developing coherent strategies for the management of perioperative hypotension requires smarter, mechanistically solid interventions delivered by RCTs where observer bias is minimised.
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Affiliation(s)
- Gareth L Ackland
- Translational Medicine and Therapeutics, William Harvey Research Institute, Queen Mary University of London, London, UK.
| | - Tom E F Abbott
- Translational Medicine and Therapeutics, William Harvey Research Institute, Queen Mary University of London, London, UK
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30
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Li S, Xu H, Song M, Shaw BI, Li QJ, Kirk AD. IFI16-STING-NF-κB signaling controls exogenous mitochondrion-induced endothelial activation. Am J Transplant 2022; 22:1578-1592. [PMID: 35322536 PMCID: PMC9177674 DOI: 10.1111/ajt.17034] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 02/21/2022] [Accepted: 03/10/2022] [Indexed: 01/25/2023]
Abstract
Mitochondria released from injured cells activate endothelial cells (ECs), fostering inflammatory processes, including allograft rejection. The stimulator of interferon genes (STING) senses endogenous mitochondrial DNA, triggering innate immune activation via NF-κB signaling. Here, we show that exogenous mitochondria exposure induces EC STING-NF-κB activation, promoting EC/effector memory T cell adhesion, which is abrogated by NF-κB and STING inhibitors. STING activation in mitochondrion-activated ECs is independent of canonical cGMP-AMP synthetase sensing/signaling, but rather is mediated by interferon gamma-inducible factor 16 (IFI16) and can be inhibited by IFI16 inhibition. Internalized mitochondria undergo mitofusion and STING-dependent mitophagy, leading to selective sequestration of internalized mitochondria. The exposure of donor hearts to exogenous mitochondria activates murine heart ECs in vivo. Collectively, our results suggest that IFI16-STING-NF-κB signaling regulates exogenous mitochondrion-induced EC activation and mitophagy, and exogenous mitochondria foster T cell-mediated CoBRR. These data suggest a novel, donor-directed, therapeutic approach toward mitigating perioperative allograft immunogenicity.
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Affiliation(s)
- Shu Li
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - He Xu
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine, Durham, NC, USA,To whom correspondence should be addressed: He Xu, MD, Departments of Surgery, Duke University School of Medicine, Edwin Jones Building Room 368, Durham, NC 27710, Phone: (919)684-4371,
| | - Mingqing Song
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - Brian I Shaw
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - Qi-Jing Li
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Allan D Kirk
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine, Durham, NC, USA,Department of Immunology, Duke University School of Medicine, Durham, NC, USA
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31
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Mitochondrial Pathophysiology on Chronic Kidney Disease. Int J Mol Sci 2022; 23:ijms23031776. [PMID: 35163697 PMCID: PMC8836100 DOI: 10.3390/ijms23031776] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/01/2022] [Accepted: 02/02/2022] [Indexed: 02/04/2023] Open
Abstract
In healthy kidneys, interstitial fibroblasts are responsible for the maintenance of renal architecture. Progressive interstitial fibrosis is thought to be a common pathway for chronic kidney diseases (CKD). Diabetes is one of the boosters of CKD. There is no effective treatment to improve kidney function in CKD patients. The kidney is a highly demanding organ, rich in redox reactions occurring in mitochondria, making it particularly vulnerable to oxidative stress (OS). A dysregulation in OS leads to an impairment of the Electron transport chain (ETC). Gene deficiencies in the ETC are closely related to the development of kidney disease, providing evidence that mitochondria integrity is a key player in the early detection of CKD. The development of novel CKD therapies is needed since current methods of treatment are ineffective. Antioxidant targeted therapies and metabolic approaches revealed promising results to delay the progression of some markers associated with kidney disease. Herein, we discuss the role and possible origin of fibroblasts and the possible potentiators of CKD. We will focus on the important features of mitochondria in renal cell function and discuss their role in kidney disease progression. We also discuss the potential of antioxidants and pharmacologic agents to delay kidney disease progression.
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32
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Early Hypertransaminasemia after Kidney Transplantation: Significance and Evolution According to Donor Type. J Clin Med 2021; 10:jcm10215168. [PMID: 34768688 PMCID: PMC8584479 DOI: 10.3390/jcm10215168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/29/2021] [Accepted: 11/01/2021] [Indexed: 11/21/2022] Open
Abstract
Early hypertransaminasemia after kidney transplantation (KT) is frequent. It has been associated with the crosstalk produced between the liver and the kidney in ischemia-reperfusion situations. However, the influence of the donor type has not been evaluated. We present a retrospective study analyzing the increase in serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) during the first three months post-KT in 151 recipients who received thymoglobulin as induction therapy, either from brain-death donors (DBD, n = 75), controlled circulatory death donors (cDCD, n = 33), or uncontrolled DCD (uDCD, n = 43). Eighty-five KT recipients from DBD who received basiliximab were included as controls. From KT recipients who received thymoglobulin, 33.6/43.4% presented with an increase in AST/ALT at 72 h post-KT, respectively. Regarding donor type, the percentage of recipients who experienced 72 h post-KT hypertransaminasemia was higher in uDCD group (65.1/83.7% vs. 20.3/26% in DBD and 20.7/27.6% in cDCD, p < 0.001). Within the control group, 9.4/12.9% of patients presented with AST/ALT elevation. One month after transplant, AST/ALT values returned to baseline in all groups. The multivariate analysis showed that uDCD recipients had 6- to 12-fold higher risk of developing early post-KT hypertransaminasemia. Early post-KT hypertransaminasemia is a frequent and transient event related to the kidney donor type, being more frequent in uDCD recipients.
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33
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Wu Z, Liang J, Huang W, Jiang L, Paul C, Lin B, Zheng J, Wang Y. Prompt Graft Cooling Enhances Cardioprotection during Heart Transplantation Procedures through the Regulation of Mitophagy. Cells 2021; 10:2912. [PMID: 34831135 PMCID: PMC8616468 DOI: 10.3390/cells10112912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 10/11/2021] [Accepted: 10/22/2021] [Indexed: 11/22/2022] Open
Abstract
A complete and prompt cardiac arrest using a cold cardioplegic solution is routinely used in heart transplantation to protect the graft function. However, warm ischemic time is still inevitable during the procedure to isolate donor hearts in the clinical setting. Our knowledge of the mechanism changes prevented by cold storage, and how warm ischemia damages donor hearts, is extremely poor. The potential consequences of this inevitable warm ischemic time to grafts, and the underlying potential protective mechanism of prompt graft cooling, have been studied in order to explore an advanced graft protection strategy. To this end, a surgical procedure, including 10-15 min warm ischemic time during procurement, was performed in mouse models to mimic the clinical situation (Group I), and compared to a group of mice that had the procurement performed with prompt cooling procedures (Group II). The myocardial morphologic changes (including ultrastructure) were then assessed by electron and optical microscopy after 6 h of cold preservation. Furthermore, syngeneic heart transplantation was performed after 6 h of cold preservation to measure the graft heart function. An electron microscopy showed extensive damage, including hypercontracted myofibers with contraction bands, and damaged mitochondria that released mitochondrial contents in Group I mice, while similar patterns of damage were not observed in the mice from Group II. The results from both the electron microscopy and immunoblotting verified that cardiac mitophagy (protective mitochondrial autophagy) was present in the mice from Group II, but was absent in the mice from Group I. Moreover, the mice from Group II demonstrated faster rebeating times and higher beating scores, as compared to the mice from Group I. The pressure catheter system results indicated that the graft heart function was significantly more improved in the mice from Group II than in those from Group I, as demonstrated by the left ventricle systolic pressure (31.96 ± 6.54 vs. 26.12 ± 8.87 mmHg), the +dp/dt (815.6 ± 215.4 vs. 693.9 ± 153.8 mmHg/s), and the -dp/dt: (492.4 ± 92.98 vs. 418.5 ± 118.9 mmHg/s). In conclusion, the warm ischemic time during the procedure impaired the graft function and destroyed the activation of mitophagy. Thus, appropriate mitophagy activation has emerged as a promising therapeutic target that may be essential for graft protection and functional improvement during heart transplantation.
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Affiliation(s)
- Zhichao Wu
- Department of Cardiovascular Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China;
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; (J.L.); (W.H.); (L.J.); (C.P.); (B.L.)
| | - Jialiang Liang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; (J.L.); (W.H.); (L.J.); (C.P.); (B.L.)
| | - Wei Huang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; (J.L.); (W.H.); (L.J.); (C.P.); (B.L.)
| | - Lin Jiang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; (J.L.); (W.H.); (L.J.); (C.P.); (B.L.)
| | - Christian Paul
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; (J.L.); (W.H.); (L.J.); (C.P.); (B.L.)
| | - Bonnie Lin
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; (J.L.); (W.H.); (L.J.); (C.P.); (B.L.)
| | - Junmeng Zheng
- Department of Cardiovascular Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China;
| | - Yigang Wang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; (J.L.); (W.H.); (L.J.); (C.P.); (B.L.)
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34
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Wang Y, Li Y, Xu Y. Pyroptosis in Kidney Disease. J Mol Biol 2021; 434:167290. [PMID: 34626644 DOI: 10.1016/j.jmb.2021.167290] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 09/24/2021] [Accepted: 09/29/2021] [Indexed: 01/06/2023]
Abstract
In the last several decades, apoptosis interference has been considered clinically irrelevant in the context of renal injury. Recent discovery of programmed necrotic cell death, including necroptosis, ferroptosis, and pyroptosis refreshed our understanding of the role of cell death in kidney disease. Pyroptosis is characterized by a lytic pro- inflammatory type of cell death resulting from gasdermin-induced membrane permeabilization via activation of inflammatory caspases and inflammasomes. The danger-associated molecular patterns (DAMPs), alarmins and pro-inflammatory cytokines are released from pyroptotic cells in an uncontrolled manner, which provoke inflammation, resulting in secondary organ or tissue injuries. The caspases and inflammasome activation-related proteins and pore-forming effector proteins known as GSDMD and GSDME have been implicated in a variety of acute and chronic microbial and non-microbial kidney diseases. Here, we review the recent advances in pathological mechanisms of pyroptosis in kidney disease and highlight the potential therapeutic strategies in future.
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Affiliation(s)
- Yujia Wang
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Yinshuang Li
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Yanfang Xu
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
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35
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Batal I, Serban G, Mohan S, Husain SA, Vasilescu ER, Crew RJ, Dube G, Sandoval PR, Coley SM, Santoriello D, Stokes MB, D'Agati VD, Cohen DJ, Markowitz G, Hardy MA, Ratner LE. The clinical significance of receiving a kidney allograft from deceased donor with chronic histologic changes. Mod Pathol 2021; 34:1795-1805. [PMID: 33986461 DOI: 10.1038/s41379-021-00815-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 04/03/2021] [Accepted: 04/04/2021] [Indexed: 12/22/2022]
Abstract
Allograft survival of deceased donor kidneys with suboptimal histology (DRTx/suboptimal histology: >10% glomerulosclerosis, >10% tubulointerstitial scarring, or >mild vascular sclerosis) is inferior to both DRTx with optimal histology (DRTx/optimal histology) and living donor kidneys irrespective of histologic changes (LRTx). In this report, we explored the reasons behind this guarded outcome with a special focus on the role of alloimmunity. We initially assessed gene expression in 39 time-zero allograft biopsies using the Nanostring 770 genes PanCancer Immune Profiling Panel. Subsequently, we studied 696 consecutive adult kidney allograft recipients that were grouped according to allograft type and histology at time-zero biopsy [DRTx/suboptimal histology (n = 194), DRTx/optimal histology (n = 166), and LRTx (n = 336)]. Part-1: Several immune pathways were upregulated in time-zero biopsies from DRTx/suboptimal histology (n = 11) compared to LRTx (n = 17) but not to DRTx/optimal histology (n = 11). Part-2: Amongst the three groups of recipients, DRTx/suboptimal histology had the highest incidence of acute rejection episodes, most of which occurred during the first year after transplantation (early rejection). This increase was mainly attributed to T cell mediated rejection, while the incidence of antibody-mediated rejection was similar amongst the three groups. Importantly, early acute T cell mediated rejection was a strong independent predictor for allograft failure in DRTx/suboptimal histology (adjusted HR: 2.13, P = 0.005) but not in DRTx/optimal histology nor in LRTx. Our data highlight an increased baseline immunogenicity in DRTx/suboptimal histology compared to LRTx but not to DRTx/optimal histology. However, our results suggest that donor chronic histologic changes in DRTx may help transfer such increased baseline immunogenicity into clinically relevant acute rejection episodes that have detrimental effects on allograft survival. These findings may provide a rationale for enhanced immunosuppression in recipients of DRTx with baseline chronic histologic changes to minimize subsequent acute rejection and to prolong allograft survival.
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Affiliation(s)
- Ibrahim Batal
- Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
| | - Geo Serban
- Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Sumit Mohan
- Medicine, Division of Nephrology, Columbia University Irving Medical Center, New York, NY, USA.,Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Syed A Husain
- Medicine, Division of Nephrology, Columbia University Irving Medical Center, New York, NY, USA
| | - Elena-Rodica Vasilescu
- Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Russel J Crew
- Medicine, Division of Nephrology, Columbia University Irving Medical Center, New York, NY, USA
| | - Geoffrey Dube
- Medicine, Division of Nephrology, Columbia University Irving Medical Center, New York, NY, USA
| | - P Rodrigo Sandoval
- Surgery, Division of Transplantation, Columbia University Irving Medical Center, New York, NY, USA
| | - Shana M Coley
- Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Dominick Santoriello
- Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Michael B Stokes
- Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Vivette D D'Agati
- Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - David J Cohen
- Medicine, Division of Nephrology, Columbia University Irving Medical Center, New York, NY, USA
| | - Glen Markowitz
- Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Mark A Hardy
- Surgery, Division of Transplantation, Columbia University Irving Medical Center, New York, NY, USA
| | - Lloyd E Ratner
- Surgery, Division of Transplantation, Columbia University Irving Medical Center, New York, NY, USA
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Deletion of TLR4 reduces apoptosis and improves histology in a murine kidney transplant model. Sci Rep 2021; 11:16182. [PMID: 34376755 PMCID: PMC8355104 DOI: 10.1038/s41598-021-95504-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 07/07/2021] [Indexed: 12/04/2022] Open
Abstract
Acute kidney injury (AKI) after transplantation of human deceased donor kidneys is associated with upregulation of tubular toll like receptor 4 (TLR4), but whether TLR4 is required for AKI is unknown. We hypothesized that TLR4 knockout mice (TLR4KO) subjected to cold ischemia followed by kidney transplant (CI + Txp) would be protected from AKI. C57Bl/6J wild type or TLR4KO kidneys were subjected to CI + Txp into wild type recipients. Tubular cell apoptosis, tubular injury and cast formation were significantly improved in recipients of TLR4KO kidneys. TLR4KO kidneys also demonstrated significantly decreased expression of the effector caspase 8. Brush border injury scores and serum creatinine were not different in recipients of TLR4KO versus wild type kidneys. Phosphorylated RIP3 and MLKL through which TLR4 signals programmed necrosis were expressed in both recipient groups. In addition, TNF-α and TNFR1 expression were significantly increased in recipient serum and TLR4KO kidneys respectively after CI + Txp, suggesting continued activation of programmed necrosis despite TLR4 deletion. Our results suggest that TLR4 deletion decreases apoptosis via inhibition of the death receptor pathway and decreases tubular injury and cast formation.
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Lu C, Wang C, Xiao H, Chen M, Yang Z, Liang Z, Wang H, Liu Y, Yang Y, Wang Q. Ethyl pyruvate: A newly discovered compound against ischemia-reperfusion injury in multiple organs. Pharmacol Res 2021; 171:105757. [PMID: 34302979 DOI: 10.1016/j.phrs.2021.105757] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/21/2021] [Accepted: 07/02/2021] [Indexed: 12/23/2022]
Abstract
Ischemia-reperfusion injury (IRI) is a process whereby an initial ischemia injury and subsequent recovery of blood flow, which leads to the propagation of an innate immune response and the changes of structural and functional of multiple organs. Therefore, IRI is considered to be a great challenge in clinical treatment such as organ transplantation or coronary angioplasty. In recent years, ethyl pyruvate (EP), a derivative of pyruvate, has received great attention because of its stability and low toxicity. Previous studies have proved that EP has various pharmacological activities, including anti-inflammation, anti-oxidative stress, anti-apoptosis, and anti-fibrosis. Compelling evidence has indicated EP plays a beneficial role in a variety of acute injury models, such as brain IRI, myocardial IRI, renal IRI, and hepatic IRI. Moreover, EP can not only effectively inhibit multiple IRI-induced pathological processes, but also improve the structural and functional lesion of tissues and organs. In this study, we review the recent progress in the research on EP and discuss their implications for a better understanding of multiple organ IRI, and the prospects of targeting the EP for therapeutic intervention.
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Affiliation(s)
- Chenxi Lu
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Guangming Road, Shenmu, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Changyu Wang
- Department of Cardiology, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, 10 Fengcheng Three Road, Xi'an, China
| | - Haoxiang Xiao
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Guangming Road, Shenmu, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Mengfan Chen
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Guangming Road, Shenmu, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Zhi Yang
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Guangming Road, Shenmu, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Zhenxing Liang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East, Zhengzhou, China
| | - Haiying Wang
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Guangming Road, Shenmu, China
| | - Yonglin Liu
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Guangming Road, Shenmu, China
| | - Yang Yang
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Guangming Road, Shenmu, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China.
| | - Qiang Wang
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Guangming Road, Shenmu, China.
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Lai HJ, Zhan YQ, Qiu YX, Ling YH, Zhang XY, Chang ZN, Zhang YN, Liu ZM, Wen SH. HMGB1 signaling-regulated endoplasmic reticulum stress mediates intestinal ischemia/reperfusion-induced acute renal damage. Surgery 2021; 170:239-248. [PMID: 33745733 DOI: 10.1016/j.surg.2021.01.042] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 01/18/2021] [Accepted: 01/24/2021] [Indexed: 12/28/2022]
Abstract
BACKGROUND Ischemia/reperfusion of the intestine often leads to distant organ injury, but the mechanism of intestinal ischemia/reperfusion-induced renal dysfunction is still not clear. The present study aimed to investigate the mechanisms of acute renal damage after intestinal ischemia/reperfusion challenge and explore the role of released high-mobility group box-1 in this process. METHODS Intestinal ischemia/reperfusion was induced in male Sprague-Dawley rats by clamping the superior mesenteric artery for 1.5 hours. At different reperfusion time points, anti-high-mobility group box-1 neutralizing antibodies or ethyl pyruvate were administered to neutralize or inhibit circulating high-mobility group box-1, respectively. RESULTS Significant kidney injury was observed after 6 hours of intestinal reperfusion, as indicated by increased serum levels of urea nitrogen and creatinine, increased expression of neutrophil gelatinase-associated lipocalin, interleukin-6, and MIP-2, and enhanced cell apoptosis, as indicated by cleaved caspase 3 levels in renal tissues. The levels of phosphorylated eIF2ɑ, activating transcription factor 4, and C/EBP-homologous protein (CHOP) were markedly elevated, indicating the activation of endoplasmic reticulum stress in the impaired kidney. High-mobility group box-1 translocated to cytoplasm in the intestine and serum concentrations of high-mobility group box-1 increased notably during the reperfusion phase. Both anti-high-mobility group box-1 antibodies and ethyl pyruvate treatment significantly reduced serum high-mobility group box-1 concentrations, attenuated endoplasmic reticulum stress in renal tissue and inhibited the development of renal damage. Moreover, the elevated expression of receptor for advanced glycation end products in the kidneys after intestinal ischemia/reperfusion was abrogated after high-mobility group box-1 inhibition. CONCLUSION These results suggested that high-mobility group box-1 signaling regulated endoplasmic reticulum stress and promoted intestinal ischemia/reperfusion-induced acute kidney injury. High-mobility group box-1 neutralization/inhibition might serve as a pharmacological intervention strategy for these pathophysiological processes.
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Affiliation(s)
- Han-Jin Lai
- Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Ya-Qing Zhan
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Yu-Xin Qiu
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Yi-Hong Ling
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Xu-Yu Zhang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Ze-Nan Chang
- Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Yi-Nan Zhang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Zi-Meng Liu
- Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
| | - Shi-Hong Wen
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
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Ashayeri Ahmadabad R, Mirzaasgari Z, Gorji A, Khaleghi Ghadiri M. Toll-Like Receptor Signaling Pathways: Novel Therapeutic Targets for Cerebrovascular Disorders. Int J Mol Sci 2021; 22:ijms22116153. [PMID: 34200356 PMCID: PMC8201279 DOI: 10.3390/ijms22116153] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 06/02/2021] [Accepted: 06/04/2021] [Indexed: 12/11/2022] Open
Abstract
Toll-like receptors (TLRs), a class of pattern recognition proteins, play an integral role in the modulation of systemic inflammatory responses. Cerebrovascular diseases (CVDs) are a group of pathological conditions that temporarily or permanently affect the brain tissue mostly via the decrease of oxygen and glucose supply. TLRs have a critical role in the activation of inflammatory cascades following hypoxic-ischemic events and subsequently contribute to neuroprotective or detrimental effects of CVD-induced neuroinflammation. The TLR signaling pathway and downstream cascades trigger immune responses via the production and release of various inflammatory mediators. The present review describes the modulatory role of the TLR signaling pathway in the inflammatory responses developed following various CVDs and discusses the potential benefits of the modulation of different TLRs in the improvement of functional outcomes after brain ischemia.
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Affiliation(s)
- Rezan Ashayeri Ahmadabad
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran 1996835911, Iran; (R.A.A.); (Z.M.)
| | - Zahra Mirzaasgari
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran 1996835911, Iran; (R.A.A.); (Z.M.)
- Department of Neurology, Iran University of Medical Sciences, Tehran 1593747811, Iran
| | - Ali Gorji
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran 1996835911, Iran; (R.A.A.); (Z.M.)
- Epilepsy Research Center, Westfälische Wilhelms-Universität, 48149 Münster, Germany
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran
- Department of Neurosurgery, Westfälische Wilhelms-Universität, 48149 Münster, Germany;
- Department of Neurology, Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany
- Correspondence: ; Tel.: +49-251-8355564; Fax: +49-251-8347479
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Novel Insights into the Molecular Mechanisms of Ischemia/Reperfusion Injury in Kidney Transplantation. TRANSPLANTOLOGY 2021. [DOI: 10.3390/transplantology2020018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Ischemia reperfusion injury (IRI) is one of the most important mechanisms involved in delayed or reduced graft function after kidney transplantation. It is a complex pathophysiological process, followed by a pro-inflammatory response that enhances the immunogenicity of the graft and the risk of acute rejection. Many biologic processes are involved in its development, such as transcriptional reprogramming, the activation of apoptosis and cell death, endothelial dysfunction and the activation of the innate and adaptive immune response. Recent evidence has highlighted the importance of complement activation in IRI cascade, which expresses a pleiotropic action on tubular cells, on vascular cells (pericytes and endothelial cells) and on immune system cells. The effects of IRI in the long term lead to interstitial fibrosis and tubular atrophy, which contribute to chronic graft dysfunction and subsequently graft failure. Furthermore, several metabolic alterations occur upon IRI. Metabolomic analyses of IRI detected a “metabolic profile” of this process, in order to identify novel biomarkers that may potentially be useful for both early diagnosis and monitoring the therapeutic response. The aim of this review is to update the most relevant molecular mechanisms underlying IRI, and also to discuss potential therapeutic targets in future clinical practice.
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Yang C, Yang C, Huang Z, Zhang J, Chen N, Guo Y, Zahoor A, Deng G. Reduced expression of MiR-125a-5p aggravates LPS-induced experimental acute kidney injury pathology by targeting TRAF6. Life Sci 2021; 288:119657. [PMID: 34048808 DOI: 10.1016/j.lfs.2021.119657] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 05/13/2021] [Accepted: 05/18/2021] [Indexed: 02/07/2023]
Abstract
AIMS Patients with acute kidney injury (AKI) have higher mortality, and sepsis is among its main causes. MicroRNAs (miRNAs) are essential for regulating kidney function and could have curative potential. This study explored the possibility to treat AKI with miR-125a-5p and reveal the possible mechanism. MATERIALS AND METHODS LPS-induced mouse model and LPS-induced RAW264.7 cell model of AKI were established and treated with miR-125a-5p mimics or inhibitors. Serum creatinine and blood urea were measured to evaluate kidney function. The pathological changes of kidney tissues were detected by H&E and PAS staining technique, and the infiltration of macrophages were observed by immunohistochemistry. RAW264.7 cell viability, TRAF6 and cytokines expressions under LPS stimulation were measured. The role and therapeutic potential of miR-125a-5p were verified in vivo and in vitro after given miR-125a-5p mimics or inhibitors. KEY FINDINGS LPS-induced mice had increasing serum creatinine and urea, and evident pathological changes, including severe tubular dilatation and macrophages infiltration. TRAF6 expression in the kidney was significantly higher, while miR-125a-5p expression was suppressed. MiR-125a-5p targeted TRAF6, and its overexpression deactivated NF-κB signaling pathway, reducing downstream TNF-α, IL-1β and IL-6 expressions. MiR-125a-5p mimics rescued LPS-induced kidney damage and suppressed pro-inflammatory cytokines expression through inhibiting TRAF6/NF-κB axis. SIGNIFICANCE We highlighted that miR-125a-5p could inhibit LPS-induced acute inflammation in the kidney through targeting TRAF6/NF-κB axis. These results might contribute to the development of molecular therapy in AKI.
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Affiliation(s)
- Chao Yang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Cheng Yang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Zhi Huang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Jinxin Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Nuoer Chen
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Yingfang Guo
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Arshad Zahoor
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China; College of Veterinary Sciences, The University of Agriculture Peshawar, Pakistan
| | - Ganzhen Deng
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, People's Republic of China.
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Hoyer-Allo KJR, Späth MR, Hanssen R, Johnsen M, Brodesser S, Kaufmann K, Kiefer K, Koehler FC, Göbel H, Kubacki T, Grundmann F, Schermer B, Brüning J, Benzing T, Burst V, Müller RU. Modulation of Endocannabinoids by Caloric Restriction Is Conserved in Mice but Is Not Required for Protection from Acute Kidney Injury. Int J Mol Sci 2021; 22:ijms22115485. [PMID: 34067475 PMCID: PMC8196977 DOI: 10.3390/ijms22115485] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/12/2021] [Accepted: 05/18/2021] [Indexed: 12/20/2022] Open
Abstract
Acute kidney injury (AKI) is a frequent and critical complication in the clinical setting. In rodents, AKI can be effectively prevented through caloric restriction (CR), which has also been shown to increase lifespan in many species. In Caenorhabditis elegans (C. elegans), longevity studies revealed that a marked CR-induced reduction of endocannabinoids may be a key mechanism. Thus, we hypothesized that regulation of endocannabinoids, particularly arachidonoyl ethanolamide (AEA), might also play a role in CR-mediated protection from renal ischemia-reperfusion injury (IRI) in mammals including humans. In male C57Bl6J mice, CR significantly reduced renal IRI and led to a significant decrease of AEA. Supplementation of AEA to near-normal serum concentrations by repetitive intraperitoneal administration in CR mice, however, did not abrogate the protective effect of CR. We also analyzed serum samples taken before and after CR from patients of three different pilot trials of dietary interventions. In contrast to mice and C. elegans, we detected an increase of AEA. We conclude that endocannabinoid levels in mice are modulated by CR, but CR-mediated renal protection does not depend on this effect. Moreover, our results indicate that modulation of endocannabinoids by CR in humans may differ fundamentally from the effects in animal models.
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Affiliation(s)
- Karla Johanna Ruth Hoyer-Allo
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 37, 50937 Cologne, Germany; (K.J.R.H.-A.); (M.R.S.); (M.J.); (F.C.K.); (T.K.); (F.G.); (B.S.); (T.B.)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany; (S.B.); (K.K.); (K.K.); (J.B.)
| | - Martin Richard Späth
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 37, 50937 Cologne, Germany; (K.J.R.H.-A.); (M.R.S.); (M.J.); (F.C.K.); (T.K.); (F.G.); (B.S.); (T.B.)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany; (S.B.); (K.K.); (K.K.); (J.B.)
| | - Ruth Hanssen
- Max Planck Institute for Metabolism Research, Gleueler Str. 50, 50931 Cologne, Germany;
- Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEPD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany
| | - Marc Johnsen
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 37, 50937 Cologne, Germany; (K.J.R.H.-A.); (M.R.S.); (M.J.); (F.C.K.); (T.K.); (F.G.); (B.S.); (T.B.)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany; (S.B.); (K.K.); (K.K.); (J.B.)
| | - Susanne Brodesser
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany; (S.B.); (K.K.); (K.K.); (J.B.)
| | - Kathrin Kaufmann
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany; (S.B.); (K.K.); (K.K.); (J.B.)
| | - Katharina Kiefer
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany; (S.B.); (K.K.); (K.K.); (J.B.)
| | - Felix Carlo Koehler
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 37, 50937 Cologne, Germany; (K.J.R.H.-A.); (M.R.S.); (M.J.); (F.C.K.); (T.K.); (F.G.); (B.S.); (T.B.)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany; (S.B.); (K.K.); (K.K.); (J.B.)
| | - Heike Göbel
- Institute of Pathology, University Hospital of Cologne, Kerpener Str. 37, 50937 Cologne, Germany;
| | - Torsten Kubacki
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 37, 50937 Cologne, Germany; (K.J.R.H.-A.); (M.R.S.); (M.J.); (F.C.K.); (T.K.); (F.G.); (B.S.); (T.B.)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany; (S.B.); (K.K.); (K.K.); (J.B.)
| | - Franziska Grundmann
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 37, 50937 Cologne, Germany; (K.J.R.H.-A.); (M.R.S.); (M.J.); (F.C.K.); (T.K.); (F.G.); (B.S.); (T.B.)
| | - Bernhard Schermer
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 37, 50937 Cologne, Germany; (K.J.R.H.-A.); (M.R.S.); (M.J.); (F.C.K.); (T.K.); (F.G.); (B.S.); (T.B.)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany; (S.B.); (K.K.); (K.K.); (J.B.)
| | - Jens Brüning
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany; (S.B.); (K.K.); (K.K.); (J.B.)
- Max Planck Institute for Metabolism Research, Gleueler Str. 50, 50931 Cologne, Germany;
- Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEPD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany
| | - Thomas Benzing
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 37, 50937 Cologne, Germany; (K.J.R.H.-A.); (M.R.S.); (M.J.); (F.C.K.); (T.K.); (F.G.); (B.S.); (T.B.)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany; (S.B.); (K.K.); (K.K.); (J.B.)
| | - Volker Burst
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 37, 50937 Cologne, Germany; (K.J.R.H.-A.); (M.R.S.); (M.J.); (F.C.K.); (T.K.); (F.G.); (B.S.); (T.B.)
- Correspondence: (V.B.); (R.-U.M.)
| | - Roman-Ulrich Müller
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 37, 50937 Cologne, Germany; (K.J.R.H.-A.); (M.R.S.); (M.J.); (F.C.K.); (T.K.); (F.G.); (B.S.); (T.B.)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Joseph-Stelzmann-Straße 26, 50931 Cologne, Germany; (S.B.); (K.K.); (K.K.); (J.B.)
- Correspondence: (V.B.); (R.-U.M.)
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Lin J, Wang H, Liu C, Cheng A, Deng Q, Zhu H, Chen J. Dendritic Cells: Versatile Players in Renal Transplantation. Front Immunol 2021; 12:654540. [PMID: 34093544 PMCID: PMC8170486 DOI: 10.3389/fimmu.2021.654540] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 04/22/2021] [Indexed: 12/30/2022] Open
Abstract
Dendritic cells (DCs) induce and regulate adaptive immunity through migrating and maturing in the kidney. In this procedure, they can adopt different phenotypes—rejection-associated DCs promote acute or chronic injury renal grafts while tolerogenic DCs suppress the overwhelmed inflammation preventing damage to renal functionality. All the subsets interact with effector T cells and regulatory T cells (Tregs) stimulated by the ischemia–reperfusion procedure, although the classification corresponding to different effects remains controversial. Thus, in this review, we discuss the origin, maturation, and pathological effects of DCs in the kidney. Then we summarize the roles of divergent DCs in renal transplantation: taking both positive and negative stages in ischemia–reperfusion injury (IRI), switching phenotypes to induce acute or chronic rejection, and orchestrating surface markers for allograft tolerance via alterations in metabolism. In conclusion, we prospect that multidimensional transcriptomic analysis will revolute researches on renal transplantation by addressing the elusive mononuclear phagocyte classification and providing a holistic view of DC ontogeny and subpopulations.
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Affiliation(s)
- Jinwen Lin
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, National Key Clinical Department of Kidney Disease, Institute of Nephrology, Zhejiang University, Hangzhou, China.,The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, China
| | - Hongyi Wang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Chenxi Liu
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Ao Cheng
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Qingwei Deng
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Huijuan Zhu
- Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, National Key Clinical Department of Kidney Disease, Institute of Nephrology, Zhejiang University, Hangzhou, China.,The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, China
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44
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Rossi M, Korpak K, Doerfler A, Zouaoui Boudjeltia K. Deciphering the Role of Heme Oxygenase-1 (HO-1) Expressing Macrophages in Renal Ischemia-Reperfusion Injury. Biomedicines 2021; 9:biomedicines9030306. [PMID: 33809696 PMCID: PMC8002311 DOI: 10.3390/biomedicines9030306] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/06/2021] [Accepted: 03/10/2021] [Indexed: 12/30/2022] Open
Abstract
Ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), which contributes to the development of chronic kidney disease (CKD). Renal IRI combines major events, including a strong inflammatory immune response leading to extensive cell injuries, necrosis and late interstitial fibrosis. Macrophages act as key players in IRI-induced AKI by polarizing into proinflammatory M1 and anti-inflammatory M2 phenotypes. Compelling evidence exists that the stress-responsive enzyme, heme oxygenase-1 (HO-1), mediates protection against renal IRI and modulates macrophage polarization by enhancing a M2 subset. Hereafter, we review the dual effect of macrophages in the pathogenesis of IRI-induced AKI and discuss the critical role of HO-1 expressing macrophages.
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Affiliation(s)
- Maxime Rossi
- Department of Urology, CHU de Charleroi, Université libre de Bruxelles (ULB), 6000 Charleroi, Belgium;
- Laboratory of Experimental Medicine (ULB 222 Unit), CHU de Charleroi, Hôpital André Vésale, Université libre de Bruxelles (ULB), 6110 Montigny-le-Tilleul, Belgium;
- Correspondence: (M.R.); (K.Z.B.)
| | - Kéziah Korpak
- Laboratory of Experimental Medicine (ULB 222 Unit), CHU de Charleroi, Hôpital André Vésale, Université libre de Bruxelles (ULB), 6110 Montigny-le-Tilleul, Belgium;
- Department of Geriatric Medicine, CHU de Charleroi, Hôpital André Vésale, Université libre de Bruxelles (ULB), 6110 Montigny-le-Tilleul, Belgium
| | - Arnaud Doerfler
- Department of Urology, CHU de Charleroi, Université libre de Bruxelles (ULB), 6000 Charleroi, Belgium;
| | - Karim Zouaoui Boudjeltia
- Laboratory of Experimental Medicine (ULB 222 Unit), CHU de Charleroi, Hôpital André Vésale, Université libre de Bruxelles (ULB), 6110 Montigny-le-Tilleul, Belgium;
- Correspondence: (M.R.); (K.Z.B.)
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45
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Dwyer GK, Turnquist HR. Untangling Local Pro-Inflammatory, Reparative, and Regulatory Damage-Associated Molecular-Patterns (DAMPs) Pathways to Improve Transplant Outcomes. Front Immunol 2021; 12:611910. [PMID: 33708206 PMCID: PMC7940545 DOI: 10.3389/fimmu.2021.611910] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 01/05/2021] [Indexed: 12/28/2022] Open
Abstract
Detrimental inflammatory responses after solid organ transplantation are initiated when immune cells sense pathogen-associated molecular patterns (PAMPs) and certain damage-associated molecular patterns (DAMPs) released or exposed during transplant-associated processes, such as ischemia/reperfusion injury (IRI), surgical trauma, and recipient conditioning. These inflammatory responses initiate and propagate anti-alloantigen (AlloAg) responses and targeting DAMPs and PAMPs, or the signaling cascades they activate, reduce alloimmunity, and contribute to improved outcomes after allogeneic solid organ transplantation in experimental studies. However, DAMPs have also been implicated in initiating essential anti-inflammatory and reparative functions of specific immune cells, particularly Treg and macrophages. Interestingly, DAMP signaling is also involved in local and systemic homeostasis. Herein, we describe the emerging literature defining how poor outcomes after transplantation may result, not from just an over-abundance of DAMP-driven inflammation, but instead an inadequate presence of a subset of DAMPs or related molecules needed to repair tissue successfully or re-establish tissue homeostasis. Adverse outcomes may also arise when these homeostatic or reparative signals become dysregulated or hijacked by alloreactive immune cells in transplant niches. A complete understanding of the critical pathways controlling tissue repair and homeostasis, and how alloimmune responses or transplant-related processes disrupt these will lead to new immunotherapeutics that can prevent or reverse the tissue pathology leading to lost grafts due to chronic rejection.
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Affiliation(s)
- Gaelen K Dwyer
- Departments of Surgery and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Hēth R Turnquist
- Departments of Surgery and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
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46
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A Cell-Penetrating Peptide That Blocks Toll-Like Receptor Signaling Protects Kidneys against Ischemia-Reperfusion Injury. Int J Mol Sci 2021; 22:ijms22041627. [PMID: 33562802 PMCID: PMC7915942 DOI: 10.3390/ijms22041627] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 01/29/2021] [Accepted: 02/01/2021] [Indexed: 01/14/2023] Open
Abstract
Renal ischemia-reperfusion injury (IRI) is involved in the majority of clinical conditions that manifest as renal function deterioration; however, specific treatment for this type of injury is still far from clinical use. Since Toll-like receptor (TLR)-mediated signaling is a key mediator of IRI, we examined the effect of a multiple-TLR-blocking peptide named TLR-inhibitory peptide 1 (TIP1), which exerts the strongest action on TLR4, on renal IRI. We subjected C57BL/6 mice to 23 min of renal pedicle clamping preceded by intraperitoneal injection with a vehicle or TIP1. Sham control mice underwent flank incision only. Mouse kidneys were harvested after 24 h of reperfusion for histology, western blot, RT-PCR, and flow cytometry analysis. Pretreatment with TIP1 lowered the magnitude of elevated plasma creatinine levels and attenuated tubular injury. TIP1 treatment also reduced mRNA expression of inflammatory cytokines and decreased apoptotic cells and oxidative stress in post-ischemic kidneys. In kidneys pretreated with TIP1, the infiltration of macrophages and T helper 17 cells was less abundant than those in the IRI only group. These results suggest that TIP1 has a potential beneficial effect in attenuating the degree of kidney damage induced by IRI.
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Vázquez-Carballo C, Guerrero-Hue M, García-Caballero C, Rayego-Mateos S, Opazo-Ríos L, Morgado-Pascual JL, Herencia-Bellido C, Vallejo-Mudarra M, Cortegano I, Gaspar ML, de Andrés B, Egido J, Moreno JA. Toll-Like Receptors in Acute Kidney Injury. Int J Mol Sci 2021; 22:ijms22020816. [PMID: 33467524 PMCID: PMC7830297 DOI: 10.3390/ijms22020816] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/09/2021] [Accepted: 01/11/2021] [Indexed: 12/16/2022] Open
Abstract
Acute kidney injury (AKI) is an important health problem, affecting 13.3 million individuals/year. It is associated with increased mortality, mainly in low- and middle-income countries, where renal replacement therapy is limited. Moreover, survivors show adverse long-term outcomes, including increased risk of developing recurrent AKI bouts, cardiovascular events, and chronic kidney disease. However, there are no specific treatments to decrease the adverse consequences of AKI. Epidemiological and preclinical studies show the pathological role of inflammation in AKI, not only at the acute phase but also in the progression to chronic kidney disease. Toll-like receptors (TLRs) are key regulators of the inflammatory response and have been associated to many cellular processes activated during AKI. For that reason, a number of anti-inflammatory agents targeting TLRs have been analyzed in preclinical studies to decrease renal damage during AKI. In this review, we updated recent knowledge about the role of TLRs, mainly TLR4, in the initiation and development of AKI as well as novel compounds targeting these molecules to diminish kidney injury associated to this pathological condition.
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Affiliation(s)
- Cristina Vázquez-Carballo
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, 28040 Madrid, Spain; (C.V.-C.); (S.R.-M.); (L.O.-R.); (C.H.-B.)
| | - Melania Guerrero-Hue
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (M.G.-H.); (C.G.-C.); (J.L.M.-P.); (M.V.-M.)
| | - Cristina García-Caballero
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (M.G.-H.); (C.G.-C.); (J.L.M.-P.); (M.V.-M.)
| | - Sandra Rayego-Mateos
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, 28040 Madrid, Spain; (C.V.-C.); (S.R.-M.); (L.O.-R.); (C.H.-B.)
| | - Lucas Opazo-Ríos
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, 28040 Madrid, Spain; (C.V.-C.); (S.R.-M.); (L.O.-R.); (C.H.-B.)
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
| | - José Luis Morgado-Pascual
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (M.G.-H.); (C.G.-C.); (J.L.M.-P.); (M.V.-M.)
| | - Carmen Herencia-Bellido
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, 28040 Madrid, Spain; (C.V.-C.); (S.R.-M.); (L.O.-R.); (C.H.-B.)
| | - Mercedes Vallejo-Mudarra
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (M.G.-H.); (C.G.-C.); (J.L.M.-P.); (M.V.-M.)
| | - Isabel Cortegano
- Immunobiology Department, Carlos III Health Institute, 28220 Majadahonda (Madrid), Spain; (I.C.); (M.L.G.); (B.d.A.)
| | - María Luisa Gaspar
- Immunobiology Department, Carlos III Health Institute, 28220 Majadahonda (Madrid), Spain; (I.C.); (M.L.G.); (B.d.A.)
| | - Belén de Andrés
- Immunobiology Department, Carlos III Health Institute, 28220 Majadahonda (Madrid), Spain; (I.C.); (M.L.G.); (B.d.A.)
| | - Jesús Egido
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, 28040 Madrid, Spain; (C.V.-C.); (S.R.-M.); (L.O.-R.); (C.H.-B.)
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
- Correspondence: (J.E.); (J.A.M.); Tel.: +34-915504800 (J.E.); +34-957-218039 (J.A.M.)
| | - Juan Antonio Moreno
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (M.G.-H.); (C.G.-C.); (J.L.M.-P.); (M.V.-M.)
- Biomedical Research Networking Center on Cardiovascular Diseases (CIBERCV), 28029 Madrid, Spain
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, 140471 Cordoba, Spain
- Correspondence: (J.E.); (J.A.M.); Tel.: +34-915504800 (J.E.); +34-957-218039 (J.A.M.)
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48
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Ren Q, Cheng L, Yi J, Ma L, Pan J, Gou SJ, Fu P. Toll-like Receptors as Potential Therapeutic Targets in Kidney Diseases. Curr Med Chem 2020; 27:5829-5854. [PMID: 31161985 DOI: 10.2174/0929867325666190603110907] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 03/15/2019] [Accepted: 05/13/2019] [Indexed: 02/08/2023]
Abstract
Toll-like Receptors (TLRs) are members of pattern recognition receptors and serve a pivotal role in host immunity. TLRs response to pathogen-associated molecular patterns encoded by pathogens or damage-associated molecular patterns released by dying cells, initiating an inflammatory cascade, where both beneficial and detrimental effects can be exerted. Accumulated evidence has revealed that TLRs are closely associated with various kidney diseases but their roles are still not well understood. This review updated evidence on the roles of TLRs in the pathogenesis of kidney diseases including urinary tract infection, glomerulonephritis, acute kidney injury, transplant allograft dysfunction and chronic kidney diseases.
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Affiliation(s)
- Qian Ren
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Lu Cheng
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Jing Yi
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Liang Ma
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Jing Pan
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Shen-Ju Gou
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Ping Fu
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
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49
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Fernández AR, Sánchez-Tarjuelo R, Cravedi P, Ochando J, López-Hoyos M. Review: Ischemia Reperfusion Injury-A Translational Perspective in Organ Transplantation. Int J Mol Sci 2020; 21:ijms21228549. [PMID: 33202744 PMCID: PMC7696417 DOI: 10.3390/ijms21228549] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/10/2020] [Accepted: 11/11/2020] [Indexed: 02/07/2023] Open
Abstract
Thanks to the development of new, more potent and selective immunosuppressive drugs together with advances in surgical techniques, organ transplantation has emerged from an experimental surgery over fifty years ago to being the treatment of choice for many end-stage organ diseases, with over 139,000 organ transplants performed worldwide in 2019. Inherent to the transplantation procedure is the fact that the donor organ is subjected to blood flow cessation and ischemia during harvesting, which is followed by preservation and reperfusion of the organ once transplanted into the recipient. Consequently, ischemia/reperfusion induces a significant injury to the graft with activation of the immune response in the recipient and deleterious effect on the graft. The purpose of this review is to discuss and shed new light on the pathways involved in ischemia/reperfusion injury (IRI) that act at different stages during the donation process, surgery, and immediate post-transplant period. Here, we present strategies that combine various treatments targeted at different mechanistic pathways during several time points to prevent graft loss secondary to the inflammation caused by IRI.
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Affiliation(s)
- André Renaldo Fernández
- Immunology, Universitary Hospital Marqués de Valdecilla- Research Institute IDIVAL Santander, 390008 Santander, Spain;
| | - Rodrigo Sánchez-Tarjuelo
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (R.S.-T.); (J.O.)
- Immunología de Trasplantes, Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda (Madrid), Spain
| | - Paolo Cravedi
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
| | - Jordi Ochando
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (R.S.-T.); (J.O.)
- Immunología de Trasplantes, Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda (Madrid), Spain
| | - Marcos López-Hoyos
- Immunology, Universitary Hospital Marqués de Valdecilla- Research Institute IDIVAL Santander, 390008 Santander, Spain;
- Red de Investigación Renal (REDINREN), 28040 Madrid, Spain
- Correspondence: ; Tel.: +34-942-292759
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50
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Lichota A, Szewczyk EM, Gwozdzinski K. Factors Affecting the Formation and Treatment of Thrombosis by Natural and Synthetic Compounds. Int J Mol Sci 2020; 21:E7975. [PMID: 33121005 PMCID: PMC7663413 DOI: 10.3390/ijms21217975] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/22/2020] [Accepted: 10/23/2020] [Indexed: 12/13/2022] Open
Abstract
Venous thromboembolism (VTE) refers to deep vein thrombosis (DVT), whose consequence may be a pulmonary embolism (PE). Thrombosis is associated with significant morbidity and mortality and is the third most common cardiovascular disease after myocardial infarction and stroke. DVT is associated with the formation of a blood clot in a deep vein in the body. Thrombosis promotes slowed blood flow, hypoxia, cell activation, and the associated release of many active substances involved in blood clot formation. All thrombi which adhere to endothelium consist of fibrin, platelets, and trapped red and white blood cells. In this review, we summarise the impact of various factors affecting haemostatic disorders leading to blood clot formation. The paper discusses the causes of thrombosis, the mechanism of blood clot formation, and factors such as hypoxia, the involvement of endothelial cells (ECs), and the activation of platelets and neutrophils along with the effects of bacteria and reactive oxygen species (ROS). Mechanisms related to the action of anticoagulants affecting coagulation factors including antiplatelet drugs have also been discussed. However, many aspects related to the pathogenesis of thrombosis still need to be clarified. A review of the drugs used to treat and prevent thrombosis and natural anticoagulants that occur in the plant world and are traditionally used in Far Eastern medicine has also been carried out.
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Affiliation(s)
- Anna Lichota
- Department of Pharmaceutical Microbiology and Microbiological Diagnostic, Faculty of Pharmacy, Medical University of Lodz, 90-235 Lodz, Poland; (A.L.); (E.M.S.)
| | - Eligia M. Szewczyk
- Department of Pharmaceutical Microbiology and Microbiological Diagnostic, Faculty of Pharmacy, Medical University of Lodz, 90-235 Lodz, Poland; (A.L.); (E.M.S.)
| | - Krzysztof Gwozdzinski
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland
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