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Xue L, Jiang S, Wan XY. Protective Effects of Sesamol on Renal Ischemia-Reperfusion Injury Via Regulation of Nuclear Factor Erythroid 2-Related Factor 2 Pathway. Transplant Proc 2024; 56:290-296. [PMID: 38350822 DOI: 10.1016/j.transproceed.2023.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 12/28/2023] [Indexed: 02/15/2024]
Abstract
BACKGROUND Sesamol is a natural antioxidant known for its potent antioxidant and free radical scavenging properties. This study aimed to explore the therapeutic effects and underlying mechanisms of sesamol in the development of renal ischemia-reperfusion injury (IRI) in mice. METHODS C57BL/6J wild-type mice were divided into 3 groups: IR group, treated with normal saline after undergoing the IRI procedure; Sesamol + IR group, treated with 30 mg/kg/d of sesamol after the IRI procedure; and Sham group, treated with normal saline but not subjected to the IRI process. Renal IRI was induced by performing a right kidney nephrectomy and subjecting the left kidney to 30-minute ischemia, followed by 24-hour reperfusion. Kidney tissues and serum were collected 24 hours post-IRI to assess the impact of sesamol on renal function after IRI. Serum creatinine and blood urea nitrogen levels were assessed, and renal cell apoptosis was detected through terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. The levels of interleukin 1β and interleukin 18 in kidney tissues, as well as indicators of oxidative stress, were also measured. Furthermore, Nrf2-deficient mice were used to examine the protective function of the nuclear factor erythroid 2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 (NQO1) signaling pathways induced by sesamol, as determined by western blot assay. RESULTS Sesamol demonstrated significant improvement in renal function, along with reductions in renal tubular injury, cell necrosis, and apoptosis in mice. It also effectively lowered key inflammatory mediator levels. Sesamol exhibited antioxidant properties by reducing malondialdehyde levels and enhancing superoxide dismutase activities 24 hours after IRI. Western blot assay revealed increased Nrf2, HO-1, and NQO-1 protein levels with sesamol treatment. Notably, Nrf2-deficient mice did not exhibit the beneficial effects of sesamol. CONCLUSIONS This study demonstrates that sesamol effectively alleviates renal IRI by enhancing antioxidant defenses and reducing inflammation potentially through the Nrf2/HO-1 and NQO1 signaling pathways.
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Affiliation(s)
- Lu Xue
- Department of Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, People's Republic of China
| | - Su Jiang
- Department of Rehabilitation Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, People's Republic of China
| | - Xian-Yao Wan
- Department of Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, People's Republic of China.
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Tran TAT, Iwata Y, Hoang LT, Kitajima S, Yoneda-Nakagawa S, Oshima M, Sakai N, Toyama T, Yamamura Y, Yamazaki H, Hara A, Shimizu M, Sako K, Minami T, Yuasa T, Horikoshi K, Hayashi D, Kajikawa S, Wada T. Protective Role of MAVS Signaling for Murine Lipopolysaccharide-Induced Acute Kidney Injury. Immunohorizons 2024; 8:1-18. [PMID: 38169549 PMCID: PMC10835654 DOI: 10.4049/immunohorizons.2300069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 11/14/2023] [Indexed: 01/05/2024] Open
Abstract
Despite treatment advances, acute kidney injury (AKI)-related mortality rates are still high in hospitalized adults, often due to sepsis. Sepsis and AKI could synergistically worsen the outcomes of critically ill patients. TLR4 signaling and mitochondrial antiviral signaling protein (MAVS) signaling are innate immune responses essential in kidney diseases, but their involvement in sepsis-associated AKI (SA-AKI) remains unclear. We studied the role of MAVS in kidney injury related to the TLR4 signaling pathway using a murine LPS-induced AKI model in wild-type and MAVS-knockout mice. We confirmed the importance of M1 macrophage in SA-AKI through in vivo assessment of inflammatory responses. The TLR4 signaling pathway was upregulated in activated bone marrow-derived macrophages, in which MAVS helped maintain the LPS-suppressed TLR4 mRNA level. MAVS regulated redox homeostasis via NADPH oxidase Nox2 and mitochondrial reverse electron transport in macrophages to alleviate the TLR4 signaling response to LPS. Hypoxia-inducible factor 1α (HIF-1α) and AP-1 were key regulators of TLR4 transcription and connected MAVS-dependent reactive oxygen species signaling with the TLR4 pathway. Inhibition of succinate dehydrogenase could partly reduce inflammation in LPS-treated bone marrow-derived macrophages without MAVS. These findings highlight the renoprotective role of MAVS in LPS-induced AKI by regulating reactive oxygen species generation-related genes and maintaining redox balance. Controlling redox homeostasis through MAVS signaling may be a promising therapy for SA-AKI.
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Affiliation(s)
- Trang Anh Thi Tran
- Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan
| | - Yasunori Iwata
- Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan
- Division of Infection Control, Kanazawa University Hospital, Kanazawa, Japan
| | - Linh Thuy Hoang
- Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan
| | - Shinji Kitajima
- Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan
- Division of Blood Purification, Kanazawa University Hospital, Kanazawa, Japan
| | | | - Megumi Oshima
- Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan
| | - Norihiko Sakai
- Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan
- Division of Blood Purification, Kanazawa University Hospital, Kanazawa, Japan
| | - Tadashi Toyama
- Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan
| | - Yuta Yamamura
- Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan
| | - Hiroka Yamazaki
- Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan
| | - Akinori Hara
- Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan
| | - Miho Shimizu
- Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan
| | - Keisuke Sako
- Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan
| | - Taichiro Minami
- Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan
| | - Takahiro Yuasa
- Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan
| | - Keisuke Horikoshi
- Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan
| | - Daiki Hayashi
- Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan
| | - Sho Kajikawa
- Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan
| | - Takashi Wada
- Department of Nephrology and Rheumatology, Kanazawa University, Kanazawa, Japan
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Litvinova E, Bounaix C, Hanouna G, Da Silva J, Noailles L, Beaudoin L, Padden M, Bellamri N, Lehuen A, Daugas E, Monteiro RC, Flament H. MAIT cells altered phenotype and cytotoxicity in lupus patients are linked to renal disease severity and outcome. Front Immunol 2023; 14:1205405. [PMID: 37885889 PMCID: PMC10598677 DOI: 10.3389/fimmu.2023.1205405] [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: 04/13/2023] [Accepted: 07/26/2023] [Indexed: 10/28/2023] Open
Abstract
Introduction Systemic lupus erythematosus (SLE) is an autoimmune disease in which circulating immune complexes can cause different types of glomerulonephritis, according to immune deposits and to the type of glomerular cell injury. Proliferative lesions represent the most severe form of lupus nephritis (LN) and often lead to kidney failure and death. Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells that recognize microbial-derived ligands from the riboflavin synthesis pathway. Although abundant in peripheral blood, MAIT cells are enriched in mucosal and inflamed tissues. While previous studies have reported concordant results concerning lower MAIT cell frequencies in the blood of SLE patients, no information is known about MAIT cell function and LN severity and outcome. Methods In the current study, we analyzed the baseline phenotype and function of peripheral blood MAIT cells by flow cytometry in 26 patients with LN and in a control group of 16 healthy individuals. Results We observe that MAIT cell frequencies are markedly reduced in blood of LN patients. MAIT cells from patients have an altered phenotype in terms of migration, proliferation and differentiation markers, notably in most severe forms of LN. Frequencies of PMA/ionomycin stimulated MAIT cells secreting effector molecules, such as proinflammatory IL-17 and cytotoxic protein granzyme B, are higher in LN patients. Patients undergoing a complete renal remission after immunosuppressive therapy had higher MAIT cell frequency, lower expression of proliferation marker Ki-67 and granzyme B (GzB) at inclusion. Remarkably, GzB production defines a predictive model for complete remission. Discussion We report here that blood MAIT cells display proinflammatory and cytotoxic function in severe lupus nephritis which may play a pathogenesis role, but without association with systemic lupus activity. Finally, low cytotoxic profile of MAIT cells may represent a promising prognostic factor of lupus nephritis remission one year after induction therapy.
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Affiliation(s)
- Elena Litvinova
- Service d’Immunologie, Hôpital Bichat-Claude Bernard, Paris, France
| | - Carine Bounaix
- Université Paris Cité, Centre de Recherche sur l’Inflammation Institut national de la santé et de la recherche médicale (INSERM) Unité Mixte de Recherche (UMR)1149 & Centre national de la recherche scientifique (CNRS) équipe mixte de recherche (EMR)8252, Inflamex Laboratory of Excellence, Paris, France
| | - Guillaume Hanouna
- Service de Néphrologie, Assistance publique - Hôpitaux de Paris (AP-HP), Hôpital Bichat-Claude Bernard, Paris, France
| | - Jennifer Da Silva
- Université Paris Cité, Centre de Recherche sur l’Inflammation Institut national de la santé et de la recherche médicale (INSERM) Unité Mixte de Recherche (UMR)1149 & Centre national de la recherche scientifique (CNRS) équipe mixte de recherche (EMR)8252, Inflamex Laboratory of Excellence, Paris, France
| | - Laura Noailles
- Université Paris Cité, Centre de Recherche sur l’Inflammation Institut national de la santé et de la recherche médicale (INSERM) Unité Mixte de Recherche (UMR)1149 & Centre national de la recherche scientifique (CNRS) équipe mixte de recherche (EMR)8252, Inflamex Laboratory of Excellence, Paris, France
| | - Lucie Beaudoin
- Université de Paris, Institut Cochin, Institut national de la santé et de la recherche médicale (INSERM) U1016, Centre national de la recherche scientifique (CNRS) Unité Mixte de Recherche (UMR) 8104, Inflamex Laboratory of Excellence, Paris, France
| | - Michael Padden
- Service de Néphrologie, Assistance publique - Hôpitaux de Paris (AP-HP), Hôpital Bichat-Claude Bernard, Paris, France
| | - Nessrine Bellamri
- Université Paris Cité, Centre de Recherche sur l’Inflammation Institut national de la santé et de la recherche médicale (INSERM) Unité Mixte de Recherche (UMR)1149 & Centre national de la recherche scientifique (CNRS) équipe mixte de recherche (EMR)8252, Inflamex Laboratory of Excellence, Paris, France
| | - Agnès Lehuen
- Université de Paris, Institut Cochin, Institut national de la santé et de la recherche médicale (INSERM) U1016, Centre national de la recherche scientifique (CNRS) Unité Mixte de Recherche (UMR) 8104, Inflamex Laboratory of Excellence, Paris, France
| | - Eric Daugas
- Université Paris Cité, Centre de Recherche sur l’Inflammation Institut national de la santé et de la recherche médicale (INSERM) Unité Mixte de Recherche (UMR)1149 & Centre national de la recherche scientifique (CNRS) équipe mixte de recherche (EMR)8252, Inflamex Laboratory of Excellence, Paris, France
- Service de Néphrologie, Assistance publique - Hôpitaux de Paris (AP-HP), Hôpital Bichat-Claude Bernard, Paris, France
| | - Renato C. Monteiro
- Service d’Immunologie, Hôpital Bichat-Claude Bernard, Paris, France
- Université Paris Cité, Centre de Recherche sur l’Inflammation Institut national de la santé et de la recherche médicale (INSERM) Unité Mixte de Recherche (UMR)1149 & Centre national de la recherche scientifique (CNRS) équipe mixte de recherche (EMR)8252, Inflamex Laboratory of Excellence, Paris, France
| | - Héloïse Flament
- Service d’Immunologie, Hôpital Bichat-Claude Bernard, Paris, France
- Université Paris Cité, Centre de Recherche sur l’Inflammation Institut national de la santé et de la recherche médicale (INSERM) Unité Mixte de Recherche (UMR)1149 & Centre national de la recherche scientifique (CNRS) équipe mixte de recherche (EMR)8252, Inflamex Laboratory of Excellence, Paris, France
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Saurin S, Meineck M, Rohr M, Roth W, Opatz T, Erkel G, Pautz A, Weinmann-Menke J. The macrocyclic lactone oxacyclododecindione reduces fibrosis progression. Front Pharmacol 2023; 14:1200164. [PMID: 37383717 PMCID: PMC10294233 DOI: 10.3389/fphar.2023.1200164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 05/23/2023] [Indexed: 06/30/2023] Open
Abstract
Background: Renal fibrosis is one of the most important triggers of chronic kidney disease (CKD), and only a very limited number of therapeutic options are available to stop fibrosis progression. As fibrosis is characterized by inflammation, myofibroblast activation, and extracellular matrix (ECM) deposition, a drug that can address all these processes might be an interesting therapeutic option. Methods: We tested in vivo in an ischemia-reperfusion (I/R) model in C57BL/6 mice and in kidney tubular epithelial cells (TEC) (HK2 cell line and primary cells) whether the natural product oxacyclododecindione (Oxa) reduces fibrosis progression in kidney disease. This was evaluated by Western blot, mRNA expression, and mass spectrometry secretome analyses, as well as by immunohistochemistry. Results: Indeed, Oxa blocked the expression of epithelial-mesenchymal transition marker proteins and reduced renal damage, immune cell infiltration, and collagen expression and deposition, both in vivo and in vitro. Remarkably, the beneficial effects of Oxa were also detected when the natural product was administered at a time point of established fibrotic changes, a situation close to the clinical situation. Initial in vitro experiments demonstrated that a synthetic Oxa derivative possesses similar features. Conclusion: Although open questions such as possible side effects need to be investigated, our results indicate that the combination of anti-inflammatory and anti-fibrotic effects of Oxa make the substance a promising candidate for a new therapeutic approach in fibrosis treatment, and thus in the prevention of kidney disease progression.
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Affiliation(s)
- Sabrina Saurin
- Department of Nephrology, Center of Immunotherapy, Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Myriam Meineck
- Department of Nephrology, Center of Immunotherapy, Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Markus Rohr
- Department of Molecular Biotechnology and Systems Biology, RPTU Kaiserslautern-Landau, Kaiserslautern, Germany
| | - Wilfried Roth
- Institute of Pathology, Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Till Opatz
- Department of Chemistry, Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Gerhard Erkel
- Department of Molecular Biotechnology and Systems Biology, RPTU Kaiserslautern-Landau, Kaiserslautern, Germany
| | - Andrea Pautz
- Institute of Pharmacology, Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Julia Weinmann-Menke
- Department of Nephrology, Center of Immunotherapy, Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
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Biomarkers in Urolithiasis. Urol Clin North Am 2023; 50:19-29. [DOI: 10.1016/j.ucl.2022.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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González-Sánchez HM, Baek JH, Weinmann-Menke J, Ajay AK, Charles JFF, Noda M, Franklin RA, Rodríguez-Morales P, Kelley VR. IL-34 and protein-tyrosine phosphatase receptor type-zeta-dependent mechanisms limit arthritis in mice. J Transl Med 2022; 102:846-858. [PMID: 35288653 DOI: 10.1038/s41374-022-00772-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 02/02/2022] [Accepted: 02/08/2022] [Indexed: 11/09/2022] Open
Abstract
Myeloid cell mediated mechanisms regulate synovial joint inflammation. IL-34, a macrophage (Mø) growth and differentiation molecule, is markedly expressed in neutrophil and Mø-rich arthritic synovium. IL-34 engages a newly identified independent receptor, protein-tyrosine phosphatase, receptor-type, zeta (PTPRZ), that we find is expressed by Mø. As IL-34 is prominent in rheumatoid arthritis, we probed for the IL-34 and PTPRZ-dependent myeloid cell mediated mechanisms central to arthritis using genetic deficient mice in K/BxN serum-transfer arthritis. Unanticipatedly, we now report that IL-34 and PTPRZ limited arthritis as intra-synovial pathology and bone erosion were more severe in IL-34 and PTPRZ KO mice during induced arthritis. We found that IL-34 and PTPRZ: (i) were elevated, bind, and induce downstream signaling within the synovium in arthritic mice and (ii) were upregulated in the serum and track with disease activity in rheumatoid arthritis patients. Mechanistically, IL-34 and PTPRZ skewed Mø toward a reparative phenotype, and enhanced Mø clearance of apoptotic neutrophils, thereby decreasing neutrophil recruitment and intra-synovial neutrophil extracellular traps. With fewer neutrophils and neutrophil extracellular traps in the synovium, destructive inflammation was restricted, and joint pathology and bone erosion diminished. These novel findings suggest that IL-34 and PTPRZ-dependent mechanisms in the inflamed synovium limit, rather than promote, inflammatory arthritis.
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Affiliation(s)
- Hilda Minerva González-Sánchez
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.,CONACyT - Centro de Investigación Sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca, Mexico
| | - Jea-Hyun Baek
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.,School of Life Science, Handong Global University, Pohang, Gyeongbuk, Republic of Korea
| | - Julia Weinmann-Menke
- Department of Nephrology and Rheumatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Amrendra Kumar Ajay
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | | | - Masaharu Noda
- Homeostatic Mechanism Research Unit, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Kanagawa, Japan
| | - Ruth Anne Franklin
- Department of Immunology, Harvard Medical School, Boston, MA, USA.,Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | | | - Vicki Rubin Kelley
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
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Sedmaki K, Karnam K, Sharma P, Mahale A, Routholla G, Ghosh B, Prakash Kulkarni O. HDAC6 inhibition attenuates renal injury by reducing IL-1β secretion and RIP kinase mediated necroptosis in acute oxalate nephropathy. Int Immunopharmacol 2022; 110:108919. [PMID: 35717839 DOI: 10.1016/j.intimp.2022.108919] [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: 03/24/2022] [Revised: 05/19/2022] [Accepted: 05/31/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Pathogenesis of acute kidney injury is driven by necro-inflammation, which is comprised of IL-1β mediated inflammation and RIP-1 mediated tubular necroptosis. HDAC6 is reported to regulate both inflammation and cell death. In the present study, we explored the role of HDAC6 in the lysosomal exocytosis of IL-1β and RIP-1 mediated necroptosis in the context of oxalate nephropathy. METHODS Raw 264.7 macrophages and NRK52E stimulated with oxalate crystals and LPS with or without HDAC6 inhibitor for in vitro experiments. Acute oxalate nephropathy was induced in C57BL/6 mice by injecting sodium oxalate (75 mg/kg). For the drug intervention study, Tubastain A (TSA) was given an hour before injection of sodium oxalate. Mice were sacrificed 24 hrs after the oxalate injection, blood and kidney were harvested. Blood samples were analyzed for BUN and IL-1β levels. Renal tissues were analyzed for histology, immunohistochemistry, RNA, and protein expression. RESULTS HDAC6 and IL-1β upregulated in crystal stimulated macrophages and acute oxalate nephropathy. Pre-treatment of macrophages with TSA reduced IL-1β in supernatant without affecting the expression of pro-IL-1β and mature IL-1β in cell lysate. The effect of TSA on IL-1β secretion was influenced by tubulin acetylation. Renal epithelial cell NRK52E stimulated with crystals showed upregulation of necroptosis pathway markers and concentration-dependent cell death. TSA inhibited RIP-1, RIP3, and MLKL expression along with p-MLKL in stimulated epithelial cells. TSA treatment of oxalate nephropathy mice showed decreased inflammation and tubular cell death by regulating IL-1β and necroptosis and reduced renal injury. CONCLUSION This study highlights the role of HDAC6 in regulating the tubulin-mediated secretion of IL-1β and RIP kinase mediated necroptosis in acute oxalate nephropathy.
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Affiliation(s)
- Kavitha Sedmaki
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad campus, India
| | - Kalyani Karnam
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad campus, India
| | - Pravesh Sharma
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad campus, India
| | - Ashutosh Mahale
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad campus, India
| | - Ganesh Routholla
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad campus, India
| | - Balaram Ghosh
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad campus, India
| | - Onkar Prakash Kulkarni
- Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad campus, India.
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Thomas JM, Huuskes BM, Sobey CG, Drummond GR, Vinh A. The IL-18/IL-18R1 signalling axis: Diagnostic and therapeutic potential in hypertension and chronic kidney disease. Pharmacol Ther 2022; 239:108191. [PMID: 35461924 DOI: 10.1016/j.pharmthera.2022.108191] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/13/2022] [Accepted: 04/14/2022] [Indexed: 02/06/2023]
Abstract
Chronic kidney disease (CKD) is inherently an inflammatory condition, which ultimately results in the development of end stage renal disease or cardiovascular events. Low-grade inflammatory diseases such as hypertension and diabetes are leading causes of CKD. Declines in renal function correlate with elevated circulating pro-inflammatory cytokines in patients with these conditions. The inflammasome is an important inflammatory signalling platform that has been associated with low-grade chronic inflammatory diseases. Notably, activation and assembly of the inflammasome causes the auto cleavage of pro-caspase-1 into its active form, which then processes the pro-inflammatory cytokines pro-interleukin (IL)-1β and pro-IL-18 into their active forms. Currently, the nod-like receptor protein 3 (NLRP3) inflammasome has been implicated in the development of CKD in pre-clinical and clinical settings, and the ablation or inhibition of inflammasome components have been shown to be reno-protective in models of CKD. While clinical trials have demonstrated that neutralisation of IL-1β signalling by the drug anakinra lowers inflammation markers in haemodialysis patients, ongoing preclinical studies are showing that this ability to attenuate disease is limited in progressive models of kidney disease. These results suggest a potential predominant role for IL-18 in the development of CKD. This review will discuss the role of the inflammasome and its pro-inflammatory product IL-18 in the development of renal fibrosis and inflammation that contribute to the pathophysiology of CKD. Furthermore, we will examine the potential of the IL-18 signalling axis as an anti-inflammatory target in CKD and its usefulness as diagnostic biomarker to predict acute kidney injury.
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Affiliation(s)
- Jordyn M Thomas
- Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Brooke M Huuskes
- Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology & Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, Australia
| | - Christopher G Sobey
- Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology & Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, Australia
| | - Grant R Drummond
- Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology & Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, Australia.
| | - Antony Vinh
- Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology & Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, Australia
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The Interleukin-1 (IL-1) Superfamily Cytokines and Their Single Nucleotide Polymorphisms (SNPs). J Immunol Res 2022; 2022:2054431. [PMID: 35378905 PMCID: PMC8976653 DOI: 10.1155/2022/2054431] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/24/2022] [Accepted: 03/08/2022] [Indexed: 12/19/2022] Open
Abstract
Interleukins (ILs)—which are important members of cytokines—consist of a vast group of molecules, including a wide range of immune mediators that contribute to the immunological responses of many cells and tissues. ILs are immune-glycoproteins, which directly contribute to the growth, activation, adhesion, differentiation, migration, proliferation, and maturation of immune cells; and subsequently, they are involved in the pro and anti-inflammatory responses of the body, by their interaction with a wide range of receptors. Due to the importance of immune system in different organisms, the genes belonging to immune elements, such as ILs, have been studied vigorously. The results of recent investigations showed that the genes pertaining to the immune system undergo progressive evolution with a constant rate. The occurrence of any mutation or polymorphism in IL genes may result in substantial changes in their biology and function and may be associated with a wide range of diseases and disorders. Among these abnormalities, single nucleotide polymorphisms (SNPs) can represent as important disruptive factors. The present review aims at concisely summarizing the current knowledge available on the occurrence, properties, role, and biological consequences of SNPs within the IL-1 family members.
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Linh H, Iwata Y, Senda Y, Sakai-Takemori Y, Nakade Y, Oshima M, Yoneda-Nakagawa S, Ogura H, Sato K, Minami T, Kitajima S, Toyama T, Yamamura Y, Miyakawa T, Hara A, Shimizu M, Furuichi K, Sakai N, Yamada H, Asanuma K, Matsushima K, Wada T. Intestinal Bacterial Translocation Contributes to Diabetic Kidney Disease. J Am Soc Nephrol 2022; 33:1105-1119. [PMID: 35264456 PMCID: PMC9161796 DOI: 10.1681/asn.2021060843] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 02/22/2022] [Indexed: 11/03/2022] Open
Abstract
Background In recent years, many studies have focused on the intestinal environment to elucidate pathogenesis of various diseases, including kidney diseases. Impairment of the intestinal barrier function, the "leaky gut," reportedly contributes to pathological processes in some disorders. Mitochondrial antiviral signaling protein (MAVS), a component of innate immunity, maintains intestinal integrity. The effects of disrupted intestinal homeostasis associated with MAVS signaling in diabetic kidney disease remains unclear. Methods To evaluate the contribution of intestinal barrier impairment to kidney injury under diabetic conditions, we induced diabetic kidney disease in wild-type and MAVS knockout mice through unilateral nephrectomy and streptozotocin treatment. We then assessed effects on the kidney, intestinal injuries, and bacterial translocation. Results MAVS knockout diabetic mice showed more severe glomerular and tubular injuries compared with wild-type diabetic mice. Owing to impaired intestinal integrity, the presence of intestine-derived Klebsiella oxytoca and elevated IL-17 were detected in the circulation and kidneys of diabetic mice, especially in diabetic MAVS knockout mice. Stimulation of tubular epithelial cells with K. oxytoca activated MAVS pathways and the phosphorylation of Stat3 and ERK1/2, leading to the production of kidney injury molecule-1 (KIM-1). Nevertheless, MAVS inhibition induced inflammation in the intestinal epithelial cells and KIM-1 production in tubular epithelial cells under K. oxytoca supernatant or IL-17 stimulation. Treatment with neutralizing anti-IL-17 antibody treatment had renoprotective effects. In contrast, lipopolysaccharide administration accelerated kidney injury in the murine diabetic kidney disease model. Conclusions Impaired MAVS signaling both in the kidney and intestine contributes to the disrupted homeostasis, leading to diabetic kidney disease progression. Controlling intestinal homeostasis may offer a novel therapeutic approach for this condition.
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Affiliation(s)
- Hoang Linh
- H Linh, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Yasunori Iwata
- Y Iwata, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Yasuko Senda
- Y Senda, Division of Infection Control, Kanazawa University Hospital, Kanazawa, Japan
| | - Yukiko Sakai-Takemori
- Y Sakai-Takemori, Division of Infection Control, Kanazawa University Hospital, Kanazawa, Japan
| | - Yusuke Nakade
- Y Nakade, Division of Infection Control, Kanazawa University Hospital, Kanazawa, Japan
| | - Megumi Oshima
- M Oshima, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Shiori Yoneda-Nakagawa
- S Yoneda-Nakagawa, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Hisayuki Ogura
- H Ogura, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Koichi Sato
- K Sato, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Taichiro Minami
- T Minami, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Shinji Kitajima
- S Kitajima, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Tadashi Toyama
- T Toyama, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Yuta Yamamura
- Y Yamamura, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Taro Miyakawa
- T Miyakawa, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Akinori Hara
- A Hara, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Miho Shimizu
- M Shimizu, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Kengo Furuichi
- K Furuichi, Division of Nephrology, Kanazawa Medical University School of Medicine Graduate School of Medicine, Kahoku-gun, Japan
| | - Norihiko Sakai
- N Sakai, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Hiroyuki Yamada
- H Yamada, Department of Nephrology, Chiba University Graduate School of Medicine School of Medicine, Chiba, Japan
| | - Katsuhiko Asanuma
- K Asanuma, Department of Nephrology, Chiba University Graduate School of Medicine School of Medicine, Chiba, Japan
| | - Kouji Matsushima
- K Matsushima, Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute of Biomedical Sciences, Tokyo University of Science, Shinjuku-ku, Japan
| | - Takashi Wada
- T Wada, Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
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11
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Thomas JM, Ling YH, Huuskes B, Jelinic M, Sharma P, Saini N, Ferens DM, Diep H, Krishnan SM, Kemp-Harper BK, O'Connor PM, Latz E, Arumugam TV, Guzik TJ, Hickey MJ, Mansell A, Sobey CG, Vinh A, Drummond GR. IL-18 (Interleukin-18) Produced by Renal Tubular Epithelial Cells Promotes Renal Inflammation and Injury During Deoxycorticosterone/Salt-Induced Hypertension in Mice. Hypertension 2021; 78:1296-1309. [PMID: 34488433 DOI: 10.1161/hypertensionaha.120.16437] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
IL-18 (interleukin-18) is elevated in hypertensive patients, but its contribution to high blood pressure and end-organ damage is unknown. We examined the role of IL-18 in the development of renal inflammation and injury in a mouse model of low-renin hypertension. Hypertension was induced in male C57BL6/J (WT) and IL-18−/− mice by uninephrectomy, deoxycorticosterone acetate (2.4 mg/d, s.c.) and 0.9% drinking saline (1K/DOCA/salt). Normotensive controls received uninephrectomy and placebo (1K/placebo). Blood pressure was measured via tail cuff or radiotelemetry. After 21 days, kidneys were harvested for (immuno)histochemical, quantitative-PCR and flow cytometric analyses of fibrosis, inflammation, and immune cell infiltration. 1K/DOCA/salt-treated WT mice developed hypertension, renal fibrosis, upregulation of proinflammatory genes, and accumulation of CD3+ T cells in the kidneys. They also displayed increased expression of IL-18 on tubular epithelial cells. IL-18−/− mice were profoundly protected from hypertension, renal fibrosis, and inflammation. Bone marrow transplantation between WT and IL-18−/− mice revealed that IL-18-deficiency in non-bone marrow-derived cells alone afforded equivalent protection against hypertension and renal injury as global IL-18 deficiency. IL-18 receptor subunits—interleukin-18 receptor 1 and IL-18R accessory protein—were upregulated in kidneys of 1K/DOCA/salt-treated WT mice and localized to T cells and tubular epithelial cells. T cells from kidneys of 1K/DOCA/salt-treated mice produced interferon-γ upon ex vivo stimulation with IL-18, whereas those from 1K/placebo mice did not. In conclusion, IL-18 production by tubular epithelial cells contributes to elevated blood pressure, renal inflammation, and fibrosis in 1K/DOCA/salt-treated mice, highlighting it as a promising therapeutic target for hypertension and kidney disease.
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Affiliation(s)
- Jordyn M Thomas
- Centre for Cardiovascular Biology and Disease Research and Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., C.G.S., A.V., G.R.D.)
| | - Yeong H Ling
- Department of Pharmacology, Biomedicine Discovery Institute, Cardiovascular Disease Program, Monash University, Clayton, Australia (Y.H.L., D.M.F., S.M.K., B.K.K.-H.)
| | - Brooke Huuskes
- Centre for Cardiovascular Biology and Disease Research and Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., C.G.S., A.V., G.R.D.)
| | - Maria Jelinic
- Centre for Cardiovascular Biology and Disease Research and Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., C.G.S., A.V., G.R.D.)
| | - Prerna Sharma
- Centre for Cardiovascular Biology and Disease Research and Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., C.G.S., A.V., G.R.D.)
| | - Narbada Saini
- Centre for Cardiovascular Biology and Disease Research and Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., C.G.S., A.V., G.R.D.)
| | - Dorota M Ferens
- Department of Pharmacology, Biomedicine Discovery Institute, Cardiovascular Disease Program, Monash University, Clayton, Australia (Y.H.L., D.M.F., S.M.K., B.K.K.-H.)
| | - Henry Diep
- Centre for Cardiovascular Biology and Disease Research and Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., C.G.S., A.V., G.R.D.)
| | - Shalini M Krishnan
- Department of Pharmacology, Biomedicine Discovery Institute, Cardiovascular Disease Program, Monash University, Clayton, Australia (Y.H.L., D.M.F., S.M.K., B.K.K.-H.)
| | - Barbara K Kemp-Harper
- Department of Pharmacology, Biomedicine Discovery Institute, Cardiovascular Disease Program, Monash University, Clayton, Australia (Y.H.L., D.M.F., S.M.K., B.K.K.-H.)
| | - Paul M O'Connor
- Department of Physiology, Medical College of Georgia, Augusta University (P.M.O.)
| | - Eicke Latz
- Institute of Innate Immunity, University Hospital, University of Bonn, Germany (E.L.)
- German Center for Neurodegenerative Diseases, Bonn, Germany (E.L.)
| | - Thiruma V Arumugam
- Centre for Cardiovascular Biology and Disease Research and Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., C.G.S., A.V., G.R.D.)
| | - Tomasz J Guzik
- Department of Medicine, Jagiellonian University, Collegium Medicum, Krakow, Poland (T.J.G.)
- BHF Centre of Research Excellence, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (T.J.G.)
| | - Michael J Hickey
- Department of Medicine, Centre for Inflammatory Diseases, Monash University, Clayton, Australia (M.J.H.)
| | - Ashley Mansell
- Hudson Institute of Medical Research, Clayton, Australia (A.M.)
| | - Christopher G Sobey
- Centre for Cardiovascular Biology and Disease Research and Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., C.G.S., A.V., G.R.D.)
- Baker Heart and Diabetes Institute, Prahran, Australia (C.G.S., G.R.D.)
| | - Antony Vinh
- Centre for Cardiovascular Biology and Disease Research and Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., C.G.S., A.V., G.R.D.)
| | - Grant R Drummond
- Centre for Cardiovascular Biology and Disease Research and Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, Australia (J.M.T., B.M.H., M.J., P.S., N.S., H.D., T.V.A., C.G.S., A.V., G.R.D.)
- Baker Heart and Diabetes Institute, Prahran, Australia (C.G.S., G.R.D.)
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12
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Wu YR, Hsing CH, Chiu CJ, Huang HY, Hsu YH. Roles of IL-1 and IL-10 family cytokines in the progression of systemic lupus erythematosus: Friends or foes? IUBMB Life 2021; 74:143-156. [PMID: 34668305 DOI: 10.1002/iub.2568] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 09/03/2021] [Accepted: 09/28/2021] [Indexed: 12/20/2022]
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology that can affect nearly every organ system in the body. Besides genetic and environmental factors, unbalanced pro-inflammatory and anti-inflammatory cytokines contribute to immune dysregulation, trigger an inflammatory response, and induce tissue and organ damage. Inflammatory responses in SLE can be promoted and/or maintained by the availability of cytokines that are overproduced systemically and/or in local tissues. Several key cytokines have been considered potential targets for the reduction of chronic inflammation in SLE. Recent studies indicated that dysregulated production of several cytokines, including those of the IL-1 family and IL-10 family, orchestrate immune activation and self-tolerance, play critical roles in the pathogenesis of SLE. Among IL-1 family cytokines, IL-1, IL-18, IL-33, IL-36, IL-37, and IL-38 had been the most thoroughly investigated in SLE. Additionally, IL-10 family cytokines, IL-10, IL-20, IL-22, IL-26, IL-28, and IL-29 are dysregulated in SLE. Therefore, a better understanding of the initiation and progression of SLE may provide suitable novel targets for therapeutic intervention. In this review, we discuss the involvement of inflammation in the pathogenesis of SLE, with a focus on IL-1 family and IL-10 family cytokines, and highlight pathophysiological approaches and therapeutic potential for treating SLE.
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Affiliation(s)
- Yi-Rou Wu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chung-Hsi Hsing
- Department of Anesthesiology, Chi Mei Medical Center, Tainan, Taiwan.,Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
| | - Chiao-Juno Chiu
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hsin-Yi Huang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Hsiang Hsu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Clinical Medicine Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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13
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Zhang KJ, Wu Q, Jiang SM, Ding L, Liu CX, Xu M, Wang Y, Zhou Y, Li L. Pyroptosis: A New Frontier in Kidney Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6686617. [PMID: 34007404 PMCID: PMC8102120 DOI: 10.1155/2021/6686617] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 03/31/2021] [Accepted: 04/20/2021] [Indexed: 12/18/2022]
Abstract
Pyroptosis is a pattern of programmed cell death that significantly differs from apoptosis and autophagy in terms of cell morphology and function. The process of pyroptosis is characterized predominantly by the formation of gasdermin protein family-mediated membrane perforation, cell collapse, and the release of inflammatory factors, including IL-1β and IL-18. In recent years, with the rise of pyroptosis research, scholars have devoted time to study the mechanism of pyroptosis in kidney-related diseases. Pyroptosis is probably involved in kidney diseases through two pathways: the caspase-1-mediated canonical pathway and the caspase-4/5/11-mediated noncanonical pathway. In addition, some scholars have identified targets for the treatment of kidney-related diseases from the viewpoint of pyroptosis and developed corresponding medicines, which may become a recommendation for prognosis, targeted treatment, and clinical diagnosis of kidney diseases. This paper focuses on the up-to-date advances in the field of pyroptosis, especially on the key pathogenic role of pyroptosis in the development and progression of kidney diseases. It presents a more in-depth understanding of the pathogenesis of kidney diseases and introduces novel therapeutic targets for the prevention and clinical treatment of kidney diseases.
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Affiliation(s)
- Ke-jia Zhang
- Department of Pathophysiology, Xuzhou Medical University, Xuzhou 221009, China
- Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou 221009, China
| | - Qi Wu
- Department of Physiology, Xuzhou Medical University, Xuzhou 221009, China
| | - Shi-min Jiang
- Department of Pathophysiology, Xuzhou Medical University, Xuzhou 221009, China
| | - Lei Ding
- Department of Pathophysiology, Xuzhou Medical University, Xuzhou 221009, China
| | - Chao-xia Liu
- Department of Pathophysiology, Xuzhou Medical University, Xuzhou 221009, China
| | - Ming Xu
- Department of Pathophysiology, Xuzhou Medical University, Xuzhou 221009, China
| | - Ying Wang
- Department of Pathophysiology, Xuzhou Medical University, Xuzhou 221009, China
| | - Yao Zhou
- Department of Pathophysiology, Xuzhou Medical University, Xuzhou 221009, China
- Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou 221009, China
| | - Li Li
- Department of Pathophysiology, Xuzhou Medical University, Xuzhou 221009, China
- Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou 221009, China
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14
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Ma J, Lam IKY, Lau CS, Chan VSF. Elevated Interleukin-18 Receptor Accessory Protein Mediates Enhancement in Reactive Oxygen Species Production in Neutrophils of Systemic Lupus Erythematosus Patients. Cells 2021; 10:cells10050964. [PMID: 33919154 PMCID: PMC8143138 DOI: 10.3390/cells10050964] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/16/2021] [Accepted: 04/19/2021] [Indexed: 12/19/2022] Open
Abstract
Interleukin-18 receptor accessory protein (IL18RAP) is an indispensable subunit for the IL-18 receptor (IL-18R) complex's ability to mediate high-affinity IL-18 binding and signalling transduction. Interest in IL-18 in systemic lupus erythematosus (SLE) has been mostly focused on its role as a type 1 T helper cell-driving cytokine. The functional significance of IL18RAP in mediating the IL-18-driven response in myeloid cells in SLE remains largely unexplored. This study aimed to investigate the expression and function significance of IL18RAP in neutrophils of SLE patients. By qRT-PCR and Western blot analyses, elevated expressions of IL18RAP mRNA and protein were observed in neutrophils from SLE patients-particularly those with a history of nephritis. IL18RAP expression correlated negatively with complement 3 level and positively with disease activity, with higher expression in patients exhibiting renal and immunological manifestations. The increased IL18RAP expression in SLE neutrophils could be attributed to elevated type I interferon level in sera. Functionally, neutrophils from SLE patients showed higher IL-18-mediated enhancement in reactive oxygen species (ROS) generation, which showed positive correlation with IL18RAP expression and could be neutralized by anti-IL18RAP blocking antibodies. Taken together, our findings suggest that IL-18 could contribute to SLE pathogenesis through mediation of neutrophil dysfunction via the upregulation of IL18RAP expression.
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15
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McLeod DJ, Sebastião YV, Ching CB, Greenberg JH, Furth SL, Becknell B. Longitudinal kidney injury biomarker trajectories in children with obstructive uropathy. Pediatr Nephrol 2020; 35:1907-1914. [PMID: 32444926 PMCID: PMC7502482 DOI: 10.1007/s00467-020-04602-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 05/01/2020] [Accepted: 05/05/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Congenital obstructive uropathy (OU) is a leading cause of pediatric kidney failure, representing a unique mechanism of injury, in part from renal tubular stretch and ischemia. Tubular injury biomarkers have potential to improve OU-specific risk stratification. METHODS Patients with OU were identified in the Chronic Kidney Disease in Children (CKiD) study. "Cases" were defined as individuals receiving any kidney replacement therapy (KRT), while "controls" were age- and time-on-study matched and KRT free at last study visit. Urine and plasma neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), and liver-type fatty acid-binding protein (L-FABP) levels were measured at enrollment and annually and compared between cases and controls. Urine values were normalized to urine creatinine. RESULTS In total, 22 cases and 22 controls were identified, with median (interquartile range) ages of 10.5 (9.0-13.0) and 15.9 (13.9-16.9) years at baseline and outcome, respectively. At enrollment there were no differences noted between cases and controls for any urine (u) or plasma (p) biomarker measured. However, the mean pNGAL and uL-FABP/creatinine increased throughout the study period in cases (15.38 ng/ml per year and 0.20 ng/ml per mg/dl per year, respectively, p = 0.01 for both) but remained stable in controls. This remained constant after controlling for baseline glomerular filtration rate (GFR). CONCLUSIONS In children with OU, pNGAL and uL-FABP levels increased over the 5 years preceding KRT; independent of baseline GFR. Future studies are necessary to identify optimal cutoff values and to determine if these markers outperform current clinical predictors.
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Affiliation(s)
- Daryl J McLeod
- Section of Urology, Nationwide Children's Hospital, Columbus, OH, 43205, USA.
- Center for Surgical Outcomes Research, Nationwide Children's Hospital, Columbus, OH, 43205, USA.
| | - Yuri V Sebastião
- Center for Surgical Outcomes Research, Nationwide Children's Hospital, Columbus, OH, 43205, USA
| | - Christina B Ching
- Section of Urology, Nationwide Children's Hospital, Columbus, OH, 43205, USA
- Center for Clinical and Translational Research, Nationwide Children's Hospital, Columbus, OH, 43205, USA
| | - Jason H Greenberg
- Department of Pediatrics, Section of Nephrology, Yale University School of Medicine, New Haven, CT, 06510, USA
| | - Susan L Furth
- Department of Pediatrics, Division of Nephrology, Perelman School of Medicine at the University of Pennsylvania and the Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Brian Becknell
- Center for Clinical and Translational Research, Nationwide Children's Hospital, Columbus, OH, 43205, USA
- Department of Pediatrics, Section of Nephrology, Nationwide Children's Hospital, Columbus, OH, 43205, USA
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16
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Migliorini P, Italiani P, Pratesi F, Puxeddu I, Boraschi D. The IL-1 family cytokines and receptors in autoimmune diseases. Autoimmun Rev 2020; 19:102617. [PMID: 32663626 DOI: 10.1016/j.autrev.2020.102617] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Accepted: 03/13/2020] [Indexed: 12/12/2022]
Abstract
The role of the cytokines and receptors of the IL-1 family in inflammation is well known. Several cytokines of the family have a powerful inflammatory activity, with IL-1β being the best-characterized factor. The inflammatory activity of IL-1 cytokines is regulated by other factors of the family, including receptor antagonists, soluble receptors and anti-inflammatory cytokines. The causative role of IL-1β is well-established in autoinflammatory diseases, mainly due to gain-of-function mutations in genes encoding the IL-1β-maturing inflammasome. Exaggerated production of IL-1β and IL-18 correlates with disease and disease severity also in several autoimmune and chronic inflammatory and degenerative pathologies, although it is not clear whether they have a causative role or are only involved in the downstream disease symptoms. A better understanding of the pathological role of IL-1 family cytokines in autoimmunity involves a deeper evaluation, in the pathological situations, of the possible anomalies in the feed-back anti-inflammatory mechanisms that in physiological reactions control and dump IL-1-mediated inflammation. Thus, we expect that IL-1 cytokines may be pathogenic only when, in addition to enhanced production, there is a concomitant failure of their control mechanisms. In this review we will examine the current knowledge on the role of IL-1 family cytokines in autoimmune and chronic inflammatory and degenerative diseases, with a particular focus on their endogenous control mechanisms, mainly based on soluble receptors/inhibitors and receptor antagonists. This will allow us to formulate a knowledge-based hypothesis on the involvement of IL-1 cytokines in the pathogenesis vs. the clinical features of these diseases.
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Affiliation(s)
- Paola Migliorini
- Clinical Immunology and Allergy Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | - Paola Italiani
- Institute of Biochemistry and Cell Biology, National Research Council, Via Pietro Castellino 111, 80131 Napoli, Italy
| | - Federico Pratesi
- Clinical Immunology and Allergy Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | - Ilaria Puxeddu
- Clinical Immunology and Allergy Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | - Diana Boraschi
- Institute of Biochemistry and Cell Biology, National Research Council, Via Pietro Castellino 111, 80131 Napoli, Italy
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17
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Shi Y, Huang C, Zhao Y, Cao Q, Yi H, Chen X, Pollock C. RIPK3 blockade attenuates tubulointerstitial fibrosis in a mouse model of diabetic nephropathy. Sci Rep 2020; 10:10458. [PMID: 32591618 PMCID: PMC7319952 DOI: 10.1038/s41598-020-67054-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 05/19/2020] [Indexed: 12/31/2022] Open
Abstract
Receptor-interacting protein kinase-3 (RIPK3) is a multifunctional regulator of cell death and inflammation. RIPK3 controls cellular signalling through the formation of the domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which is recognised to mediate renal fibrogenesis. The role of RIPK3 in diabetic kidney disease (DKD) induced renal fibrosis has not been previously determined. To define the action of RIPK3 in the development of diabetic kidney disease, wild-type (WT), RIPK3 -/- and endothelium-derived nitric oxide synthase (eNOS)-/- mice were induced to develop diabetes mellitus using multiple low doses of streptozotocin and maintained for 24 weeks. RIPK3 activity and NLRP3 expression were upregulated and fibrotic responses were increased in the kidney cortex of WT mice with established diabetic nephropathy compared to control mice. Consistently, mRNA expression of inflammasome components, as well as transforming growth factor beta 1 (TGFβ1), α smooth muscle actin (α-SMA) and collagen deposition were increased in diabetic kidneys of WT mice compared to control mice. However, these markers were normalised or significantly reversed in kidneys of diabetic RIPK3 -/- mice. Renoprotection was also observed using the RIPK3 inhibitor dabrafenib in eNOS-/- diabetic mice as demonstrated by reduced collagen deposition and myofibroblast activation. These results suggest that RIPK3 is associated with the development of renal fibrosis in DKD due to the activation of the NLRP3 inflammasome. Inhibition of RIPK3 results in renoprotection. Thus, RIPK3 may be a potential target for therapeutic intervention in patients with diabetic kidney disease.
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Affiliation(s)
- Ying Shi
- University of Sydney, Sydney Medical School, Kolling Institute of Medical Research Sydney, Sydney, NSW, 2065, Australia
| | - Chunling Huang
- University of Sydney, Sydney Medical School, Kolling Institute of Medical Research Sydney, Sydney, NSW, 2065, Australia
| | - Yongli Zhao
- The Second Affiliated Hospital of Dalian Medical University, Department of Pediatrics 467 Zhongshan Road, Shahekou District Dalian, Liaoning, CN, 116027, China
| | - Qinghua Cao
- University of Sydney, Sydney Medical School, Kolling Institute of Medical Research Sydney, Sydney, NSW, 2065, Australia
| | - Hao Yi
- University of Sydney, Sydney Medical School, Kolling Institute of Medical Research Sydney, Sydney, NSW, 2065, Australia
| | - Xinming Chen
- University of Sydney, Sydney Medical School, Kolling Institute of Medical Research Sydney, Sydney, NSW, 2065, Australia
| | - Carol Pollock
- University of Sydney, Sydney Medical School, Kolling Institute of Medical Research Sydney, Sydney, NSW, 2065, Australia.
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18
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Hughes SF, Jones N, Thomas-Wright SJ, Banwell J, Moyes AJ, Shergill I. Shock wave lithotripsy, for the treatment of kidney stones, results in changes to routine blood tests and novel biomarkers: a prospective clinical pilot-study. Eur J Med Res 2020; 25:18. [PMID: 32487191 PMCID: PMC7268594 DOI: 10.1186/s40001-020-00417-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 05/27/2020] [Indexed: 12/04/2022] Open
Abstract
Background The number of patients undergoing shock wave lithotripsy (SWL) for kidney stones is increasing annually, and as such the development of post-operative complications, such as haematuria and acute kidney injury (AKI) following SWL, is likely to increase. The aim of the study was to evaluate changes in routine blood and novel biomarkers following SWL, for the treatment of kidney stones. Methods Twelve patients undergoing SWL for solitary unilateral kidney stones were recruited. From patients (8 males and 4 females) aged between 31 and 72 years (median 43 years), venous blood samples were collected pre-operatively (baseline), at 30, 120 and 240 min post-operatively. Routine blood tests were performed using a Sysmex XE-5000, and Beckman Coulter AU5800 and AU680 analysers. NGAL, IL-18, IL-6, TNF-α, IL-10 and IL-8 concentrations were determined using commercially available ELISA kits. Results Significant (p ≤ 0.05) changes were observed in several blood parameters following SWL. NGAL concentration significantly increased, with values peaking at 30 min post-treatment (p = 0.033). Although IL-18 concentration increased, these changes were not significant (p = 0.116). IL-6 revealed a statistically significant rise from pre-operative up to 4 h post-operatively (p < 0.001), whilst TNF-α significantly increased, peaking at 30 min post-SWL (p = 0.05). There were no significant changes to IL-10 and IL-8 concentrations post-SWL (p > 0.05). Conclusions Changes to routine blood tests and specific biomarkers, in the future, may be more useful for clinicians. In turn, identification of a panel of biomarkers could provide valuable data on “normal” physiological response after lithotripsy. Ultimately, studies could be expanded to identify or predict those patients at increased risk of developing post-operative complications, such as acute kidney injury or. These studies, however, need validating involving larger cohorts.
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Affiliation(s)
- Stephen F Hughes
- North Wales Clinical Research Centre, Betsi Cadwaladr University Health Board (BCUHB) Wrexham Maelor Hospital, Wrexham, Wales, UK. .,North Wales & North West Urological Research Centre, Betsi Cadwaladr University Health Board (BCUHB) Wrexham Maelor Hospital, Wrexham, Wales, UK.
| | - Nathan Jones
- Department of Biological Sciences, University of Chester, Chester, UK.,Department of Haematology, Countess of Chester Hospital, Chester, UK
| | - Samantha J Thomas-Wright
- North Wales & North West Urological Research Centre, Betsi Cadwaladr University Health Board (BCUHB) Wrexham Maelor Hospital, Wrexham, Wales, UK.,Department of Blood Sciences, BCUHB Wrexham Maelor Hospital, Wrexham, Wales, UK
| | - Joseph Banwell
- North Wales & North West Urological Research Centre, Betsi Cadwaladr University Health Board (BCUHB) Wrexham Maelor Hospital, Wrexham, Wales, UK.,Department of Blood Sciences, BCUHB Wrexham Maelor Hospital, Wrexham, Wales, UK
| | - Alyson J Moyes
- North Wales & North West Urological Research Centre, Betsi Cadwaladr University Health Board (BCUHB) Wrexham Maelor Hospital, Wrexham, Wales, UK.,Department of Biological Sciences, University of Chester, Chester, UK.,School of Medical Sciences, Bangor University, Bangor, Wales, UK
| | - Iqbal Shergill
- North Wales Clinical Research Centre, Betsi Cadwaladr University Health Board (BCUHB) Wrexham Maelor Hospital, Wrexham, Wales, UK.,North Wales & North West Urological Research Centre, Betsi Cadwaladr University Health Board (BCUHB) Wrexham Maelor Hospital, Wrexham, Wales, UK.,The Alan de Bolla Department of Urology, BCUHB Wrexham Maelor Hospital, Wrexham, Wales, UK
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19
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Zhang H, Wang Z. Effect and Regulation of the NLRP3 Inflammasome During Renal Fibrosis. Front Cell Dev Biol 2020; 7:379. [PMID: 32039201 PMCID: PMC6992891 DOI: 10.3389/fcell.2019.00379] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 12/17/2019] [Indexed: 12/15/2022] Open
Abstract
Renal fibrosis is a common pathological process where certain primary or secondary kidney diseases can continue to progress to the end-stage of the kidney disease; however, the molecular mechanisms underlying renal fibrosis remain unclear. Recently, research focusing on examining the function of inflammasomes has attracted a great deal of attention, and data derived from these research projects have increased our understanding of the effects and regulation of inflammasomes during renal fibrosis. Based on this, the present review summarizes recent findings in regard to NLRP3 inflammasome functions during various kidney diseases, and these findings indicate that the NLRP3 inflammasome not only mediates the inflammatory response but is also associated with pyroptosis, mitochondrial regulation, and myofibroblast differentiation during renal fibrosis. These novel findings provide us with a more in-depth understanding of the pathogenesis of renal fibrosis and will aid in the identification of new targets that can be used for the prevention and treatment of this disease.
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Affiliation(s)
- Hong Zhang
- Provincial Key Laboratory for Developmental Biology and Neurosciences, Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, China
| | - Zhengchao Wang
- Provincial Key Laboratory for Developmental Biology and Neurosciences, Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, China
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20
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Kim YG, Kim SM, Kim KP, Lee SH, Moon JY. The Role of Inflammasome-Dependent and Inflammasome-Independent NLRP3 in the Kidney. Cells 2019; 8:cells8111389. [PMID: 31694192 PMCID: PMC6912448 DOI: 10.3390/cells8111389] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 10/23/2019] [Accepted: 10/30/2019] [Indexed: 01/27/2023] Open
Abstract
Cytoplasmic nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) forms an inflammasome with apoptosis-associated speck-like protein containing a CARD (ASC) and pro-caspase-1, which is followed by the cleavage of pro-caspase-1 to active caspase-1 and ultimately the activation of IL-1β and IL-18 and induction of pyroptosis in immune cells. NLRP3 activation in kidney diseases aggravates inflammation and subsequent fibrosis, and this effect is abrogated by genetic or pharmacologic deletion of NLRP3. Inflammasome-dependent NLRP3 mediates the progression of kidney diseases by escalating the inflammatory response in immune cells and the cross-talk between immune cells and renal nonimmune cells. However, recent studies have suggested that NLRP3 has several inflammasome-independent functions in the kidney. Inflammasome-independent NLRP3 regulates apoptosis in tubular epithelial cells by interacting with mitochondria and mediating mitochondrial reactive oxygen species production and mitophagy. This review will summarize the mechanisms by which NLRP3 functions in the kidney in both inflammasome-dependent and inflammasome-independent ways and the role of NLRP3 and NLRP3 inhibitors in kidney diseases.
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Affiliation(s)
- Yang Gyun Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University Medical School, Seoul 02447, Korea; (Y.G.K.); (S.-M.K.); (S.-H.L.)
| | - Su-Mi Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University Medical School, Seoul 02447, Korea; (Y.G.K.); (S.-M.K.); (S.-H.L.)
| | - Ki-Pyo Kim
- Division of Nephrology and Hypertension, Department of Internal Medicine, Inha University of Medicine, Incheon 22212, Korea;
| | - Sang-Ho Lee
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University Medical School, Seoul 02447, Korea; (Y.G.K.); (S.-M.K.); (S.-H.L.)
| | - Ju-Young Moon
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University Medical School, Seoul 02447, Korea; (Y.G.K.); (S.-M.K.); (S.-H.L.)
- Correspondence: ; Tel.: +82-2-440-6262
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21
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Kamel M, El-Sayed A. Utilization of herpesviridae as recombinant viral vectors in vaccine development against animal pathogens. Virus Res 2019; 270:197648. [PMID: 31279828 DOI: 10.1016/j.virusres.2019.197648] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Revised: 06/27/2019] [Accepted: 06/28/2019] [Indexed: 02/06/2023]
Abstract
Throughout the past few decades, numerous viral species have been generated as vaccine vectors. Every viral vector has its own distinct characteristics. For example, the family herpesviridae encompasses several viruses that have medical and veterinary importance. Attenuated herpesviruses are developed as vectors to convey heterologous immunogens targeting several serious and crucial pathogens. Some of these vectors have already been licensed for use in the veterinary field. One of their prominent features is their capability to accommodate large amount of foreign DNA, and to stimulate both cell-mediated and humoral immune responses. A better understanding of vector-host interaction builds up a robust foundation for the future development of herpesviruses-based vectors. At the time, many molecular tools are applied to enable the generation of herpesvirus-based recombinant vaccine vectors such as BAC technology, homologous and two-step en passant mutagenesis, codon optimization, and the CRISPR/Cas9 system. This review article highlights the most important techniques applied in constructing recombinant herpesviruses vectors, advantages and disadvantages of each recombinant herpesvirus vector, and the most recent research regarding their use to control major animal diseases.
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Affiliation(s)
- Mohamed Kamel
- Faculty of Veterinary Medicine, Department of Medicine and Infectious Diseases, Cairo University, Giza, Egypt.
| | - Amr El-Sayed
- Faculty of Veterinary Medicine, Department of Medicine and Infectious Diseases, Cairo University, Giza, Egypt
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22
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Miao N, Yin F, Xie H, Wang Y, Xu Y, Shen Y, Xu D, Yin J, Wang B, Zhou Z, Cheng Q, Chen P, Xue H, Zhou L, Liu J, Wang X, Zhang W, Lu L. The cleavage of gasdermin D by caspase-11 promotes tubular epithelial cell pyroptosis and urinary IL-18 excretion in acute kidney injury. Kidney Int 2019; 96:1105-1120. [PMID: 31405732 DOI: 10.1016/j.kint.2019.04.035] [Citation(s) in RCA: 152] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 04/02/2019] [Accepted: 04/25/2019] [Indexed: 02/08/2023]
Abstract
Inflammation and tubular cell death are the hallmarks of acute kidney injury. However, the precise mechanism underlying these effects has not been fully elucidated. Here we tested whether caspase-11, an inflammatory member of the caspase family, was increased in cisplatin or ischemia-reperfusion-induced acute kidney injury. Caspase-11 knockout mice after cisplatin treatment exhibited attenuated deterioration of renal functional, reduced tubular damage, reduced macrophage and neutrophil infiltration, and decreased urinary IL-18 excretion. Mechanistically, the upregulation of caspase-11 by either cisplatin or ischemia-reperfusion cleaved gasdermin D (GSDMD) into GSDMD-N, which translocated onto the plasma membrane, thus triggering cell pyroptosis and facilitated IL-18 release in primary cultured renal tubular cells. These results were further confirmed in GSDMD knockout mice that cisplatin-induced renal morphological and functional deterioration as well as urinary IL-18 excretion were alleviated. Furthermore, deficiency of GSDMD significantly suppressed cisplatin-induced IL-18 release but not the transcription and maturation level of IL-18 in tubular cells. Thus, our study indicates that caspase-11/GSDMD dependent tubule cell pyroptosis plays a significant role in initiating tubular cell damage, urinary IL-18 excretion and renal functional deterioration in acute kidney injury.
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Affiliation(s)
- Naijun Miao
- Department of Physiology and Pathophysiology, School of Basic Medicine Science, Fudan University, Shanghai, China
| | - Fan Yin
- Department of Physiology and Pathophysiology, School of Basic Medicine Science, Fudan University, Shanghai, China
| | - Hongyan Xie
- Department of Physiology and Pathophysiology, School of Basic Medicine Science, Fudan University, Shanghai, China
| | - Yanzhe Wang
- Department of Nephrology, Shanghai Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Yiang Xu
- Department of Physiology and Pathophysiology, School of Basic Medicine Science, Fudan University, Shanghai, China
| | - Yang Shen
- Department of Physiology and Pathophysiology, School of Basic Medicine Science, Fudan University, Shanghai, China
| | - Dan Xu
- Department of Physiology and Pathophysiology, School of Basic Medicine Science, Fudan University, Shanghai, China
| | - Jianyong Yin
- Department of Nephrology and Rheumatology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Bao Wang
- Department of Physiology and Pathophysiology, School of Basic Medicine Science, Fudan University, Shanghai, China
| | - Zhuanli Zhou
- Department of Physiology and Pathophysiology, School of Basic Medicine Science, Fudan University, Shanghai, China
| | - Qian Cheng
- Department of Physiology and Pathophysiology, School of Basic Medicine Science, Fudan University, Shanghai, China
| | - Panpan Chen
- Department of Physiology and Pathophysiology, School of Basic Medicine Science, Fudan University, Shanghai, China
| | - Hong Xue
- Department of Physiology and Pathophysiology, School of Basic Medicine Science, Fudan University, Shanghai, China
| | - Li Zhou
- Department of Physiology and Pathophysiology, School of Basic Medicine Science, Fudan University, Shanghai, China
| | - Jun Liu
- Department of Physiology and Pathophysiology, School of Basic Medicine Science, Fudan University, Shanghai, China
| | - Xiaoxia Wang
- Department of Nephrology, Shanghai Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, China.
| | - Wei Zhang
- Department of Physiology and Pathophysiology, School of Basic Medicine Science, Fudan University, Shanghai, China.
| | - Limin Lu
- Department of Physiology and Pathophysiology, School of Basic Medicine Science, Fudan University, Shanghai, China.
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23
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Mulay SR. Multifactorial functions of the inflammasome component NLRP3 in pathogenesis of chronic kidney diseases. Kidney Int 2019; 96:58-66. [PMID: 30922667 DOI: 10.1016/j.kint.2019.01.014] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 01/01/2019] [Accepted: 01/04/2019] [Indexed: 12/26/2022]
Abstract
The NLRP3 inflammasome is a cytosolic multiprotein caspase-activating complex platform involved in innate immunity required for the maturation and release of interleukin (IL)-1β and IL-18. Both cytokines activate their respective receptors present on cells inside and outside kidneys, resulting in the release of other proinflammatory cytokines to set up an inflammatory milieu both within the kidney and systemically. The canonical NLRP3-ASC-caspase-1-IL-1β-IL-18 axis has been shown to contribute to the pathophysiology of several kidney diseases by regulating renal necroinflammation. However, many recent studies have emphasized the inflammasome-independent functions of NLRP3 in chronic kidney disease (CKD) pathogenesis. This review highlights the contribution of the inflammasome-independent functions of NLPR3, for example, in fibrotic tissue remodeling, in tubular epithelial cell apoptosis, and in metabolic pathways, during the development and progression of CKD in various experimental models and humans. Interestingly, therapies targeting the inflammasome effectors (e.g., IL-1 receptor antagonists and IL-1β) have been approved for therapeutic use for NLRP3-dependent diseases; however, no NLRP3 antagonists have been approved for therapeutic use until now. This review highlights the double-edged sword-like functions of NLRP3 in the regulation of renal necroinflammation and fibrosis and therefore emphasizes the urgent need for specific NLRP3 inhibitors because of the broad therapeutic potential they offer for the treatment of CKD.
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Affiliation(s)
- Shrikant R Mulay
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India.
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24
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Wada Y, Gonzalez-Sanchez HM, Weinmann-Menke J, Iwata Y, Ajay AK, Meineck M, Kelley VR. IL-34-Dependent Intrarenal and Systemic Mechanisms Promote Lupus Nephritis in MRL- Faslpr Mice. J Am Soc Nephrol 2019; 30:244-259. [PMID: 30622154 DOI: 10.1681/asn.2018090901] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 11/16/2018] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND In people with SLE and in the MRL-Faslpr lupus mouse model, macrophages and autoantibodies are central to lupus nephritis. IL-34 mediates macrophage survival and proliferation, is expressed by tubular epithelial cells (TECs), and binds to the cFMS receptor on macrophages and to a newly identified second receptor, PTPRZ. METHODS To investigate whether IL-34-dependent intrarenal and systemic mechanisms promote lupus nephritis, we compared lupus nephritis and systemic illness in MRL-Faslpr mice expressing IL-34 and IL-34 knockout (KO) MRL-Faslpr mice. We also assessed expression of IL-34 and the cFMS and PTPRZ receptors in patients with lupus nephritis. RESULTS Intrarenal IL-34 and its two receptors increase during lupus nephritis in MRL-Faslpr mice. In knockout mice lacking IL-34, nephritis and systemic illness are suppressed. IL-34 fosters intrarenal macrophage accumulation via monocyte proliferation in bone marrow (which increases circulating monocytes that are recruited by chemokines into the kidney) and via intrarenal macrophage proliferation. This accumulation leads to macrophage-mediated TEC apoptosis. We also found suppression of circulating autoantibodies and glomerular antibody deposits in the knockout mice. This is consistent with fewer activated and proliferating intrarenal and splenic B cells in mice lacking IL-34, and with our novel discovery that PTPRZ is expressed by macrophages, B and T cells. These findings appear translatable to human patients with lupus nephritis, whose expression of IL-34, cFMS, and PTPRZ is similar to that seen in the MRL-Faslpr lupus mouse model. Moreover, expression of IL-34 in TECs correlates with disease activity. CONCLUSIONS IL-34 is a promising novel therapeutic target for patients with lupus nephritis.
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Affiliation(s)
- Yukihiro Wada
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; and
| | - Hilda M Gonzalez-Sanchez
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; and
| | - Julia Weinmann-Menke
- Department of Nephrology and Rheumatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Yasunori Iwata
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; and
| | - Amrendra K Ajay
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; and
| | - Myriam Meineck
- Department of Nephrology and Rheumatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Vicki R Kelley
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; and
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25
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Peng X, Yang T, Liu G, Liu H, Peng Y, He L. Piperine ameliorated lupus nephritis by targeting AMPK-mediated activation of NLRP3 inflammasome. Int Immunopharmacol 2018; 65:448-457. [PMID: 30388519 DOI: 10.1016/j.intimp.2018.10.025] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 10/15/2018] [Accepted: 10/16/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Lupus nephritis (LN) is a leading cause of mortality. The activation of NLRP3 inflammasome contributed to LN development and thus became a therapeutic target. Here we assessed the therapeutic potential of piperine, a bioactive compound known to target NLRP3 inflammasome, on LN development both in vivo and in vitro. METHODS LN was induced in BALB/c mice via intraperitoneal injection of pristane. Upon treatment with increasing doses of piperine, we assessed renal lesions, measured serum levels of pro-inflammatory cytokines, and examined expressions of key components of NLRP3 inflammasome in kidney. To explore the molecular mechanisms, we treated the proximal tubular epithelial HK-2 cells with lipopolysaccharide (LPS) and ATP, and examined the effects of piperine on pyroptosis and the activation of NLRP3 inflammasome. Furthermore, we assessed the significance of AMPK signaling in piperine functions in HK-2 cells. RESULTS In pristane-injected mice, piperine significantly ameliorated LN development in a dose-dependent manner, which was associated with the inhibition of NLRP3 inflammasome and the reduction of serum IL-1β, but not of IL-18 level. In HK-2 cells, piperine potently inhibited pyroptosis and the activation of NLRP3 inflammasome in response to LPS + ATP. The effects of piperine were mediated by blocking AMPK activation, and the AMPK agonist metformin bypassed the activities of piperine, and resumed pyroptosis as well as the activation on NLRP3 inflammasome. CONCLUSIONS By targeting AMPK, piperine significantly suppressed the activation of NLRP3 inflammasome, inhibited the release of pro-inflammatory cytokines, blocked the pyroptosis of tubular epithelial cells, and thus suppressed the development of LN.
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Affiliation(s)
- Xiaofei Peng
- Department of Rheumatology and Immunology, The Second Xiangya Hospital, Central South University, Changsha 410000, Hunan, PR China
| | - Tao Yang
- Department of Otolaryngology, Head and Neck Surgery, the Second Xiangya Hospital, Central South University, Changsha 410000, Hunan, PR China
| | - Guoyong Liu
- Department of Nephrology, The First Affiliated Hospital of Changde Vocational Technical College, Changde 415000, Hunan, PR China
| | - Hong Liu
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha 410000, Hunan, PR China
| | - Youming Peng
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha 410000, Hunan, PR China
| | - Liyu He
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha 410000, Hunan, PR China.
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26
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Kefaloyianni E, Muthu ML, Kaeppler J, Sun X, Sabbisetti V, Chalaris A, Rose-John S, Wong E, Sagi I, Waikar SS, Rennke H, Humphreys BD, Bonventre JV, Herrlich A. ADAM17 substrate release in proximal tubule drives kidney fibrosis. JCI Insight 2018; 1:87023. [PMID: 27642633 DOI: 10.1172/jci.insight.87023] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Kidney fibrosis following kidney injury is an unresolved health problem and causes significant morbidity and mortality worldwide. In a study into its molecular mechanism, we identified essential causative features. Acute or chronic kidney injury causes sustained elevation of a disintegrin and metalloprotease 17 (ADAM17); of its cleavage-activated proligand substrates, in particular of pro-TNFα and the EGFR ligand amphiregulin (pro-AREG); and of the substrates' receptors. As a consequence, EGFR is persistently activated and triggers the synthesis and release of proinflammatory and profibrotic factors, resulting in macrophage/neutrophil ingress and fibrosis. ADAM17 hypomorphic mice, specific ADAM17 inhibitor-treated WT mice, or mice with inducible KO of ADAM17 in proximal tubule (Slc34a1-Cre) were significantly protected against these effects. In vitro, in proximal tubule cells, we show that AREG has unique profibrotic actions that are potentiated by TNFα-induced AREG cleavage. In vivo, in acute kidney injury (AKI) and chronic kidney disease (CKD, fibrosis) patients, soluble AREG is indeed highly upregulated in human urine, and both ADAM17 and AREG expression show strong positive correlation with fibrosis markers in related kidney biopsies. Our results indicate that targeting of the ADAM17 pathway represents a therapeutic target for human kidney fibrosis.
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Affiliation(s)
| | | | - Jakob Kaeppler
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Xiaoming Sun
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Venkata Sabbisetti
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Athena Chalaris
- Institute for Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Stefan Rose-John
- Institute for Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Eitan Wong
- Weizmann Institute of Science, Rehovot, Israel
| | - Irit Sagi
- Weizmann Institute of Science, Rehovot, Israel
| | - Sushrut S Waikar
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Helmut Rennke
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Benjamin D Humphreys
- Division of Nephrology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Joseph V Bonventre
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Andreas Herrlich
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
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27
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He J, Sun M, Tian S. Procyanidin B2 prevents lupus nephritis development in mice by inhibiting NLRP3 inflammasome activation. Innate Immun 2018; 24:307-315. [PMID: 29874961 PMCID: PMC6830913 DOI: 10.1177/1753425918780985] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Lupus nephritis (LN) is a multifactorial event that contributes to the long-term mortality of systemic lupus erythematosus (SLE). Activation of NLRP3 inflammasome has been known to play a role in SLE pathogenesis. We evaluated the renal protection effects of procyanidin B2 (PCB2) and the involvement of NLRP3 in a mouse model involving MRL/lpr and MRL/MpJ mice. Kidney injury was evaluated by measuring the renal clinical and pathological features, renal immune complex deposition, and serum anti-double-stranded (anti-dsDNA) Abs. ELISA and Western blotting were used to detect NLRP3 inflammasome activation and IL-1β/IL-18 production. NLRP3 gene silencing was introduced into MRL/lpr mice by short hairpin RNA, and the renal damage was compared with the treatment of PCB2. PCB2 remarkably reduced renal damage in MRL/lpr mice, reflected by the reduced proteinuria, and serum levels of blood urea nitrogen and creatinine, as well as pathological features with less renal injury. PCB2 significantly reduced renal immune complex deposition and serum anti-dsDNA levels, notably inhibited the NLRP3 inflammasome activation, and reduced the renal and serum levels of IL-1β and IL-18 in MRL/lpr mice compared with those of NLRP3 gene-silenced MRL-lpr mice. PCB2 significantly suppressed LN in MRL-lpr mice by inhibiting the activation of NLRP3 inflammasome and subsequent IL-1β and IL-18 production. This finding explores a novel mechanism by which procyanidin exerts inflammatory suppression effects and its clinical benefits in LN prevention.
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Affiliation(s)
- Junhui He
- Department of Urology Surgery, Heze Municipal Hospital, China
| | - Mingchong Sun
- Department of Urology Surgery, Heze Municipal Hospital, China
| | - Sujian Tian
- Department of Urology Surgery, Heze Municipal Hospital, China
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28
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Yamanishi K, Mukai K, Hashimoto T, Ikubo K, Nakasho K, El-Darawish Y, Li W, Okuzaki D, Watanabe Y, Hayakawa T, Nojima H, Yamanishi H, Okamura H, Matsunaga H. Physiological and molecular effects of interleukin-18 administration on the mouse kidney. J Transl Med 2018. [PMID: 29514661 PMCID: PMC5842592 DOI: 10.1186/s12967-018-1426-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The cytokine interleukin-18 was originally identified as an interferon-γ-inducing proinflammatory factor; however, there is increasing evidence to suggest that it has non-immunological effects on physiological functions. We previously investigated the potential pathophysiological relationship between interleukin-18 and dyslipidemia, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis, and suggested interleukin-18 as a possible novel treatment for not only these diseases but also for cancer immunotherapy. Before clinical application, the effects of interleukin-18 on the kidney need to be determined. In the current study, we examined the kidney of interleukin-18 knockout (Il18-/-) mice and the effects of interleukin-18 on the kidney following intravenous administration of recombinant interleukin-18. METHODS Il18-/- male mice were generated on the C57Bl/6 background and littermate C57Bl/6 Il18+/+ male mice were used as controls. To assess kidney damage, serum creatinine and blood urea nitrogen levels were measured and histopathological analysis was performed. For molecular analysis, microarray and quantitative reverse transcription PCR was performed using mice 6 and 12 weeks old. To evaluate the short- and long-term effects of interleukin-18 on the kidney, recombinant interleukin-18 was administered for 2 and 12 weeks, respectively. RESULTS Compared with Il18+/+ mice, Il18-/- mice developed kidney failure in their youth-6 weeks of age, but the condition was observed to improve as the mice aged, even though dyslipidemia, arteriosclerosis, and higher insulin resistance occurred. Analyses of potential molecular mechanisms involved in the onset of early kidney failure in Il18-/- mice identified a number of associated genes, such as Itgam, Nov, and Ppard. Intravenous administration of recombinant interleukin-18 over both the short and long term showed no effects on the kidney despite significant improvement in metabolic diseases. CONCLUSIONS Short- and long-term administration of interleukin-18 appeared to have no adverse effects on the kidney in these mice, suggesting that administration may be a safe and novel treatment for metabolic diseases and cancer.
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Affiliation(s)
- Kyosuke Yamanishi
- Department of Neuropsychiatry, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Keiichiro Mukai
- Department of Neuropsychiatry, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Takuya Hashimoto
- Department of Neuropsychiatry, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Kaoru Ikubo
- Department of Neuropsychiatry, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Keiji Nakasho
- Department of Pathology, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Yosif El-Darawish
- Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Wen Li
- Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Daisuke Okuzaki
- DNA-Chip Development Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, 565-0871, Japan.,Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, 565-0871, Japan
| | - Yuko Watanabe
- Hirakata General Hospital for Developmental Disorders, 2-1-1 Tsudahigashi, Hirakata, Osaka, 573-0122, Japan
| | - Tetsu Hayakawa
- Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Hiroshi Nojima
- DNA-Chip Development Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, 565-0871, Japan.,Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, 565-0871, Japan
| | - Hiromichi Yamanishi
- Hirakata General Hospital for Developmental Disorders, 2-1-1 Tsudahigashi, Hirakata, Osaka, 573-0122, Japan
| | - Haruki Okamura
- Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
| | - Hisato Matsunaga
- Department of Neuropsychiatry, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan.
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Italiani P, Manca ML, Angelotti F, Melillo D, Pratesi F, Puxeddu I, Boraschi D, Migliorini P. IL-1 family cytokines and soluble receptors in systemic lupus erythematosus. Arthritis Res Ther 2018; 20:27. [PMID: 29422069 PMCID: PMC5806463 DOI: 10.1186/s13075-018-1525-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Accepted: 01/22/2018] [Indexed: 12/13/2022] Open
Abstract
Background Dysregulated production of cytokines has a critical role in systemic lupus. The aim of this work is to identify, by a comprehensive analysis of IL-1 family cytokines and receptors in serum, correlation between cytokines/receptors’ levels and the clinical and serological features of the disease. Methods A full clinical evaluation was performed in 74 patients with systemic lupus erythematosus (SLE). C3, C4, anti-dsDNA and anti-C1q antibodies were measured. Cytokines of the IL-1 family (IL-1α, IL-1β, IL-33, IL-18), soluble receptors (sIL-1R1, sIL-1R2, sIL-1R3, ST2/sIL-1R4) and antagonists (IL-1Ra, IL-18 binding protein (IL-18BP)) were measured in serum by multiarray ELISA. Free IL-18 was calculated as the amount of IL-18 not inhibited by IL-18BP. Data were analysed by non-parametric tests and by multivariate analysis, using partial least squares (PLS) models. Results Total IL-18, IL-18BP, sIL-1R4 and IL-1Ra levels were higher in SLE vs. controls. Total and free IL-18 and sIL-1R4 were higher in patients with active vs. inactive disease and correlated with ECLAM, anti-C1q and anti-dsDNA antibodies. sIL-1R2 was higher in patients with inactive disease, was negatively correlated with ECLAM and anti-C1q antibodies and was positively correlated with C3 levels. PLS identified sIL-1R4, sIL-1R2 and anti-dsDNA as variables distinguishing patients with active from those with inactive disease; sIL-1R4, IL-18BP and anti-dsDNA identified patients with active nephritis; sIL-1R4, C3, IL-18 and free IL-18 identified patients with haematological involvement. Conclusion The data support the use of IL-18, sIL-1R2 and sIL-1R4 as biomarkers of disease activity and organ involvement, and suggest that failure in the inhibition of IL-1 activation may be a critical event in the active stages of SLE.
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Affiliation(s)
- Paola Italiani
- Institute of Protein Biochemistry, National Research Council, Naples, Italy
| | - Maria Laura Manca
- Clinical Immunology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Francesca Angelotti
- Clinical Immunology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Daniela Melillo
- Institute of Protein Biochemistry, National Research Council, Naples, Italy
| | - Federico Pratesi
- Clinical Immunology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Ilaria Puxeddu
- Clinical Immunology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Diana Boraschi
- Institute of Protein Biochemistry, National Research Council, Naples, Italy
| | - Paola Migliorini
- Clinical Immunology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
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Abstract
Inflammasomes influence a diverse range of kidney disease, including acute and chronic kidney diseases, and those mediated by innate and adaptive immunity. Both IL-18 and in particular IL-1β are validated therapeutic targets in several kidney diseases. In addition to leukocyte-derived inflammasomes, renal tissue cells express functional inflammasome components. Furthermore, a range of endogenous substances that directly activate inflammasomes also mediate kidney injury. Many of the functional studies have focussed on the NLRP3 inflammasome, and there is also evidence for the involvement of other inflammasomes in some conditions. While, at least in some disease, the mechanistic details of the involvement of the inflammasome remain to be elucidated, therapies focussed on inflammasomes and their products have potential in treating kidney disease in the future.
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Affiliation(s)
- Holly L Hutton
- Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia
| | - Maliha A Alikhan
- Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia
| | - A Richard Kitching
- Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia.
- Department of Nephrology, Monash Health, Clayton, VIC, Australia.
- Department of Paediatric Nephrology, Monash Health, Clayton, VIC, Australia.
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31
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Schwarting A, Relle M, Meineck M, Föhr B, Triantafyllias K, Weinmann A, Roth W, Weinmann-Menke J. Renal tubular epithelial cell-derived BAFF expression mediates kidney damage and correlates with activity of proliferative lupus nephritis in mouse and men. Lupus 2017; 27:243-256. [PMID: 28659046 DOI: 10.1177/0961203317717083] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
B-cell activating factor of the tumour necrosis factor family (BAFF) is a cytokine, mainly produced by hematopoietic cells (e.g. monocytes/macrophages, dendritic cells), indispensable for B-cell maturation. The BLISS studies have demonstrated that blocking BAFF by the human monoclonal antibody belimumab is a valuable therapeutic approach in patients with clinically and serologically active systemic lupus erythematosus (SLE). However, the defined sources of BAFF, which contributes to SLE, are still unclear. Recent findings show that BAFF expression is not restricted to myeloid cells. Since lupus nephritis is the main cause of morbidity and mortality for SLE patients, the aim of this study was to investigate whether renal tubular epithelial cells (TEC) are an important source of BAFF and thus may contribute to the pathogenesis and progression of SLE. We found BAFF expression both in cultured murine and human TEC. These results could be verified with in situ data from the kidney. Moreover, BAFF expression in the kidneys of lupus-prone MRL- Faslpr mice correlated with disease activity, and BAFF expression on TEC in biopsies of patients with diffuse proliferative lupus nephritis showed a correlation with the histopathological activity index. In vitro functional assays revealed an autocrine loop of BAFF with its binding receptors on TEC, resulting in a strong induction of colony stimulating factor-1. Finally, we identified divergent effects of BAFF on TEC depending on the surrounding milieu ('inflammatory versus non-inflammatory'). Taken together, our findings indicate that renal-derived BAFF may play an important role in the pathophysiology of the systemic autoimmune disease SLE.
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Affiliation(s)
- A Schwarting
- 1 Department of Internal Medicine I, Division of Rheumatology and Clinical Immunology, University Medical Center of the Johannes Gutenberg University Mainz, Germany.,2 Acura Rheumatology Center Rhineland Palatinate, Bad Kreuznach, Germany
| | - M Relle
- 1 Department of Internal Medicine I, Division of Rheumatology and Clinical Immunology, University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - M Meineck
- 1 Department of Internal Medicine I, Division of Rheumatology and Clinical Immunology, University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - B Föhr
- 1 Department of Internal Medicine I, Division of Rheumatology and Clinical Immunology, University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - K Triantafyllias
- 2 Acura Rheumatology Center Rhineland Palatinate, Bad Kreuznach, Germany
| | - A Weinmann
- 1 Department of Internal Medicine I, Division of Rheumatology and Clinical Immunology, University Medical Center of the Johannes Gutenberg University Mainz, Germany.,3 Clinical Registry Unit, University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - W Roth
- 4 Tissue Bank and Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - J Weinmann-Menke
- 1 Department of Internal Medicine I, Division of Rheumatology and Clinical Immunology, University Medical Center of the Johannes Gutenberg University Mainz, Germany
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Pichler R, Afkarian M, Dieter BP, Tuttle KR. Immunity and inflammation in diabetic kidney disease: translating mechanisms to biomarkers and treatment targets. Am J Physiol Renal Physiol 2017; 312:F716-F731. [PMID: 27558558 PMCID: PMC6109808 DOI: 10.1152/ajprenal.00314.2016] [Citation(s) in RCA: 184] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 08/16/2016] [Indexed: 01/10/2023] Open
Abstract
Increasing incidences of obesity and diabetes have made diabetic kidney disease (DKD) the leading cause of chronic kidney disease and end-stage renal disease worldwide. Despite current pharmacological treatments, including strategies for optimizing glycemic control and inhibitors of the renin-angiotensin system, DKD still makes up almost one-half of all cases of end-stage renal disease in the United States. Compelling and mounting evidence has clearly demonstrated that immunity and inflammation play a paramount role in the pathogenesis of DKD. This article reviews the involvement of the immune system in DKD and identifies important roles of key immune and inflammatory mediators. One of the most recently identified biomarkers is serum amyloid A, which appears to be relatively specific for DKD. Novel and evolving treatment approaches target protein kinases, transcription factors, chemokines, adhesion molecules, growth factors, advanced glycation end-products, and other inflammatory molecules. This is the beginning of a new era in the understanding and treatment of DKD, and we may have finally reached a tipping point in our fight against the growing burden of DKD.
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Affiliation(s)
- Raimund Pichler
- Division of Nephrology, University of Washington, Seattle, Washington;
| | - Maryam Afkarian
- Division of Nephrology, Kidney Research Institute, University of Washington, Seattle, Washington; and
| | - Brad P Dieter
- Division of Nephrology, Kidney Research Institute, University of Washington, Seattle, Washington; and
- Providence Health Care, Spokane, Washington
| | - Katherine R Tuttle
- Division of Nephrology, Kidney Research Institute, University of Washington, Seattle, Washington; and
- Providence Health Care, Spokane, Washington
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Hutton HL, Ooi JD, Holdsworth SR, Kitching AR. The NLRP3 inflammasome in kidney disease and autoimmunity. Nephrology (Carlton) 2017; 21:736-44. [PMID: 27011059 DOI: 10.1111/nep.12785] [Citation(s) in RCA: 167] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2016] [Revised: 03/16/2016] [Accepted: 03/17/2016] [Indexed: 12/12/2022]
Abstract
The NLRP3 inflammasome is an intracellular platform that converts the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 to their active forms in response to 'danger' signals, which can be either host or pathogen derived, and mediates a form of inflammatory cell death called pyroptosis. This component of the innate immune system was initially discovered because of its role in rare autoinflammatory syndromes called cryopyrinopathies, but it has since been shown to mediate injurious inflammation in a broad range of diseases. Inflammasome activation occurs in both immune cells, primarily macrophages and dendritic cells, and in some intrinsic kidney cells such as the renal tubular epithelium. The NLRP3 inflammasome has been implicated in the pathogenesis of a number of renal conditions, including acute kidney injury, chronic kidney disease, diabetic nephropathy and crystal-related nephropathy. The inflammasome also plays a role in autoimmune kidney disease, as IL-1β and IL-18 influence adaptive immunity through modulation of T helper cell subsets, skewing development in favour of Th17 and Th1 cells that are important in the development of autoimmunity. Both IL-1 blockade and two recently identified specific NLRP3 inflammasome blockers, MCC950 and β-hydroxybutyrate, have shown promise in the treatment of inflammasome-mediated conditions. These targeted therapies have the potential to be of benefit in the growing number of kidney diseases in which the NLRP3 inflammasome has been implicated.
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Affiliation(s)
- Holly L Hutton
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Melbourne, Victoria, Australia.,Department of Nephrology, Monash Health, Melbourne, Victoria, Australia
| | - Joshua D Ooi
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Melbourne, Victoria, Australia
| | - Stephen R Holdsworth
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Melbourne, Victoria, Australia.,Department of Nephrology, Monash Health, Melbourne, Victoria, Australia
| | - A Richard Kitching
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Melbourne, Victoria, Australia.,Department of Nephrology, Monash Health, Melbourne, Victoria, Australia.,Department of Paediatric Nephrology, Monash Health, Melbourne, Victoria, Australia
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Interleukin-18 deficiency protects against renal interstitial fibrosis in aldosterone/salt-treated mice. Clin Sci (Lond) 2016; 130:1727-39. [DOI: 10.1042/cs20160183] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 07/13/2016] [Indexed: 12/30/2022]
Abstract
Interleukin (IL)-18 is a member of the IL-1 family of cytokines and was described originally as an interferon γ-inducing factor. Aldosterone plays a central role in the regulation of sodium and potassium homoeostasis by binding to the mineralocorticoid receptor and contributes to kidney and cardiovascular damage. Aldosterone has been reported to induce IL-18, resulting in cardiac fibrosis with induced IL-18-mediated osteopontin (OPN). We therefore hypothesized that aldosterone-induced renal fibrosis via OPN may be mediated by IL-18. To verify this hypothesis, we compared mice deficient in IL-18 and wild-type (WT) mice in a model of aldosterone/salt-induced hypertension. IL-18−/− and C57BL/6 WT mice were used for the uninephrectomized aldosterone/salt hypertensive model, whereas NRK-52E cells (rat kidney epithelial cells) were used in an in vitro model. In the present in vivo study, IL-18 protein expression was localized in medullary tubules in the WT mice, whereas in aldosterone-infused WT mice this expression was up-regulated markedly in the proximal tubules, especially in injured and dilated tubules. This renal damage caused by aldosterone was attenuated significantly by IL-18 knockout with down-regulation of OPN expression. In the present in vitro study, aldosterone directly induced IL-18 gene expression in renal tubular epithelial cells in a concentration- and time-dependent manner. These effects were inhibited completely by spironolactone. IL-18 may be a key mediator of aldosterone-induced renal fibrosis by inducing OPN, thereby exacerbating renal interstitial fibrosis. Inhibition of IL-18 may therefore provide a potential target for therapeutic intervention aimed at preventing the progression of renal injury.
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35
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Elsherbiny NM, Al-Gayyar MMH. The role of IL-18 in type 1 diabetic nephropathy: The problem and future treatment. Cytokine 2016; 81:15-22. [PMID: 26836949 DOI: 10.1016/j.cyto.2016.01.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 01/21/2016] [Accepted: 01/24/2016] [Indexed: 12/18/2022]
Abstract
Diabetic vascular complication is a leading cause of diabetic nephropathy, a progressive increase in urinary albumin excretion coupled with elevated blood pressure leading to declined glomerular filtration and eventually end stage renal failure. There is growing evidence that activated inflammation is contributing factor to the pathogenesis of diabetic nephropathy. Meanwhile, IL-18, a member of the IL-1 family of inflammatory cytokines, is involved in the development and progression of diabetic nephropathy. However, the benefits derived from the current therapeutics for diabetic nephropathy strategies still provide imperfect protection against renal progression. This imperfection points to the need for newer therapeutic agents that have potential to affect primary mechanisms contributing to the pathogenesis of diabetic nephropathy. Therefore, the recognition of IL-18 as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.
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Affiliation(s)
- Nehal M Elsherbiny
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt
| | - Mohammed M H Al-Gayyar
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia.
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36
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Scarpioni R, Ricardi M, Albertazzi V. Secondary amyloidosis in autoinflammatory diseases and the role of inflammation in renal damage. World J Nephrol 2016; 5:66-75. [PMID: 26788465 PMCID: PMC4707170 DOI: 10.5527/wjn.v5.i1.66] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2015] [Accepted: 12/11/2015] [Indexed: 02/06/2023] Open
Abstract
The release of proinflammatory cytokines during inflammation represents an attempt to respond to injury, but it may produce detrimental effects. The inflammasome is a large, multiprotein complex that drives proinflammatory cytokine production in response to infection and tissue injury; the best-characterized inflammasome is the nod-like receptor protein-3 (NLRP3). Once activated, inflammasome leads to the active form of caspase-1, the enzyme required for the maturation of interleukin-1beta. Additional mechanisms bringing to renal inflammatory, systemic diseases and fibrotic processes were recently reported, via the activation of the inflammasome that consists of NLRP3, apoptosis associated speck-like protein and caspase-1. Several manuscripts seem to identify NLRP3 inflammasome as a possible therapeutic target in the treatment of progressive chronic kidney disease. Serum amyloid A (SAA), as acute-phase protein with also proinflammatory properties, has been shown to induce the secretion of cathepsin B and inflammasome components from human macrophages. SAA is a well recognised potent activator of the NLRP3. Here we will address our description on the involvement of the kidney in autoinflammatory diseases driven mainly by secondary, or reactive, AA amyloidosis with a particular attention on novel therapeutic approach which has to be addressed in suppressing underlying inflammatory disease and reducing the SAA concentration.
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Citral alleviates an accelerated and severe lupus nephritis model by inhibiting the activation signal of NLRP3 inflammasome and enhancing Nrf2 activation. Arthritis Res Ther 2015; 17:331. [PMID: 26584539 PMCID: PMC4653837 DOI: 10.1186/s13075-015-0844-6] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 10/29/2015] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Lupus nephritis (LN) is a major complication of systemic lupus erythematosus. NLRP3 inflammasome activation, reactive oxygen species (ROS) and mononuclear leukocyte infiltration in the kidney have been shown to provoke the acceleration and deterioration of LN, such as accelerated and severe LN (ASLN). Development of a novel therapeutic remedy based on these molecular events to prevent the progression of the disease is clinically warranted. METHODS Citral (3,7-dimethyl-2,6-octadienal), a major active compound in a Chinese herbal medicine Litsea cubeba, was used to test its renoprotective effects in a lipopolysaccharide (LPS)-induced mouse ASLN model by examining NLRP3 inflammasome activation, ROS and COX-2 production as well as Nrf2 activation. The analysis of mechanisms of action of Citral also involved its effects on IL-1β secretion and signaling pathways of NLRP3 inflammasome in LPS-primed peritoneal macrophages or J774A macrophages. RESULTS Attenuated proteinuria, renal function impairment, and renal histopathology, the latter including intrinsic cell proliferation, cellular crescents, neutrophil influx, fibrinoid necrosis in the glomerulus, and peri-glomerular infiltration of mononuclear leukocytes as well as glomerulonephritis activity score were observed in Citral-treated ASLN mice. In addition, Citral inhibited NLRP3 inflammasome activation and levels of ROS, NAD(P)H oxidase subunit p47(phox), or COX-2, and it enhanced the activation of nuclear factor E2-related factor 2 (Nrf2). In LPS-primed macrophages, Citral reduced ATP-induced IL-1β secretion and caspase-1 activation, but did not affect LPS-induced NLRP3 protein expression. CONCLUSION Our data show that Citral alleviates the mouse ASLN model by inhibition of the activation signal, but not the priming signal, of NLRP3 inflammasome and enhanced activation of Nrf2 antioxidant signaling.
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Jafari-Nakhjavani MR, Abedi-Azar S, Nejati B. Correlation of plasma interleukin-18 concentration and severity of renal involvement and disease activity in systemic lupus erythematosus. J Nephropathol 2015; 5:28-33. [PMID: 27047807 PMCID: PMC4790184 DOI: 10.15171/jnp.2016.05] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 11/01/2015] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by activation of T and polyclonal B lymphocytes. IL-18 was originally identified as a factor which enhances IFN-γ production and is a potent inducer of the inflammatory mediators by T cells, causing severe inflammatory disorders in SLE. OBJECTIVES This study aimed to evaluate the association of plasma interlukine-18 (IL-18) concentration and severity of lupus nephritis (LN) and disease activity in SLE patients. PATIENTS AND METHODS In this cross-sectional study, 113 patients with SLE and 50 healthy individuals were examined. Serum level of IL-18 was measured. The severity and activity of the disease was determined by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score. The severity of kidney involvement was studied by renal biopsy, serum creatinine and 24 hours urine protein level. RESULTS The mean level of serum IL-18 was significantly higher in the patients than controls (577.67 ± 649.95 versus 60.48 ± 19.53 pg/ml; P < 0.001). In SLE patients with active disease level of serum IL-18 was significantly higher than chronic disease (622.77 ± 716.54 versus 182 ± 184.37 pg/ml; P < 0.001). The serum level of IL-18 was significantly higher in stage IV (P < 0.001) and V (P < 0.001) of patients with LN, than other stages. CONCLUSIONS The current study showed that the serum IL-18 is significantly higher in the patients than controls and it significantly correlated with sever renal involvement and disease activity in SLE patients.
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Affiliation(s)
| | - Sima Abedi-Azar
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Babak Nejati
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Schirmer B, Wedekind D, Glage S, Neumann D. Deletion of IL-18 Expression Ameliorates Spontaneous Kidney Failure in MRLlpr Mice. PLoS One 2015; 10:e0140173. [PMID: 26465326 PMCID: PMC4605611 DOI: 10.1371/journal.pone.0140173] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 09/21/2015] [Indexed: 01/14/2023] Open
Abstract
The role of IL-18 in the pathogenesis of systemic lupus erythematosus is still not definitively solved. In this study, we generated MRLlpr mice, which develop a disease resembling systemic lupus erythematosus, genetically devoid of IL-18 expression. These mice in comparison to IL-18-competent MRLlpr mice show reduced signs of renal pathogenesis, while other parameters such as mean survival time, lymphadenopathy, constitutive interferon-γ production, and frequency of CD3+B220+ abnormal T cells were without differences. We conclude that in the systemic lupus erythematosus syndrom IL-18 is involved specifically in the renal pathogenesis.
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Affiliation(s)
- Bastian Schirmer
- Institute of Pharmacology, Hannover Medical School, Hannover, Germany
| | - Dirk Wedekind
- Institute of Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Silke Glage
- Institute of Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Detlef Neumann
- Institute of Pharmacology, Hannover Medical School, Hannover, Germany
- * E-mail:
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Masood H, Che R, Zhang A. Inflammasomes in the Pathophysiology of Kidney Diseases. KIDNEY DISEASES 2015; 1:187-93. [PMID: 27536679 DOI: 10.1159/000438843] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 07/17/2015] [Indexed: 01/08/2023]
Abstract
BACKGROUND The inflammasome is a complex of proteins in the cytoplasm that consists of three main components: a sensor protein (receptor), an adapter protein and caspase-1. Inflammasomes are the critical components of innate immunity and have been gradually recognized as a critical mediator in various autoimmune diseases; also, their role in chronic kidney disease and acute kidney injury has been gradually accepted. SUMMARY Inflammasomes triggered by infectious or sterile injuries transfer proinflammatory mediators into mature ones through innate danger-signaling platforms. Information on inflammasomes in kidney disease will help to uncover the underlying mechanisms of nephropathy and provide novel therapeutic targets in the future. KEY MESSAGES The inflammasomes can be activated by a series of exogenous and endogenous stimuli, including pathogen-and danger-associated molecular patterns released from or caused by damaged cells. The NACHT, LRR and PYD domain-containing protein 3 (NLRP3) in the kidney exerts its effect not only by the 'canonical' pathway of IL-1β and IL-18 secretion but also by 'noncanonical' pathways, such as tumor growth factor-β signaling, epithelial-mesenchymal transition and fibrosis. In both clinical and experimental data, the NLRP3 inflammasome was reported to be involved in the pathogenesis of chronic kidney disease and acute kidney injury. However, the underlying mechanisms are not fully understood. Therapies targeting the activation of the NLRP3 inflammasome or blocking its downstream effectors appear attractive for the pursuit of neuropathy treatments.
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Affiliation(s)
- Humaira Masood
- Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, PR China
| | - Ruochen Che
- Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, PR China
| | - Aihua Zhang
- Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, PR China
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Zheng LL, Guo XQ, Zhu QL, Chao AJ, Fu PF, Wei ZY, Wang SJ, Chen HY, Cui BA. Construction and immunogenicity of a recombinant pseudorabies virus co-expressing porcine circovirus type 2 capsid protein and interleukin 18. Virus Res 2015; 201:8-15. [DOI: 10.1016/j.virusres.2015.02.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 02/07/2015] [Accepted: 02/10/2015] [Indexed: 10/24/2022]
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Deveci K, Korkmaz S, Senel S, Deveci H, Sancakdar E, Uslu AU, Deniz A, Alkan F, Seker MM, Sencan M. Do neutrophil gelatinase-associated lipocalin and interleukin-18 predict renal dysfunction in patients with familial Mediterranean fever and amyloidosis? Ren Fail 2013; 36:339-44. [PMID: 24320110 DOI: 10.3109/0886022x.2013.865486] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND The aim of this study was to evaluate whether neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL-18) predict renal disfunction in patients with familial Mediterranean fever (FMF). METHODS This prospective study consisted of 102 patients with FMF in attack-free period, and 40 matched healthy controls. Of the patients, nine were diagnosed as amyloidosis. The patients were divided into two groups according to eGFR as below 120 mL per minute and above 120 mL per minute. Also, patients were divided into three groups according to the degree of urinary albumin excretion as normoalbuminuric, microalbuminuric, and macroalbuminuric. The serum levels of IL-18 (sIL-18) and NGAL (sNGAL), and urinary levels of IL-18 (uIL-18) and NGAL (uNGAL) were measured by using ELISA kits. RESULTS The levels of sIL-18, sNGAL, uIL-18, and uNGAL were detected significantly higher in FMF patients, particularly in patients with amyloidosis, when compared to controls. sNGAL, uIL-18, and uNGAL were significantly higher in patients with eGFR < 120 mL per minute than in patients with eGFR ≥ 120 mL per minute. sNGAL, uIL-18, and uNGAL were correlated significantly with urinary albumin excretion, additionally, were inverse correlated with eGFR. The most remarkable findings of this study are of the higher values of sIL-18, sNGAL, uIL-18, and uNGAL in both normoalbuminuric FMF patients and patients with eGFR ≥ 120 mL per minute. CONCLUSIONS The results of this study suggest that sIL-18, uIL-18, sNGAL, and uNGAL are reliable markers of early renal disfunction in FMF patients, and may let us take measures from the early stage of renal involvement.
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Affiliation(s)
- Köksal Deveci
- Department of Clinical Biochemistry, School of Medicine, Cumhuriyet University , Sivas , Turkey
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Yap DYH, Lai KN. The role of cytokines in the pathogenesis of systemic lupus erythematosus - from bench to bedside. Nephrology (Carlton) 2013; 18:243-55. [PMID: 23452295 DOI: 10.1111/nep.12047] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2013] [Indexed: 12/23/2022]
Abstract
The pathogenesis of systemic lupus erythematosus (SLE) entails a complex interaction between the different arms of the immune system. While autoantibodies production and immune complex deposition are cornered as hallmark features of SLE, there is growing evidence to propose the pathogenic role of cytokines in this disease. Examples of these cytokines include BLys, interleukin-6, interleukin-17, interleukin-18, type I interferons and tumour necrosis factor alpha. These cytokines all assume pivotal functions to orchestrate the differentiation, maturation and activation of various cell types, which would mediate local inflammatory process and tissue injury. The knowledge on these cytokines not only fosters our understanding of the disease, but also provides insights in devising biomarkers and targeted therapies. In this review, we focus on cytokines which have substantial pathogenic significance and also highlight the possible clinical applications of these cytokines.
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Affiliation(s)
- Desmond Yat Hin Yap
- Division of Nephrology, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong SAR
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Lorenz G, Darisipudi MN, Anders HJ. Canonical and non-canonical effects of the NLRP3 inflammasome in kidney inflammation and fibrosis. Nephrol Dial Transplant 2013; 29:41-8. [PMID: 24026244 DOI: 10.1093/ndt/gft332] [Citation(s) in RCA: 168] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
NLRP-3 inflammasome is one of several intracellular danger recognition platforms that integrates infectious or non-infectious types of danger into the expression of pro-inflammatory cytokines to set-up inflammation for danger control. NLRP3 activation induces three types of caspase-1-mediated responses: secretion of IL-1beta, secretion of IL-18 and a programmed form of cell death, referred to as pyroptosis. Similar to the well-documented impact of Toll-like receptor-driven danger signalling in kidney disease, evolving data now suggest a similar involvement of the NLRP3 inflammasome in renal inflammation. Here, we discuss the accumulating data on NLRP3 in the kidney: its IL-1beta and IL-18-dependent 'canonical' effects and the current evidence for its 'non-canonical' effects, e.g. in tumor growth factor (TGF)-beta signalling, epithelial-mesenchymal transition and fibrosis. Research in this area will certainly uncover yet unknown aspects of danger signalling in the kidney and how it drives renal inflammation and immunopathology.
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Affiliation(s)
- Georg Lorenz
- Renal Division, Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig Maximilians Universität, München-Innenstadt, Munich, Germany
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Bossaller L, Rathinam VAK, Bonegio R, Chiang PI, Busto P, Wespiser AR, Caffrey DR, Li QZ, Mohan C, Fitzgerald KA, Latz E, Marshak-Rothstein A. Overexpression of membrane-bound fas ligand (CD95L) exacerbates autoimmune disease and renal pathology in pristane-induced lupus. THE JOURNAL OF IMMUNOLOGY 2013; 191:2104-14. [PMID: 23918976 DOI: 10.4049/jimmunol.1300341] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Loss-of-function mutations in the Fas death receptor or its ligand result in a lymphoproliferative syndrome and exacerbate clinical disease in most lupus-prone strains of mice. One exception is mice injected with 2,6,10,14-tetramethylpentadecane (TMPD), a hydrocarbon oil commonly known as pristane, which induces systemic lupus erythematosus-like disease. Although Fas/Fas ligand (FasL) interactions have been strongly implicated in the activation-induced cell death of both lymphocytes and other APCs, FasL can also trigger the production of proinflammatory cytokines. FasL is a transmembrane protein with a matrix metalloproteinase cleavage site in the ectodomain. Matrix metalloproteinase cleavage inactivates membrane-bound FasL and releases a soluble form reported to have both antagonist and agonist activity. To better understand the impact of FasL cleavage on both the proapoptotic and proinflammatory activity of FasL, its cleavage site was deleted through targeted mutation to produce the deleted cleavage site (ΔCS) mouse line. ΔCS mice express higher levels of membrane-bound FasL than do wild-type mice and fail to release soluble FasL. To determine to what extent FasL promotes inflammation in lupus mice, TMPD-injected FasL-deficient and ΔCS BALB/c mice were compared with control TMPD-injected BALB/c mice. We found that FasL deficiency significantly reduced the early inflammatory exudate induced by TMPD injection. In contrast, ΔCS mice developed a markedly exacerbated disease profile associated with a higher frequency of splenic neutrophils and macrophages, a profound change in anti-nuclear Ab specificity, and markedly increased proteinuria and kidney pathology compared with controls. These results demonstrate that FasL promotes inflammation in TMPD-induced autoimmunity, and its cleavage limits FasL proinflammatory activity.
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Affiliation(s)
- Lukas Bossaller
- Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA
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Matsui F, Rhee A, Hile KL, Zhang H, Meldrum KK. IL-18 induces profibrotic renal tubular cell injury via STAT3 activation. Am J Physiol Renal Physiol 2013; 305:F1014-21. [PMID: 23904224 DOI: 10.1152/ajprenal.00620.2012] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
IL-18 is an important mediator of obstruction-induced renal fibrosis and renal tubular epithelial cell (TEC) injury. IL-18's proinflammatory properties have been attributed, in part, to NF-κB activation and the stimulation of cytokine gene expression; however, STAT3 has increasingly been shown to mediate renal fibrotic injury. We therefore hypothesized that IL-18 mediates profibrotic TEC injury via STAT3 activation. Male C57BL6 wild-type mice and transgenic mice for human IL-18-binding protein were subjected to unilateral ureteral obstruction or sham operation. The kidneys were harvested 1 or 2 wk afterward and analyzed for active STAT3 (p-STAT3) expression (Western blotting, immunohistochemistry) and suppressor of cytokine signaling 3 (SOCS3) expression. In a separate arm, renal tubular cells (HK-2) were directly stimulated with IL-18 for 2 days with or without the STAT3 inhibitor S3I-201 (50 μM). Cell lysates were then analyzed for p-STAT3 and SOCS3 expression, profibrotic cellular changes (collagen and α-SMA expression), and tubular cell apoptosis. p-STAT3 and SOCS3 expression increased significantly in response to obstruction; however, a significant reduction in p-STAT3 and SOCS3 expression occurred following 1 wk, but not 2 wk, of obstruction in the presence of IL-18 neutralization. In vitro results similarly demonstrate increased p-STAT3, SOCS3, α-SMA, and collagen III expression, and increased collagen production and TEC apoptosis in response to IL-18 stimulation, but the response was significantly diminished in the presence of STAT3 inhibition. These results demonstrate that IL-18-induces profibrotic cellular changes and collagen production in TECs via STAT3 activation.
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Affiliation(s)
- Futoshi Matsui
- Pediatric Urology, Univ. of Florida, Gainesville, FL 32610
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Hatef MR, Sahebari M, Rezaieyazdi Z, Nakhjavani MR, Mahmoudi M. Stronger Correlation between Interleukin 18 and Soluble Fas in Lupus Nephritis Compared with Mild Lupus. ISRN RHEUMATOLOGY 2013; 2013:850851. [PMID: 23577265 PMCID: PMC3612460 DOI: 10.1155/2013/850851] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Accepted: 02/13/2013] [Indexed: 06/02/2023]
Abstract
Lupus nephritis (LN) is a major cause of morbidity in patients with systemic lupus erythematosus (SLE). Several cytokines and apoptotic markers such as IL-18 and soluble Fas (sFas) have been assumed to play a role in the pathogenesis of LN. Previous studies confirmed that serum concentrations of sFas and IL-18 are increased in SLE. However, only a few studies have suggested a possible correlation between IL-18 and sFas. This study was planned to continue our previous study on the correlation between those markers to evaluate this correlation in LN. Thirty-two patients with only LN and 46 patients without any major organ involvement participated in this study. SLEDAI score (except for scores related to nephritis) was the same in these two groups. In both groups, patients with any other major organ involvement were excluded. We found a significant rise in the serum concentrations of sFas (P = 0.03) and IL-18 (P = 0.02) in patients with proteinuria compared to those without it. This study showed that the correlation between sFas and IL-18 in LN (P < 0.001, r p = 0.5) is significantly stronger than it is in mild SLE (P < 0.001, r p = 0.4) with similar nonrenal SLEDAI score (P = 0.032, z = 1.85). Between these two serum markers, sFas is the only predictor of proteinuria.
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Affiliation(s)
- Mohammad Reza Hatef
- Rheumatology, Rheumatic Diseases Research Center (RDRC), School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Sahebari
- Rheumatology, Rheumatic Diseases Research Center (RDRC), School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Rezaieyazdi
- Rheumatology, Rheumatic Diseases Research Center (RDRC), School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Nakhjavani
- Rheumatology, Rheumatology Department, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahmoud Mahmoudi
- Immunology, Immunology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Mohsen MA, Abdel Karim SA, Abbas TM, Amin M. Serum interleukin-18 levels in patients with systemic lupus erythematosus: Relation with disease activity and lupus nephritis. EGYPTIAN RHEUMATOLOGIST 2013. [DOI: 10.1016/j.ejr.2012.09.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Rhee AC, Cain AL, Hile KL, Zhang H, Matsui F, Meldrum KK. IL-18 activation is dependent on Toll-like receptor 4 during renal obstruction. J Surg Res 2012; 183:278-84. [PMID: 23260234 DOI: 10.1016/j.jss.2012.11.038] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2012] [Revised: 11/15/2012] [Accepted: 11/19/2012] [Indexed: 01/28/2023]
Abstract
PURPOSE Interleukin 18 (IL-18) is a critical mediator of obstruction-induced renal injury. Although previous studies have demonstrated that IL-18 participates in a positive feedback loop via the IL-18 receptor (IL-18R) and localized renal IL-18 and IL-18R production to tubular epithelial cells (TEC), the mechanism of IL-18 activation during obstruction remains unclear. We hypothesized that IL-18 activation is dependent on Toll-like receptor 4 (TLR4) signaling during renal obstruction. MATERIALS AND METHODS Male C57BL6 TLR4 knockout (TLR4KO) and wild-type (WT) mice were subjected to unilateral ureteral obstruction versus sham operation for 1 wk. The animals were sacrificed, and renal cortical tissue was harvested and analyzed for TLR4 expression (Western blot), active IL-18 production (enzyme-linked immunosorbent assay, real-time polymerase chain reaction), IL-18 receptor expression (real-time polymerase chain reaction), and TLR4/IL-18 versus IL-18R cellular localization (dual immunofluorescent staining). RESULTS Renal TLR4 expression increased significantly in WT mice in response to obstruction, but remained at sham treatment levels in TLR4KO mice. IL-18 and IL-18R gene expression and active IL-18 production were similarly increased in WT mice in response to obstruction, but decreased significantly to sham treatment levels in the absence of TLR4. Dual immunofluorescent staining revealed co-localization of TLR4 and IL-18 to renal TEC during obstruction. CONCLUSION IL-18 production and activation during renal obstruction is dependent on intact TLR4 signaling. Co-localization of IL-18 and TLR4 production to TEC during obstruction suggests that TEC are the primary site of IL-18 production and activation. Further characterization of the pathway may be necessary to develop targeted therapy in obstruction-induced renal injury.
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Affiliation(s)
- Audrey C Rhee
- Department of Urology, Indiana University School of Medicine, Indianapolis, Indiana, USA
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Renal IL-18 production is macrophage independent during obstructive injury. PLoS One 2012; 7:e47417. [PMID: 23077611 PMCID: PMC3470595 DOI: 10.1371/journal.pone.0047417] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2012] [Accepted: 09/14/2012] [Indexed: 12/11/2022] Open
Abstract
Background Interleukin 18 (IL-18) is a pro-inflammatory cytokine that mediates fibrotic renal injury during obstruction. Macrophages are a well-known source of IL-18; however, renal tubular epithelial cells are also a potential source of this cytokine. We hypothesized that IL-18 is predominantly a renal tubular cell product and is produced during renal obstruction independent of macrophage infiltration. Methods To study this, male C57BL6 mice were subjected to unilateral ureteral obstruction (UUO) vs. sham operation in the presence or absence of macrophage depletion (liposomal clodronate (1 ml/100 g body weight i.v.)). The animals were sacrificed 1 week after surgery and renal cortical tissue harvested. Tissue levels of active IL-18 (ELISA), IL-18 receptor mRNA expression (real time PCR), and active caspase-1 expression (western blot) were measured. The cellular localization of IL-18 and IL-18R was assessed using dual labeling immunofluorescent staining (IFS). Results Immunohistochemical staining of renal tissue sections confirmed macrophage depletion by liposomal clodronate. IL-18 production, IL-18R expression, and active caspase 1 expression were elevated in response to renal obstruction and did not decline to a significant degree in the presence of macrophage depletion. Obstruction-induced IL-18 and IL-18R production localized predominantly to tubular epithelial cells (TEC) during obstruction despite macrophage depletion. Conclusion These results demonstrate that renal tubular epithelial cells are the primary source of IL-18 production during obstructive injury, and that tubular cell production of IL-18 occurs independent of macrophage infiltration.
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