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Hao W, Liu Q, Li X, Xu Y, Guan W, Zhang L, Dong F, Cao W, Liu S, Li W. CCL23 is a potential biomarker for antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Res Ther 2025; 27:83. [PMID: 40211307 PMCID: PMC11983769 DOI: 10.1186/s13075-025-03552-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Accepted: 03/31/2025] [Indexed: 04/14/2025] Open
Abstract
OBJECTIVE The present cohort study aimed to evaluate the value of CCL23 in diagnosis, disease activity, and prognosis in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS CCL23 levels in serum samples from 317 patients with AAV and 83 healthy controls (HCs) were measured using a customized immune response kit. RESULTS Patients with AAV had significantly elevated CL23 levels compared with HCs. CCL23 level was closely related to disease activity and was better than birmingham vasculitis activity score (BVAS) in distinguishing disease relapse from remission (area under curve: CCL23 = 0.942, BVAS = 0.84). Elevated CCL23 level was associated with poor prognosis within a 1 year follow-up period in patients with AAV (p = 0.0001). The ability of CCL23 to predict the poor prognosis of disease is better than that of five-factor score. Furthermore, elevated CCL23 levels were a risk factor for renal involvement (odds ratio = 1.722, p = 0.033), and were significantly related to serum creatinine (r = 0.381, p = 0.009) and eGFR (r = - 0.382, p = 0.01) at the time of diagnosis. High CCL23 level at diagnosis was associated with increased adverse outcomes during 1 year follow-up in patients with AAV with renal involvement (p = 0.0242). CONCLUSION Elevated serum CCL23 level was closely related with disease activity and renal involvement in patients with AAV, can be a potential biomarker for diagnosis, and can predict prognosis in patients with AAV, especially adverse renal prognosis.
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Affiliation(s)
- Weiwei Hao
- Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, NO. 1, Jianshe East Road, Zhengzhou, 450052, Henan, China
| | - Qianqian Liu
- The Third Clinical Medical College of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Xiaoping Li
- The Third Clinical Medical College of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yiran Xu
- Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, Institute of Neuroscience and The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Wenjuan Guan
- Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, NO. 1, Jianshe East Road, Zhengzhou, 450052, Henan, China
| | - Lei Zhang
- Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, NO. 1, Jianshe East Road, Zhengzhou, 450052, Henan, China
| | - Fang Dong
- Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, NO. 1, Jianshe East Road, Zhengzhou, 450052, Henan, China
| | - Wenjun Cao
- Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, NO. 1, Jianshe East Road, Zhengzhou, 450052, Henan, China
| | - Shengyun Liu
- Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, NO. 1, Jianshe East Road, Zhengzhou, 450052, Henan, China.
| | - Wei Li
- Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, NO. 1, Jianshe East Road, Zhengzhou, 450052, Henan, China.
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Ang T, Tong JY, Quigley C, Selva D. Tear inflammatory cytokine profiles in orbital inflammatory disease. Exp Eye Res 2025; 251:110205. [PMID: 39662664 DOI: 10.1016/j.exer.2024.110205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 10/22/2024] [Accepted: 12/08/2024] [Indexed: 12/13/2024]
Abstract
Tear inflammatory cytokines are a novel biomarker studied in a range of ocular surface diseases, periorbital and orbital conditions. This single-centre prospective study between 2022 and 2024 aims to characterise tear cytokine profiles (Interleukin-1β [IL-1β], IL-2, IL-6, Interferon-γ [IFN-γ] and Tumour Necrosis Factor-α [TNF- α]) in orbital inflammatory disease (OID). OID patients had pre-treatment tear collection via micropipette, and cytokine analysis via multiplex bead array analysis. Thirteen healthy controls with no prior ophthalmic history were enrolled for comparison. Eighteen tear specimens from seventeen OID patients (6 males; mean age: 52.1 ± 17.1-years-old), with one repeat tear sample taken for recurrent contralateral orbital inflammation. Diagnoses included non-specific orbital inflammation (47.1%), IgG4-related orbital disease (17.6%), orbital granulomatosis with polyangiitis (5.9%), giant cell arteritis (5.9%), herpes zoster ophthalmicus with orbital apex inflammation (5.9%), viral dacryoadenitis (5.9%), bacterial dacryoadenitis (5.9%) and orbital inflammation of uncertain cause (5.9%). Overall, OID patients, and specifically those with dacryoadenitis, had greater IL-6 levels compared to controls (P = 0.038 and 0.002, respectively). OID with dacryoadenitis had higher IL-1β levels compared to those without (P = 0.029). Higher IL-6 levels were observed in idiopathic dacryoadenitis compared to healthy controls (P = 0.008, respectively). There is significant variability in tear inflammatory cytokines profiles observed in OID. IL-1β and IL-6 levels may be non-specific markers of dacryoadenitis and may be particularly elevated in idiopathic dacryoadenitis. Tear cytokines may be affected by severity, localisation and pattern of inflammation. The utility of tear cytokines in the monitoring and prognostication of OID remains to be elucidated.
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Affiliation(s)
- Terence Ang
- The University of Adelaide, Adelaide, South Australia, Australia.
| | - Jessica Y Tong
- Department of Ophthalmology, The Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Clare Quigley
- Department of Ophthalmology, The Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Dinesh Selva
- Department of Ophthalmology, The Royal Adelaide Hospital, Adelaide, South Australia, Australia
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Yang Q, Huo E, Cai Y, Zhang Z, Dong C, Asara JM, Shi H, Wei Q. Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosis. Front Immunol 2023; 14:1259434. [PMID: 38035106 PMCID: PMC10687406 DOI: 10.3389/fimmu.2023.1259434] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 10/27/2023] [Indexed: 12/02/2023] Open
Abstract
Excessive renal fibrosis is a common pathology in progressive chronic kidney diseases. Inflammatory injury and aberrant repair processes contribute to the development of kidney fibrosis. Myeloid cells, particularly monocytes/macrophages, play a crucial role in kidney fibrosis by releasing their proinflammatory cytokines and extracellular matrix components such as collagen and fibronectin into the microenvironment of the injured kidney. Numerous signaling pathways have been identified in relation to these activities. However, the involvement of metabolic pathways in myeloid cell functions during the development of renal fibrosis remains understudied. In our study, we initially reanalyzed single-cell RNA sequencing data of renal myeloid cells from Dr. Denby's group and observed an increased gene expression in glycolytic pathway in myeloid cells that are critical for renal inflammation and fibrosis. To investigate the role of myeloid glycolysis in renal fibrosis, we utilized a model of unilateral ureteral obstruction in mice deficient of Pfkfb3, an activator of glycolysis, in myeloid cells (Pfkfb3 ΔMϕ ) and their wild type littermates (Pfkfb3 WT). We observed a significant reduction in fibrosis in the obstructive kidneys of Pfkfb3 ΔMϕ mice compared to Pfkfb3 WT mice. This was accompanied by a substantial decrease in macrophage infiltration, as well as a decrease of M1 and M2 macrophages and a suppression of macrophage to obtain myofibroblast phenotype in the obstructive kidneys of Pfkfb3 ΔMϕ mice. Mechanistic studies indicate that glycolytic metabolites stabilize HIF1α, leading to alterations in macrophage phenotype that contribute to renal fibrosis. In conclusion, our study implicates that targeting myeloid glycolysis represents a novel approach to inhibit renal fibrosis.
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Affiliation(s)
- Qiuhua Yang
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Emily Huo
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Augusta Preparatory Day School, Martinez, GA, United States
| | - Yongfeng Cai
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Zhidan Zhang
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Charles Dong
- Dental College of Georgia, Augusta University, Augusta, GA, United States
| | - John M. Asara
- Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, United States
| | - Huidong Shi
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Qingqing Wei
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
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Odler B, Tieu J, Artinger K, Chen-Xu M, Arnaud L, Kitching RA, Terrier B, Thiel J, Cid MC, Rosenkranz AR, Kronbichler A, Jayne DRW. The plethora of immunomodulatory drugs: opportunities for immune-mediated kidney diseases. Nephrol Dial Transplant 2023; 38:ii19-ii28. [PMID: 37816674 DOI: 10.1093/ndt/gfad186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Indexed: 10/12/2023] Open
Abstract
In recent decades, insights into the molecular pathways involved in disease have revolutionized the treatment of autoimmune diseases. A plethora of targeted therapies have been identified and are at varying stages of clinical development in renal autoimmunity. Some of these agents, such as rituximab or avacopan, have been approved for the treatment of immune-mediated kidney disease, but kidney disease lags behind more common autoimmune disorders in new drug development. Evidence is accumulating as to the importance of adaptive immunity, including abnormalities in T-cell activation and signaling, and aberrant B-cell function. Furthermore, innate immunity, particularly the complement and myeloid systems, as well as pathologic responses in tissue repair and fibrosis, play a key role in disease. Collectively, these mechanistic studies in innate and adaptive immunity have provided new insights into mechanisms of glomerular injury in immune-mediated kidney diseases. In addition, inflammatory pathways common to several autoimmune conditions exist, suggesting that the repurposing of some existing drugs for the treatment of immune-mediated kidney diseases is a logical strategy. This new understanding challenges the clinical investigator to translate new knowledge into novel therapies leading to better disease outcomes. This review highlights promising immunomodulatory therapies tested for immune-mediated kidney diseases as a primary indication, details current clinical trials and discusses pathways that could be targeted in the future.
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Affiliation(s)
- Balazs Odler
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Johanna Tieu
- Faculty of Health and Medical Sciences, University of Adelaide; Adelaide, Australia
- Rheumatology Unit, The Queen Elizabeth Hospital, Adelaide, Australia
- Rheumatology Unit, Lyell McEwin Hospital, Adelaide, Australia
| | - Katharina Artinger
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Michael Chen-Xu
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Laurent Arnaud
- National Reference Center for Rare Auto-immune and Systemic Diseases Est Sud-Est (RESO), Strasbourg, France
| | - Richard A Kitching
- Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia
- Departments of Nephrology and Paediatric Nephrology, Monash Medical Centre, Clayton, Victoria, Australia
| | - Benjamin Terrier
- Department of Internal Medicine, National Reference Center for Autoimmune Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris (AP-HP), Université de Paris, Paris, France
| | - Jens Thiel
- Division of Rheumatology and Immunology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Maria C Cid
- Department of Autoimmune Diseases, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Alexander R Rosenkranz
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Andreas Kronbichler
- Department of Medicine, University of Cambridge, Cambridge, UK
- Department of Internal Medicine IV, Nephrology and Hypertension, Medical University Innsbruck, Innsbruck, Austria
| | - David R W Jayne
- Department of Medicine, University of Cambridge, Cambridge, UK
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Daca A, Storoniak H, Dębska-Ślizień A, Kusztal MA, Krajewska M, Lisowska KA. Chemokines and Cytokines Profiles in Patients with Antineutrophil Cytoplasmic Antibodies-Associated Vasculitis: A Preliminary Study. Int J Mol Sci 2023; 24:15319. [PMID: 37894997 PMCID: PMC10607460 DOI: 10.3390/ijms242015319] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 10/05/2023] [Accepted: 10/16/2023] [Indexed: 10/29/2023] Open
Abstract
The damage to small vessels in AAV and inflammatory reactions are accompanied by the release of various chemokines and cytokines. Using a flow cytometry technique, we assessed the levels of specific cytokines, namely IL-1β IL-6, IL-8, IL-10, IL12p70, and TNF, and chemokines, IFN-α, IP-10, and MIG in the serum from 9 healthy volunteers and 20 AAV patients, where 11 of the patients were not treated and evaluated at the time of diagnosis and 9 were already diagnosed and taking CY + GCS. The obtained results were then compared considering the activity of the disease, the type and titre of the ANCA antibodies, the inflammatory status, and the kidneys' condition. Amongst others, the IL-6, IL-8, IL-10, TNF, and MIG levels were much higher in the serum of AAV patients than in healthy controls, whereas the level of IL-1β was higher in healthy volunteers. Additionally, the levels of IL-6, IL-10, IP-10, and MIG negatively correlated with the eGFR level, while the level of IFN-α positively correlated with the titre of PR3-ANCA. As most of the molecules are implicated in trafficking primed neutrophils towards small vessels, looking for links between the levels of these cytokines/chemokines and the clinical symptoms of AAV may facilitate the diagnosis and predict the progression of the disease.
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Affiliation(s)
- Agnieszka Daca
- Department of Pathophysiology, Medical University of Gdańsk, 80-211 Gdansk, Poland;
| | - Hanna Storoniak
- Department of Nephrology, Transplantology, and Internal Diseases, Medical University of Gdańsk, 80-211 Gdansk, Poland; (H.S.); (A.D.-Ś.)
| | - Alicja Dębska-Ślizień
- Department of Nephrology, Transplantology, and Internal Diseases, Medical University of Gdańsk, 80-211 Gdansk, Poland; (H.S.); (A.D.-Ś.)
| | - Mariusz Andrzej Kusztal
- Department of Nephrology and Translational Medicine, Medical University of Wrocław, 50-137 Wroclaw, Poland; (M.A.K.); (M.K.)
| | - Magdalena Krajewska
- Department of Nephrology and Translational Medicine, Medical University of Wrocław, 50-137 Wroclaw, Poland; (M.A.K.); (M.K.)
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Chen X, Hocher CF, Shen L, Krämer BK, Hocher B. Reno- and cardioprotective molecular mechanisms of SGLT2 inhibitors beyond glycemic control: from bedside to bench. Am J Physiol Cell Physiol 2023; 325:C661-C681. [PMID: 37519230 DOI: 10.1152/ajpcell.00177.2023] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 07/18/2023] [Accepted: 07/19/2023] [Indexed: 08/01/2023]
Abstract
Large placebo-controlled clinical trials have shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) delay the deterioration of renal function and reduce cardiovascular events in a glucose-independent manner, thereby ultimately reducing mortality in patients with chronic kidney disease (CKD) and/or heart failure. These existing clinical data stimulated preclinical studies aiming to understand the observed clinical effects. In animal models, it was shown that the beneficial effect of SGLT2i on the tubuloglomerular feedback (TGF) improves glomerular pressure and reduces tubular workload by improving renal hemodynamics, which appears to be dependent on salt intake. High salt intake might blunt the SGLT2i effects on the TGF. Beyond the salt-dependent effects of SGLT2i on renal hemodynamics, SGLT2i inhibited several key aspects of macrophage-mediated renal inflammation and fibrosis, including inhibiting the differentiation of monocytes to macrophages, promoting the polarization of macrophages from a proinflammatory M1 phenotype to an anti-inflammatory M2 phenotype, and suppressing the activation of inflammasomes and major proinflammatory factors. As macrophages are also important cells mediating atherosclerosis and myocardial remodeling after injury, the inhibitory effects of SGLT2i on macrophage differentiation and inflammatory responses may also play a role in stabilizing atherosclerotic plaques and ameliorating myocardial inflammation and fibrosis. Recent studies suggest that SGLT2i may also act directly on the Na+/H+ exchanger and Late-INa in cardiomyocytes thus reducing Na+ and Ca2+ overload-mediated myocardial damage. In addition, the renal-cardioprotective mechanisms of SGLT2i include systemic effects on the sympathetic nervous system, blood volume, salt excretion, and energy metabolism.
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Affiliation(s)
- Xin Chen
- Department of Nephrology, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Carl-Friedrich Hocher
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
- Klinik für Innere Medizin, Bundeswehrkrankenhaus Berlin, Berlin, Germany
| | - Linghong Shen
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bernhard K Krämer
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Berthold Hocher
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
- Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China
- Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, China
- IMD Institut für Medizinische Diagnostik Berlin-Potsdam GbR, Berlin, Germany
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Nezhad Nezhad MT, Rajabi M, Nekooeizadeh P, Sanjari S, Pourvirdi B, Heidari MM, Veradi Esfahani P, Abdoli A, Bagheri S, Tobeiha M. Systemic lupus erythematosus: From non-coding RNAs to exosomal non-coding RNAs. Pathol Res Pract 2023; 247:154508. [PMID: 37224659 DOI: 10.1016/j.prp.2023.154508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/01/2023] [Accepted: 05/05/2023] [Indexed: 05/26/2023]
Abstract
Systemic lupus erythematosus (SLE), as an immunological illness, frequently impacts young females. Both vulnerabilities to SLE and the course of the illness's clinical symptoms have been demonstrated to be affected by individual differences in non-coding RNA expression. Many non-coding RNAs (ncRNAs) are out of whack in patients with SLE. Because of the dysregulation of several ncRNAs in peripheral blood of patients suffering from SLE, these ncRNAs to be showed valuable as biomarkers for medication response, diagnosis, and activity. NcRNAs have also been demonstrated to influence immune cell activity and apoptosis. Altogether, these facts highlight the need of investigating the roles of both families of ncRNAs in the progress of SLE. Being aware of the significance of these transcripts perhaps elucidates the molecular pathogenesis of SLE and could open up promising avenues to create tailored treatments during this condition. In this review we summarized various non-coding RNAs and Exosomal non-coding RNAs in SLE.
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Affiliation(s)
| | - Mohammadreza Rajabi
- Student Research Committee، Shiraz University of Medical Sciences, Shiraz, Iran
| | - Pegah Nekooeizadeh
- Student Research Committee، Shiraz University of Medical Sciences, Shiraz, Iran
| | - Siavash Sanjari
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran; School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Bita Pourvirdi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran; School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Mehdi Heidari
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Department of Pediatric, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Pegah Veradi Esfahani
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran; School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Amirhossein Abdoli
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran; School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Sahar Bagheri
- Diabetes Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Mohammad Tobeiha
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Department of Pediatric, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran.
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Brieske C, Lamprecht P, Kerstein-Staehle A. Immunogenic cell death as driver of autoimmunity in granulomatosis with polyangiitis. Front Immunol 2022; 13:1007092. [PMID: 36275673 PMCID: PMC9583010 DOI: 10.3389/fimmu.2022.1007092] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 09/21/2022] [Indexed: 11/17/2022] Open
Abstract
Cell death and dysregulated clearance of dead cells play essential roles in the induction of chronic inflammatory processes and autoimmune diseases. Granulomatosis with polyangiitis (GPA), a neutrophil-driven autoimmune disorder, is characterized by necrotizing inflammation predominantly of the respiratory tract and an anti-neutrophil cytoplasmic autoantibody (ANCA)-associated systemic necrotizing vasculitis. Defective regulation of neutrophil homeostasis and cell death mechanisms have been demonstrated in GPA. Disturbed efferocytosis (i.e., phagocytosis of apoptotic neutrophils by macrophages) as well as cell death-related release of damage-associated molecular patterns (DAMP) such as high mobility group box 1 (HMGB1) contribute to chronic non-resolving inflammation in GPA. DAMP have been shown to induce innate as well as adaptive cellular responses thereby creating a prerequisite for the development of pathogenic autoimmunity. In this review, we discuss factors contributing to as well as the impact of regulated cell death (RCD) accompanied by DAMP-release as early drivers of the granulomatous tissue inflammation and autoimmune responses in GPA.
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Miao X, Tian Y, Wu L, Zhao H, Liu J, Gao F, Zhang W, Liu Q, Guo H, Yang L, Yang R, Feng X, Liu S. CircRTN4 aggravates mesangial cell dysfunction by activating the miR-513a-5p/FN axis in lupus nephritis. J Transl Med 2022; 102:966-978. [PMID: 36775425 PMCID: PMC9420678 DOI: 10.1038/s41374-022-00788-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/24/2022] [Accepted: 04/07/2022] [Indexed: 11/08/2022] Open
Abstract
Circular RNAs (circRNAs) are regulators of gene expression that can regulate cell proliferation and programmed cell death and serve as biomarkers in renal diseases. However, the specific traits and underlying mechanisms of circRNAs in the progression of lupus nephritis (LN) have not been elucidated. In the present study, we clarified that hsa_circ_0054595 (circRTN4) was upregulated in human renal mesangial cells (HRMCs). In cultured HRMCs, circRTN4 could enhance FN expression by directly interacting with miR-513a-5p. High circRTN4 expression in monocytes disseminated into HRMCs in an exosomal manner, thereby accelerating cell proliferation and extracellular matrix deposition. In addition, knockdown of circRTN4 in the kidney or peripheral blood alleviated renal damage in MRL/lpr and BALB/c mice. Clinically, high levels of circRTN4 were found in peripheral blood mononuclear cells and kidney tissues of LN patients, hence serving as an effective biomarker for LN detection and a novel therapeutic target. Our findings indicated that circRTN4 exacerbates mesangial cell dysfunction by activating the miR-513a-5p/FN axis in lupus nephritis.
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Affiliation(s)
- Xinyan Miao
- Department of Pathology; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, 050017, China
| | - Yuexin Tian
- Department of Pathology; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, 050017, China
| | - Lunbi Wu
- Department of Pathology; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, 050017, China
| | - Hang Zhao
- Department of Pathology; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, 050017, China
| | - Jinxi Liu
- Department of Pathology; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, 050017, China
| | - Fan Gao
- Department of Pathology; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, 050017, China
| | - Wei Zhang
- Department of Pathology; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, 050017, China
| | - Qingjuan Liu
- Department of Pathology; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, 050017, China
| | - Huifang Guo
- Department of Rheumatology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Lin Yang
- Department of Nephrology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Ran Yang
- Department of Pathology, Hebei Province Hospital of Chinese Medicine, Shijiazhuang, 050013, China
| | - Xiaojuan Feng
- Department of Pathology; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, 050017, China.
| | - Shuxia Liu
- Department of Pathology; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University; Key Laboratory of Kidney Diseases of Hebei Province, Shijiazhuang, 050017, China.
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10
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Martin K, Deleveaux S, Cunningham M, Ramaswamy K, Thomas B, Lerma E, Madariaga H. The presentation, etiologies, pathophysiology, and treatment of pulmonary renal syndrome: A review of the literature. Dis Mon 2022; 68:101465. [PMID: 36008166 DOI: 10.1016/j.disamonth.2022.101465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
Pulmonary renal syndrome (PRS) is a constellation of different disorders that cause both rapidly progressive glomerulonephritis and diffuse alveolar hemorrhage. While antineutrophil cytoplasmic antibody associated vasculitis and anti-glomerular basement membrane disease are the predominant causes of PRS, numerous other mechanisms have been shown to cause this syndrome, including thrombotic microangiopathies, drug exposures, and infections, among others. This syndrome has high morbidity and mortality, and early diagnosis and treatment is imperative to improve outcomes. Treatment generally involves glucocorticoids and immunosuppressive agents, but treatment targeted to the underlying disorder can improve outcomes and mitigate side effects. Familiarity with the wide range of possible causes of PRS can aid the clinician in workup, diagnosis and early initiation of treatment. This review provides a summary of the clinical presentation, etiologies, pathophysiology, and treatment of PRS.
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Affiliation(s)
| | | | | | | | - Beje Thomas
- Medstar Georgetown University Hospital, United States
| | - Edgar Lerma
- Advocate Christ Medical Center, United States
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11
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Yap BJM, Lai-Foenander AS, Goh BH, Ong YS, Duangjai A, Saokaew S, Chua CLL, Phisalprapa P, Yap WH. Unraveling the Immunopathogenesis and Genetic Variants in Vasculitis Toward Development of Personalized Medicine. Front Cardiovasc Med 2021; 8:732369. [PMID: 34621800 PMCID: PMC8491767 DOI: 10.3389/fcvm.2021.732369] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 08/26/2021] [Indexed: 12/23/2022] Open
Abstract
Leukocytoclastic vasculitis (LCV) is a systemic autoimmune disease characterized by the inflammation of the vascular endothelium. Cutaneous small vessel vasculitis (CSVV) and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) are two examples of LCV. Advancements in genomic technologies have identified risk haplotypes, genetic variants, susceptibility loci and pathways that are associated with vasculitis immunopathogenesis. The discovery of these genetic factors and their corresponding cellular signaling aberrations have enabled the development and use of novel therapeutic strategies for vasculitis. Personalized medicine aims to provide targeted therapies to individuals who show poor response to conventional interventions. For example, monoclonal antibody therapies have shown remarkable efficacy in achieving disease remission. Here, we discuss pathways involved in disease pathogenesis and the underlying genetic associations in different populations worldwide. Understanding the immunopathogenic pathways in vasculitis and identifying associated genetic variations will facilitate the development of novel and targeted personalized therapies for patients.
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Affiliation(s)
- Bryan Ju Min Yap
- School of Biosciences, Taylor's University, Subang Jaya, Malaysia
| | | | - Bey Hing Goh
- Biofunctional Molecule Exploratory Research Group (BMEX), School of Pharmacy, Monash University Malaysia, Bandar Sunway, Malaysia.,College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yong Sze Ong
- Biofunctional Molecule Exploratory Research Group (BMEX), School of Pharmacy, Monash University Malaysia, Bandar Sunway, Malaysia
| | - Acharaporn Duangjai
- Unit of Excellence in Research and Product Development of Coffee, Division of Physiology, School of Medical Sciences, University of Phayao, Phayao, Thailand.,Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.,Unit of Excellence on Clinical Outcomes Research and IntegratioN (UNICORN), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
| | - Surasak Saokaew
- Unit of Excellence in Research and Product Development of Coffee, Division of Physiology, School of Medical Sciences, University of Phayao, Phayao, Thailand.,Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.,Unit of Excellence on Clinical Outcomes Research and IntegratioN (UNICORN), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.,Unit of Excellence on Herbal Medicine, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.,Division of Pharmacy Practice, Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
| | | | - Pochamana Phisalprapa
- Division of Ambulatory Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Wei Hsum Yap
- School of Biosciences, Taylor's University, Subang Jaya, Malaysia.,Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health and Medical Sciences (FHMS), Taylor's University, Subang Jaya, Malaysia
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12
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PP2Acα promotes macrophage accumulation and activation to exacerbate tubular cell death and kidney fibrosis through activating Rap1 and TNFα production. Cell Death Differ 2021; 28:2728-2744. [PMID: 33934104 PMCID: PMC8408198 DOI: 10.1038/s41418-021-00780-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 04/02/2021] [Accepted: 04/07/2021] [Indexed: 02/01/2023] Open
Abstract
Macrophage accumulation and activation play an essential role in kidney fibrosis; however, the underlying mechanisms remain to be explored. By analyzing the kidney tissues from patients and animal models with kidney fibrosis, we found a large induction of PP2Acα in macrophages. We then generated a mouse model with inducible macrophage ablation of PP2Acα. The knockouts developed less renal fibrosis, macrophage accumulation, or tubular cell death after unilateral ureter obstruction or ischemic reperfusion injury compared to control littermates. In cultured macrophages, PP2Acα deficiency resulted in decreased cell motility by inhibiting Rap1 activity. Moreover, co-culture of PP2Acα-/- macrophages with tubular cells resulted in less tubular cell death attributed to downregulated Stat6-mediated tumor necrosis factor α (TNFα) production in macrophages. Together, this study demonstrates that PP2Acα promotes macrophage accumulation and activation, hence accelerates tubular cell death and kidney fibrosis through regulating Rap1 activation and TNFα production.
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13
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Soni H, Kumar R, Kanthakumar P, Adebiyi A. Interleukin 1 beta-induced calcium signaling via TRPA1 channels promotes mitogen-activated protein kinase-dependent mesangial cell proliferation. FASEB J 2021; 35:e21729. [PMID: 34143493 DOI: 10.1096/fj.202100367r] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/23/2021] [Accepted: 05/26/2021] [Indexed: 12/13/2022]
Abstract
Glomerular mesangial cell (GMC)-derived pleiotropic cytokine, interleukin-1 (IL-1), contributes to hypercellularity in human and experimental proliferative glomerulonephritis. IL-1 promotes mesangial proliferation and may stimulate extracellular matrix accumulation, mechanisms of which are unclear. The present study shows that the beta isoform of IL-1 (IL-1β) is a potent inducer of IL-1 type I receptor-dependent Ca2+ entry in mouse GMCs. We also demonstrate that the transient receptor potential ankyrin 1 (TRPA1) is an intracellular store-independent diacylglycerol-sensitive Ca2+ channel in the cells. IL-1β-induced Ca2+ and Ba2+ influxes in the cells were negated by pharmacological inhibition and siRNA-mediated knockdown of TRPA1 channels. IL-1β did not stimulate fibronectin production in cultured mouse GMCs and glomerular explants but promoted Ca2+ -dependent cell proliferation. IL-1β also stimulated TRPA1-dependent ERK mitogen-activated protein kinase (MAPK) phosphorylation in the cells. Concomitantly, IL-1β-induced GMC proliferation was attenuated by TRPA1 and RAF1/ MEK/ERK inhibitors. These findings suggest that IL-1β-induced Ca2+ entry via TRPA1 channels engenders MAPK-dependent mesangial cell proliferation. Hence, TRPA1-mediated Ca2+ signaling could be of pathological significance in proliferative glomerulonephritis.
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Affiliation(s)
- Hitesh Soni
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Ravi Kumar
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Praghalathan Kanthakumar
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Adebowale Adebiyi
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
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14
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Müller A, Krause B, Kerstein-Stähle A, Comdühr S, Klapa S, Ullrich S, Holl-Ulrich K, Lamprecht P. Granulomatous Inflammation in ANCA-Associated Vasculitis. Int J Mol Sci 2021; 22:ijms22126474. [PMID: 34204207 PMCID: PMC8234846 DOI: 10.3390/ijms22126474] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/04/2021] [Accepted: 06/10/2021] [Indexed: 12/21/2022] Open
Abstract
ANCA-associated vasculitis (AAV) comprises granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). While systemic vasculitis is a hallmark of all AAV, GPA is characterized by extravascular granulomatous inflammation, preferentially affecting the respiratory tract. The mechanisms underlying the emergence of neutrophilic microabscesses; the appearance of multinucleated giant cells; and subsequent granuloma formation, finally leading to scarred or destroyed tissue in GPA, are still incompletely understood. This review summarizes findings describing the presence and function of molecules and cells contributing to granulomatous inflammation in the respiratory tract and to renal inflammation observed in GPA. In addition, factors affecting or promoting the development of granulomatous inflammation such as microbial infections, the nasal microbiome, and the release of damage-associated molecular patterns (DAMP) are discussed. Further, on the basis of numerous results, we argue that, in situ, various ways of exposure linked with a high number of infiltrating proteinase 3 (PR3)- and myeloperoxidase (MPO)-expressing leukocytes lower the threshold for the presentation of an altered PR3 and possibly also of MPO, provoking the local development of ANCA autoimmune responses, aided by the formation of ectopic lymphoid structures. Although extravascular granulomatous inflammation is unique to GPA, similar molecular and cellular patterns can be found in both the respiratory tract and kidney tissue of GPA and MPA patients; for example, the antimicrobial peptide LL37, CD163+ macrophages, or regulatory T cells. Therefore, we postulate that granulomatous inflammation in GPA or PR3-AAV is intertwined with autoimmune and destructive mechanisms also seen at other sites.
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Affiliation(s)
- Antje Müller
- Department of Rheumatology & Clinical Immunology, University of Luebeck, 23562 Luebeck, Germany; (B.K.); (A.K.-S.); (S.C.); (S.K.); (P.L.)
- Correspondence: ; Tel.: +49-451-5005-0867
| | - Bettina Krause
- Department of Rheumatology & Clinical Immunology, University of Luebeck, 23562 Luebeck, Germany; (B.K.); (A.K.-S.); (S.C.); (S.K.); (P.L.)
- Institute of Anatomy & Experimental Morphology, University Hospital Hamburg-Eppendorf, University of Hamburg, 20251 Hamburg, Germany;
| | - Anja Kerstein-Stähle
- Department of Rheumatology & Clinical Immunology, University of Luebeck, 23562 Luebeck, Germany; (B.K.); (A.K.-S.); (S.C.); (S.K.); (P.L.)
| | - Sara Comdühr
- Department of Rheumatology & Clinical Immunology, University of Luebeck, 23562 Luebeck, Germany; (B.K.); (A.K.-S.); (S.C.); (S.K.); (P.L.)
| | - Sebastian Klapa
- Department of Rheumatology & Clinical Immunology, University of Luebeck, 23562 Luebeck, Germany; (B.K.); (A.K.-S.); (S.C.); (S.K.); (P.L.)
- Institute of Experimental Medicine c/o German Naval Medical Institute, Carl-Albrechts University of Kiel, 24119 Kronshagen, Germany
| | - Sebastian Ullrich
- Institute of Anatomy & Experimental Morphology, University Hospital Hamburg-Eppendorf, University of Hamburg, 20251 Hamburg, Germany;
- Municipal Hospital Kiel, 24116 Kiel, Germany
| | | | - Peter Lamprecht
- Department of Rheumatology & Clinical Immunology, University of Luebeck, 23562 Luebeck, Germany; (B.K.); (A.K.-S.); (S.C.); (S.K.); (P.L.)
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15
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Nozaki Y. New Insights Into Novel Therapeutic Targets in ANCA-Associated Vasculitis. Front Immunol 2021; 12:631055. [PMID: 33868250 PMCID: PMC8047311 DOI: 10.3389/fimmu.2021.631055] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 03/18/2021] [Indexed: 11/13/2022] Open
Abstract
Biologics targeting inflammation-related molecules in the immune system have been developed to treat rheumatoid arthritis (RA), and these RA treatments have provided revolutionary advances. Biologics may also be an effective treatment for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, particularly in patients with resistance to standard treatments. Despite the accumulation of clinical experience and the increasing understanding of the pathogenesis of vasculitis, it is becoming more difficult to cure vasculitis. The treatment of vasculitis with biologics has been examined in clinical trials, and this has also enhanced our understanding of the pathogenesis of vasculitis. A humanized anti-interleukin-5 monoclonal antibody known as mepolizumab was recently demonstrated to provide clinical benefit in the management of eosinophilic granulomatosis with polyangiitis in refractory and relapsing disease, and additional new drugs for vasculitis are being tested in clinical trials, while others are in abeyance. This review presents the new findings regarding biologics in addition to the conventional immunosuppressive therapy for ANCA-associated vasculitis.
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Affiliation(s)
- Yuji Nozaki
- Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-sayama, Japan
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16
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Thrombosis as the First Manifestation of Granulomatosis with Polyangiitis Disease in an Adolescent. Case Rep Hematol 2021; 2021:5520258. [PMID: 33763268 PMCID: PMC7946471 DOI: 10.1155/2021/5520258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/22/2021] [Accepted: 02/28/2021] [Indexed: 11/29/2022] Open
Abstract
Background Granulomatosis with polyangiitis disease (GPA) is a rare vasculitis characterized by granulomatous inflammation of respiratory tracts, glomerulonephritis, and vasculitis of other organs. Case Presentation. A 13-year-old girl was referred due to swelling and pain on her left arm. The Doppler and compression ultrasonography showed noncompressible left brachial and axillary vein thrombosis. Sinus computed tomography (CT) demonstrated pansinusitis, and spiral chest CT showed alveolar hemorrhage. Laboratory tests showed hematuria, proteinuria, and highly positive antineutrophil cytoplasmic antibody (cANCA). Laboratory tests of coagulopathy were normal. The patient was recognized as a case of GPA. Conclusion Although GPA is not frequently associated with thrombosis especially in children, this is the first report that shows thrombosis may be the first manifestation of GPA in an adolescent.
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17
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Leacy E, Brady G, Little MA. Pathogenesis of ANCA-associated vasculitis: an emerging role for immunometabolism. Rheumatology (Oxford) 2021; 59:iii33-iii41. [PMID: 32348520 DOI: 10.1093/rheumatology/keaa023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 01/02/2020] [Indexed: 12/16/2022] Open
Abstract
ANCA-associated vasculitis (AAV) is a severe systemic autoimmune disease. A key feature of AAV is the presence of Anti-Neutrophil Cytoplasmic Antibodies (ANCA) directed against myeloperoxidase (MPO) or proteinase-3 (PR3). ANCA are key to the pathogenesis of AAV, where they activate innate immune cells to drive inflammation. Pre-activation or 'priming' of immune cells appears to be important for complete cellular activation in AAV. The burgeoning field of immunometabolism has illuminated the governance of immune cell function by distinct metabolic pathways. There is ample evidence that the priming events synonymous with AAV alter immune cell metabolism. In this review we discuss the pathogenesis of AAV and its intersection with recent insights into immune cell metabolism.
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Affiliation(s)
- Emma Leacy
- Trinity Health Kidney Centre, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Gareth Brady
- Trinity Health Kidney Centre, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Mark A Little
- Trinity Health Kidney Centre, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
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18
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Kyurkchiev D, Yoneva T, Yordanova A, Kurteva E, Vasilev G, Zdravkova Y, Sheytanov I, Rashkov R, Ivanova-Todorova E. Alterations of serum levels of plasminogen, TNF-α, and IDO in granulomatosis with polyangiitis patients. Vascular 2021; 29:874-882. [PMID: 33427113 DOI: 10.1177/1708538120986305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
BACKGROUND Granulomatosis with polyangiitis (GPA) is a representative of vasculitides associated with anti-neutrophil cytoplasmic autoantibodies. "Classical" antibodies directed against proteinase 3 are involved in the pathogenesis and are part of the GPA diagnosis at the same time. Along with them, however, antibodies against Lysosomal-Associated Membrane Protein-2 (LAMP-2) and antibodies directed against plasminogen have been described in GPA.Objectives and methodology: We performed a cross-sectional study enrolling 34 patients diagnosed with GPA. Our study was aimed at looking for correlations between serum levels of LAMP-2 and plasminogen and the clinical manifestations of the GPA. Furthermore, we examined serum levels of tumor necrosis factor-alpha (TNF-α) and its associated indoleamine-pyrrole 2,3-dioxygenase (IDO), as well as we looked for a correlation between these cytokines and the clinical manifestations of GPA. RESULTS The results showed that in GPA, serum plasminogen levels were negatively associated with renal involvement (receiver operating characteristic (ROC) area under the curve (AUC) of 0.78) (95% CI 0.53-0.91), p = 0.035, and the extent of proteinuria, Spearman's Rho = -0.4, p = 0.015. Increased levels of TNF-α and IDO correlated with disease activity, Spearman's Rho =0.62, p = 0.001 and Spearman's Rho = 0.4, p = 0.022, respectively, whereas only TNF-α was increased in severe forms of GPA with lung involvement (ROC AUC of 0.8) (95% CI 0.66-0.94), p = 0.005. CONCLUSIONS In this study, we demonstrate the alteration of soluble factors, which play an important role in the pathogenesis of GPA and their relationship with the clinical manifestations of the disease. Our main results confirm the associations of increased secretory TNF-α and some clinical manifestations, and we describe for the first time decreased serum plasminogen levels and their association with renal involvement.
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Affiliation(s)
- Dobroslav Kyurkchiev
- Laboratory of Clinical immunology, University Hospital St. Ivan Rilski, Department of Clinical Immunology, Medical Faculty, Medical University of Sofia, Sofia, Bulgaria
| | - Tsvetelina Yoneva
- Department of Rheumatology, Clinic of Rheumatology, University Hospital St. Ivan Rilski, Medical Faculty, Medical University of Sofia, Sofia, Bulgaria
| | - Adelina Yordanova
- Laboratory of Clinical immunology, University Hospital St. Ivan Rilski, Department of Clinical Immunology, Medical Faculty, Medical University of Sofia, Sofia, Bulgaria
| | - Ekaterina Kurteva
- Laboratory of Clinical immunology, University Hospital St. Ivan Rilski, Department of Clinical Immunology, Medical Faculty, Medical University of Sofia, Sofia, Bulgaria
| | - Georgi Vasilev
- Laboratory of Clinical immunology, University Hospital St. Ivan Rilski, Department of Clinical Immunology, Medical Faculty, Medical University of Sofia, Sofia, Bulgaria
| | - Yana Zdravkova
- Department of Rheumatology, Clinic of Rheumatology, University Hospital St. Ivan Rilski, Medical Faculty, Medical University of Sofia, Sofia, Bulgaria
| | - Ivan Sheytanov
- Department of Rheumatology, Clinic of Rheumatology, University Hospital St. Ivan Rilski, Medical Faculty, Medical University of Sofia, Sofia, Bulgaria
| | - Rasho Rashkov
- Department of Rheumatology, Clinic of Rheumatology, University Hospital St. Ivan Rilski, Medical Faculty, Medical University of Sofia, Sofia, Bulgaria
| | - Ekaterina Ivanova-Todorova
- Laboratory of Clinical immunology, University Hospital St. Ivan Rilski, Department of Clinical Immunology, Medical Faculty, Medical University of Sofia, Sofia, Bulgaria
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19
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Immunopathogenesis of ANCA-Associated Vasculitis. Int J Mol Sci 2020; 21:ijms21197319. [PMID: 33023023 PMCID: PMC7584042 DOI: 10.3390/ijms21197319] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/26/2020] [Accepted: 09/30/2020] [Indexed: 12/11/2022] Open
Abstract
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder which affects small- and, to a lesser degree, medium-sized vessels. ANCA-associated vasculitis encompasses three disease phenotypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). This classification is largely based on clinical presentations and has several limitations. Recent research provided evidence that genetic background, risk of relapse, prognosis, and co-morbidities are more closely related to the ANCA serotype, proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, compared to the disease phenotypes GPA or MPA. This finding has been extended to the investigation of biomarkers predicting disease activity, which again more closely relate to the ANCA serotype. Discoveries related to the immunopathogenesis translated into clinical practice as targeted therapies are on the rise. This review will summarize the current understanding of the immunopathogenesis of ANCA-associated vasculitis and the interplay between ANCA serotype and proposed disease biomarkers and illustrate how the extending knowledge of the immunopathogenesis will likely translate into development of a personalized medicine approach in the management of ANCA-associated vasculitis.
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20
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Wang LY, Sun XJ, Chen M, Zhao MH. The expression of NOD2, NLRP3 and NLRC5 and renal injury in anti-neutrophil cytoplasmic antibody-associated vasculitis. J Transl Med 2019; 17:197. [PMID: 31186034 PMCID: PMC6560890 DOI: 10.1186/s12967-019-1949-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 06/05/2019] [Indexed: 02/05/2023] Open
Abstract
Background Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are intracellular sensors of pathogens and molecules from damaged cells to regulate the inflammatory response in the innate immune system. Emerging evidences suggested a potential role of NLRs in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study aimed to investigate the expression of nucleotide-binding oligomerization domain containing protein 2 (NOD2), NOD-like receptor family pyrin domain containing 3 (NLRP3) and NOD-like receptor family CARD domain containing 5 (NLRC5) in kidneys of AAV patients, and further explored their associations with clinical and pathological parameters. Methods Thirty-four AAV patients in active stage were recruited. Their renal specimens were processed with immunohistochemistry to assess the expression of three NLRs, and with double immunofluorescence to detect NLRs on intrinsic and infiltrating cells. Analysis of gene expression was also adopted in cultured human podocytes. The associations between expression of NLRs and clinicopathological parameters were analyzed. Results The expression of NOD2, NLRP3 and NLRC5 was significantly higher in kidneys from AAV patients than those from normal controls, minimal change disease or class IV lupus nephritis. These NLRs co-localized with podocytes and infiltrating inflammatory cells. The mean optical density of NOD2 in glomeruli was significantly higher in crescentic class than non-crescentic class, and correlated with levels of proteinuria and serum creatinine at renal biopsy. The mean optical density of NLRC5 in glomeruli was significantly higher in crescentic class than non-crescentic class, and correlated with proteinuria level, Birmingham Vasculitis Activity Score and the proportion of crescents in the renal specimen. Conclusions The expression of three NLRs was upregulated in kidneys of AAV patients. The expression of NOD2 and NLRC5 was associated with the severity of renal lesions in AAV.
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Affiliation(s)
- Luo-Yi Wang
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, No 8, Xishiku Street, Xicheng District, Beijing, 100034, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Xiao-Jing Sun
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, No 8, Xishiku Street, Xicheng District, Beijing, 100034, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Min Chen
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, No 8, Xishiku Street, Xicheng District, Beijing, 100034, China. .,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China. .,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.
| | - Ming-Hui Zhao
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, No 8, Xishiku Street, Xicheng District, Beijing, 100034, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
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21
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Macrophages: versatile players in renal inflammation and fibrosis. Nat Rev Nephrol 2019; 15:144-158. [PMID: 30692665 DOI: 10.1038/s41581-019-0110-2] [Citation(s) in RCA: 655] [Impact Index Per Article: 109.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/11/2018] [Indexed: 12/15/2022]
Abstract
Macrophages have important roles in immune surveillance and in the maintenance of kidney homeostasis; their response to renal injury varies enormously depending on the nature and duration of the insult. Macrophages can adopt a variety of phenotypes: at one extreme, M1 pro-inflammatory cells contribute to infection clearance but can also promote renal injury; at the other extreme, M2 anti-inflammatory cells have a reparative phenotype and can contribute to the resolution phase of the response to injury. In addition, bone marrow monocytes can differentiate into myeloid-derived suppressor cells that can regulate T cell immunity in the kidney. However, macrophages can also promote renal fibrosis, a major driver of progression to end-stage renal disease, and the CD206+ subset of M2 macrophages is strongly associated with renal fibrosis in both human and experimental diseases. Myofibroblasts are important contributors to renal fibrosis and recent studies provide evidence that macrophages recruited from the bone marrow can transition directly into myofibroblasts within the injured kidney. This process is termed macrophage-to-myofibroblast transition (MMT) and is driven by transforming growth factor-β1 (TGFβ1)-Smad3 signalling via a Src-centric regulatory network. MMT may serve as a key checkpoint for the progression of chronic inflammation into pathogenic fibrosis.
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22
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Masola V, Carraro A, Granata S, Signorini L, Bellin G, Violi P, Lupo A, Tedeschi U, Onisto M, Gambaro G, Zaza G. In vitro effects of interleukin (IL)-1 beta inhibition on the epithelial-to-mesenchymal transition (EMT) of renal tubular and hepatic stellate cells. J Transl Med 2019; 17:12. [PMID: 30616602 PMCID: PMC6323803 DOI: 10.1186/s12967-019-1770-1] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 01/02/2019] [Indexed: 02/06/2023] Open
Abstract
Background The epithelial to mesenchymal transition (EMT) is a multi-factorial biological mechanism involved in renal and hepatic fibrosis and the IL-1 beta has been assumed as a mediator of this process although data are not exhaustive. Therefore, the aim of our study was to evaluate the role of this cytokine in the EMT of renal proximal tubular epithelial cells (HK-2) and stellate cells (LX-2) and the protective/anti-fibrotic effect of its inhibition by Canakinumab (a specific human monoclonal antibody targeted against IL-1beta). Methods Both cell types were treated with IL-1 beta (10 ng/ml) for 6 and 24 h with and without Canakinumab (5 μg/ml). As control we used TGF-beta (10 ng/ml). Expression of EMT markers (vimentin, alpha-SMA, fibronectin) were evaluated through western blotting and immunofluorescence. Genes expression for matrix metalloproteinases (MMP)-2 was measured by Real-Time PCR and enzymatic activity by zymography. Cellular motility was assessed by scratch assay. Results IL-1 beta induced a significant up-regulation of EMT markers in both cell types and increased the MMP-2 protein expression and enzymatic activity, similarly to TGF-beta. Moreover, IL-1 beta induced a higher rate of motility in HK-2. Canakinumab prevented all these modifications in both cell types. Conclusions Our results clearly demonstrate the role of IL-1 beta in the EMT of renal/stellate cells and it underlines, for the first time, the therapeutic potential of its specific inhibition on the prevention/minimization of organ fibrosis. Electronic supplementary material The online version of this article (10.1186/s12967-019-1770-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Valentina Masola
- Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A. Stefani 1, 37126, Verona, VR, Italy
| | - Amedeo Carraro
- Department of General Surgery and Odontoiatrics, Liver Transplant Unit, University Hospital of Verona, Piazzale Stefani 1, 37126, Verona, Italy
| | - Simona Granata
- Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A. Stefani 1, 37126, Verona, VR, Italy
| | - Lorenzo Signorini
- Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A. Stefani 1, 37126, Verona, VR, Italy
| | - Gloria Bellin
- Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A. Stefani 1, 37126, Verona, VR, Italy
| | - Paola Violi
- Department of General Surgery and Odontoiatrics, Liver Transplant Unit, University Hospital of Verona, Piazzale Stefani 1, 37126, Verona, Italy
| | - Antonio Lupo
- Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A. Stefani 1, 37126, Verona, VR, Italy
| | - Umberto Tedeschi
- Department of General Surgery and Odontoiatrics, Liver Transplant Unit, University Hospital of Verona, Piazzale Stefani 1, 37126, Verona, Italy
| | - Maurizio Onisto
- Department of Biomedical Sciences, University of Padova, Via Ugo Bassi, 58/B, 35131, Padua, Italy
| | - Giovanni Gambaro
- Division of Nephrology and Dialysis, School of Medicine, Columbus-Gemelli Hospital Catholic University, Largo Agostino Gemelli 8, 00168, Rome, RM, Italy
| | - Gianluigi Zaza
- Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A. Stefani 1, 37126, Verona, VR, Italy.
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Oleinika K, Mauri C, Salama AD. Effector and regulatory B cells in immune-mediated kidney disease. Nat Rev Nephrol 2018; 15:11-26. [DOI: 10.1038/s41581-018-0074-7] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Korkmaz B, Caughey GH, Chapple I, Gauthier F, Hirschfeld J, Jenne DE, Kettritz R, Lalmanach G, Lamort AS, Lauritzen C, Łȩgowska M, Lesner A, Marchand-Adam S, McKaig SJ, Moss C, Pedersen J, Roberts H, Schreiber A, Seren S, Thakker NS. Therapeutic targeting of cathepsin C: from pathophysiology to treatment. Pharmacol Ther 2018; 190:202-236. [DOI: 10.1016/j.pharmthera.2018.05.011] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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25
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Puéchal X. Targeted immunotherapy strategies in ANCA-associated vasculitis. Joint Bone Spine 2018; 86:321-326. [PMID: 30201478 DOI: 10.1016/j.jbspin.2018.09.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/20/2018] [Indexed: 12/11/2022]
Abstract
Targeted immunotherapy is substantially improving the management of ANCA-associated vasculitides (AAV), which include granulomatosis with polyangiitis (GPA, Wegener's granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome). This article reviews the current role for targeted immunotherapy in AAV, its validated indications, and avenues for further development. Rituximab is a validated induction treatment for GPA and severe MPA. Rituximab in these indications is not less effective than cyclophosphamide and is particularly useful in patients with refractory or relapsing disease, women of childbearing potential, and patients previously treated with cyclophosphamide. Rituximab is more effective than cyclophosphamide for treating relapses. For remission maintenance therapy, which is indispensable, rituximab has been proven superior over conventional immunosuppressive treatment. Rituximab is licensed in the USA and in Europe for the induction treatment of severe forms of GPA and MPA. An extension study for remission maintenance therapy is ongoing. In EGPA, although maintenance treatment with the interleukin-5 antagonist mepolizumab is effective in decreasing glucocorticoid requirements and in alleviating asthma and sinonasal symptoms, its efficacy on the vasculitis remains somewhat unclear. Mepolizumab is licensed for use in EGPA, and rituximab is also being evaluated as an induction and maintenance agent. Immunoglobulins can be helpful as an adjuvant treatment for active AAV with severe immunedepression, notably when infections occur. Plasma exchange is indicated in AAV with advanced renal dysfunction and, perhaps, in the event of alveolar hemorrhage, a possibility that will be assessed in 2018 in a large international study.
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Affiliation(s)
- Xavier Puéchal
- Centre de référence des maladies systémiques auto-immunes rares, département de médecine interne, hôpital Cochin, Assistance publique-Hôpitaux de Paris, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France; Université Paris Descartes, 12, rue de l'École-de-Médecine, 75006 Paris, France; Institut Cochin, Inserm U1016, CNRS UMR 8104, Paris, France.
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26
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Raghav A, Ahmad J, Alam K. Preferential recognition of advanced glycation end products by serum antibodies and low-grade systemic inflammation in diabetes mellitus and its complications. Int J Biol Macromol 2018; 118:1884-1891. [PMID: 30009900 DOI: 10.1016/j.ijbiomac.2018.07.033] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 07/09/2018] [Accepted: 07/10/2018] [Indexed: 12/23/2022]
Abstract
BACKGROUND Advanced glycation end products (AGEs) have shown to possess antigenicity. This study analyzes the detrimental effect of non-enzymatic glycation on human serum albumin (HSA) leading to the production of antibodies. METHODS HSA (20 μM) incubated with d-glucose formed AGEs confirmed by scanning electron microscopy (SEM). DNA-damage was assessed with comet assay. Antibodies against in-vitro formed AGEs was evaluated in the sera of diabetic patients by enzyme-linked immunosorbent assay. Molecular docking was performed to demonstrate affinity of native and glycated-HSA with IgG. Low-grade systemic inflammation was quantified with IL-4, IL-6, TNF-α and NF-кβ in serum and mRNA expression. RESULTS Scanning Electron Microscopy showed the formation of aggregates in glycated-HSA. Comet assay showed DNA damage T2DM with CKD. Serum auto-antibodies in diabetes patients with chronic kidney disease (CKD) showed appreciably high recognition with glycated-HSA compared to native HSA. Molecular docking showed less affinity of glycated-HSA with IgG. Serum IL-4, IL-6, and TNF-α were found significantly higher in T2DM with CKD compared to T2DM and healthy ones. mRNA expression of IL-4, IL-6 and NF-кβ are also found significantly higher in T2DM with CKD. CONCLUSION The non-enzymatic glycation-induced damage to the HSA generate neo-epitopes that possess immunogenic response and low-grade systemic inflammation.
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Affiliation(s)
- Alok Raghav
- Rajiv Gandhi Centre for Diabetes and Endocrinology, J.N. Medical College, Aligarh Muslim University, Aligarh 202002, India
| | - Jamal Ahmad
- Rajiv Gandhi Centre for Diabetes and Endocrinology, J.N. Medical College, Aligarh Muslim University, Aligarh 202002, India.
| | - Khursheed Alam
- Department of Biochemistry, Aligarh Muslim University, Aligarh 202002, India
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Giam B, Kuruppu S, Chu PY, Smith AI, Marques FZ, Fiedler A, Horlock D, Kiriazis H, Du XJ, Kaye DM, Rajapakse NW. N-Acetylcysteine Attenuates the Development of Renal Fibrosis in Transgenic Mice with Dilated Cardiomyopathy. Sci Rep 2017; 7:17718. [PMID: 29255249 PMCID: PMC5735149 DOI: 10.1038/s41598-017-17927-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 12/01/2017] [Indexed: 02/02/2023] Open
Abstract
Mechanisms underlying the renal pathology in cardiorenal syndrome (CRS) type 2 remain elusive. We hypothesised that renal glutathione deficiency is central to the development of CRS type 2. Glutathione precursor, N-acetylcysteine (NAC;40 mg/kg/day; 8 weeks) or saline were administered to transgenic mice with dilated cardiomyopathy (DCM) and wild-type (WT) controls. Cardiac structure, function and glutathione levels were assessed at the end of this protocol. Renal fibrosis, glutathione content, expression of inflammatory and fibrotic markers, and function were also evaluated. In both genotypes, NAC had minimal effect on cardiac glutathione, structure and function (P ≥ 0.20). In NAC treated DCM mice, loss of glomerular filtration rate (GFR), tubulointerstitial and glomerular fibrosis and renal oxidised glutathione levels were attenuated by 38%, 99%, 70% and 52% respectively, compared to saline treated DCM mice (P ≤ 0.01). Renal expression of PAI-1 was greater in saline treated DCM mice than in WT mice (P < 0.05). Renal PAI-1 expression was less in NAC treated DCM mice than in vehicle treated DCM mice (P = 0.03). Renal IL-10 expression was greater in the former cohort compared to the latter (P < 0.01). These data indicate that normalisation of renal oxidized glutathione levels attenuates PAI-1 expression and renal inflammation preventing loss of GFR in experimental DCM.
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Affiliation(s)
- Beverly Giam
- Baker Heart and Diabetes Institute, Melbourne, Australia. .,Central Clinical School, Monash University, Melbourne, Australia.
| | - Sanjaya Kuruppu
- Biomedicine Discovery Institute, Department of Biochemistry & Molecular Biology, Monash University, Melbourne, Australia
| | - Po-Yin Chu
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - A Ian Smith
- Biomedicine Discovery Institute, Department of Biochemistry & Molecular Biology, Monash University, Melbourne, Australia
| | - Francine Z Marques
- Baker Heart and Diabetes Institute, Melbourne, Australia.,Central Clinical School, Monash University, Melbourne, Australia
| | - April Fiedler
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Duncan Horlock
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Helen Kiriazis
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Xiao-Jun Du
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - David M Kaye
- Baker Heart and Diabetes Institute, Melbourne, Australia.,Department of Medicine, Monash University, Melbourne, Australia
| | - Niwanthi W Rajapakse
- Baker Heart and Diabetes Institute, Melbourne, Australia.,School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Australia
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McAdoo SP, Pusey CD. Is there a role for TNFα blockade in ANCA-associated vasculitis and glomerulonephritis? Nephrol Dial Transplant 2017; 32:i80-i88. [PMID: 28391344 DOI: 10.1093/ndt/gfw361] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 09/09/2016] [Indexed: 12/16/2022] Open
Abstract
Tumour necrosis factor alpha (TNFα) is a cytokine that is pivotal in the inflammatory response. Blockade of TNFα has been shown to be effective in a number of human autoimmune diseases, including rheumatoid arthritis, raising the question of whether this approach may be effective in inflammatory kidney disease, such as ANCA-associated vasculitis (AAV). In AAV, there is considerable evidence for the role of TNFα in the pathophysiology of disease, including increased expression of TNFα mRNA in leucocytes and in renal tissue. Importantly, TNFα can induce leucocyte cell membrane expression of the autoantigens involved in vasculitis [proteinase 3 and myeloperoxidase (MPO)], thus priming cells for the effects of ANCA. In rodent models of anti-GBM disease (nephrotoxic nephritis), TNFα enhances glomerular injury and TNFα blockade using soluble TNFα receptor or anti-TNFα antibody ameliorates disease. Mice deficient in TNFα are protected from nephrotoxic nephritis and this effect is dependent mainly on intrinsic renal cells. A mouse model of anti-MPO antibody-induced glomerulonephritis is enhanced by LPS, and this effect is blocked by anti-TNFα antibody. In a rat model of AAV induced by MPO (experimental autoimmune vasculitis), anti-TNFα antibody improves renal pathology and also reduces leucocyte transmigration, as shown by intravital microscopy. In clinical studies, the Wegener's Granulomatosis Etanercept Trial (WGET) showed no benefit of additional etanercept versus standard therapy. However, there are several reasons why the results of the WGET study do not rule out the use of anti-TNFα antibody in acute renal AAV, including the study design and the considerable biological differences between the effects of etanercept and anti-TNFα antibody. There are several clinical studies demonstrating a response to anti-TNFα antibody in patients with AAV refractory to conventional treatment, and in some of these, the addition of anti-TNFα antibody was the only change in treatment. We suggest that further investigation of TNFα blockade in AAV is warranted.
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Affiliation(s)
- Stephen P McAdoo
- Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, London, UK
| | - Charles D Pusey
- Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, London, UK
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Renal Vasculitis in Childhood. CURRENT PEDIATRICS REPORTS 2017. [DOI: 10.1007/s40124-017-0138-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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30
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Caster DJ, Powell DW, Miralda I, Ward RA, McLeish KR. Re-Examining Neutrophil Participation in GN. J Am Soc Nephrol 2017; 28:2275-2289. [PMID: 28620081 DOI: 10.1681/asn.2016121271] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Significant advances in understanding the pathogenesis of GN have occurred in recent decades. Among those advances is the finding that both innate and adaptive immune cells contribute to the development of GN. Neutrophils were recognized as key contributors in early animal models of GN, at a time when the prevailing view considered neutrophils to function as nonspecific effector cells that die quickly after performing antimicrobial functions. However, advances over the past two decades have shown that neutrophil functions are more complex and sophisticated. Specifically, research has revealed that neutrophil survival is regulated by the inflammatory milieu and that neutrophils demonstrate plasticity, mediate microbial killing through previously unrecognized mechanisms, demonstrate transcriptional activity leading to the release of cytokines and chemokines, interact with and regulate cells of the innate and adaptive immune systems, and contribute to the resolution of inflammation. Therefore, neutrophil participation in glomerular diseases deserves re-evaluation. In this review, we describe advances in understanding classic neutrophil functions, review the expanded roles of neutrophils in innate and adaptive immune responses, and summarize current knowledge of neutrophil contributions to GN.
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Affiliation(s)
- Dawn J Caster
- Division of Nephrology and Hypertension, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky, .,Nephrology Section, Medicine Service, Robley Rex Veterans Affairs Medical Center, Louisville, Kentucky, and
| | - David W Powell
- Division of Nephrology and Hypertension, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
| | - Irina Miralda
- Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky
| | - Richard A Ward
- Division of Nephrology and Hypertension, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
| | - Kenneth R McLeish
- Division of Nephrology and Hypertension, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky.,Nephrology Section, Medicine Service, Robley Rex Veterans Affairs Medical Center, Louisville, Kentucky, and
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31
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Available and incoming therapies for idiopathic focal and segmental glomerulosclerosis in adults. J Nephrol 2017; 31:37-45. [DOI: 10.1007/s40620-017-0402-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 04/10/2017] [Indexed: 01/30/2023]
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Plasma Ang2 and ADAM17 levels are elevated during clinical malaria; Ang2 level correlates with severity and expression of EPCR-binding PfEMP1. Sci Rep 2016; 6:35950. [PMID: 27784899 PMCID: PMC5082358 DOI: 10.1038/srep35950] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 10/07/2016] [Indexed: 01/08/2023] Open
Abstract
The pathogenesis of Plasmodium falciparum malaria involves a complex interplay between parasite adhesion and inflammatory response that includes release of cytokines and activation of the endothelium with accompanying release of Angiopoitin 2 (Ang2) to the plasma. A-disintegrin and metalloproteinase 17 (ADAM17) is a protein responsible for releasing cytokines, including Tumor Necrosis Factor α (TNFα), and shedding of adhesion proteins. In this study, we show that plasma levels of ADAM17 are increased in Tanzanian children hospitalized with a malaria infection compared with asymptomatic children but similar to children hospitalized with other infectious diseases. The plasma levels of ADAM17 decreased during recovery after an acute malaria episode. Plasma levels of Ang2 were associated with markers of malaria severity and levels of var transcripts encoding P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) containing Cysteine Rich Inter Domain Region α1 (CIDRα1) domains predicted to bind Endothelial Protein C receptor (EPCR). ADAM17 levels were not associated with expression of var genes encoding different PfEMP1 types when controlling for age. These data are the first to report ADAM17 plasma levels in malaria-exposed individuals, and support the notion that parasite sequestration mediated by EPCR-binding PfEMP1 is associated with endothelial activation and pathology in severe paediatric malaria.
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Abstract
B cells play a central role in the immunopathogenesis of glomerulonephritides and transplant rejection. B cells secrete antibodies that contribute to tissue injury via multiple mechanisms. In addition, B cells contribute to disease pathogenesis in autoimmunity and alloimmunity by presenting antigens as well as providing costimulation and cytokines to T cells. B cells also play an immunomodulatory role in regulating the immune response by secreting cytokines that inhibit disease onset and/or progression. B cell-targeted approaches for treating immune diseases of the kidney and other organs have gained significant momentum. However, much remains to be understood about B-cell biology in order to determine the timing, duration, and context of optimal therapeutic response to B cell-targeted approaches. In this review, we discuss the multifaceted roles of B cells as enhancers and regulators of immunity with relevance to kidney disease and transplantation.
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Affiliation(s)
| | - Fadi G Lakkis
- Departments of Medicine (Renal-Electrolyte), Surgery, and Immunology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, and
| | - Geetha Chalasani
- Departments of Medicine (Renal-Electrolyte), Surgery, and Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, and Renal Section, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, Pennsylvania
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Adachi T, Arito M, Suematsu N, Kamijo-Ikemori A, Omoteyama K, Sato T, Kurokawa MS, Okamoto K, Kimura K, Shibagaki Y, Kato T. Roles of layilin in TNF-α-induced epithelial-mesenchymal transformation of renal tubular epithelial cells. Biochem Biophys Res Commun 2015; 467:63-9. [PMID: 26410531 DOI: 10.1016/j.bbrc.2015.09.121] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 09/22/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND Tumor necrosis factor (TNF)-α is suggested to induce epithelial-mesenchymal transformation (EMT) of renal tubular epithelial cells that possibly exacerbates renal interstitial fibrosis in glomerulonephritis (GN). We here investigated whether layilin (LAYN), a c-type lectin-homologous protein, was involved in the EMT process. METHODS Expression of LAYN was investigated in kidneys of mice administered with TNF-α and in a clear cell renal carcinoma cell line of KMRC-1 stimulated with TNF-α by quantitative polymerase chain reaction (qPCR) and/or western blotting. Expression of LAYN was assessed immunohistochemically in renal biopsy samples of patients with various types of GN. Changes of EMT markers and cell morphology by TNF-α and transforming growth factor (TGF)-β in LAYN-knocked down KMRC-1 cells were investigated by qPCR and immunocytochemistry. RESULTS Administration of TNF-α increased expression of LAYN in renal tubular epithelia in mice. TNF-α but not TGF-β increased expression of LAYN in KMRC-1 cells. Renal biopsy samples from the patients with GN showed high expression of LAYN in tubular epithelial cells. TNF-α induced up-regulation of vimentin, down-regulation of E-cadherin, and fibroblast-like morphological change in KMRC-1 cells, indicating occurrence of EMT. These changes were not observed in the LAYN-knocked down cells. In contrast, similarly occurred TGF-β-induced EMT was not affected by the LAYN knockdown. CONCLUSION Our data indicate that LAYN is involved in the TNF-α-induced EMT of renal tubular epithelial cells. LAYN may play roles in the generation of renal interstitial fibrosis in GN via TNF-α-induced EMT.
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Affiliation(s)
- Takayuki Adachi
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, Kanagawa, Japan; Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Mitsumi Arito
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, Kanagawa, Japan
| | - Naoya Suematsu
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, Kanagawa, Japan
| | | | - Kazuki Omoteyama
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, Kanagawa, Japan
| | - Toshiyuki Sato
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, Kanagawa, Japan
| | - Manae S Kurokawa
- Disease Biomarker Analysis and Molecular Regulation, St. Marianna University Graduate School of Medicine, Kanagawa, Japan
| | - Kazuki Okamoto
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, Kanagawa, Japan
| | - Kenjiro Kimura
- Japan Community Health Care Organization Tokyo Takanawa Hospital, Tokyo, Japan
| | - Yugo Shibagaki
- Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Tomohiro Kato
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, Kanagawa, Japan.
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Immune Homeostasis in Epithelial Cells: Evidence and Role of Inflammasome Signaling Reviewed. J Immunol Res 2015; 2015:828264. [PMID: 26355424 PMCID: PMC4556877 DOI: 10.1155/2015/828264] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 07/07/2015] [Indexed: 12/12/2022] Open
Abstract
The epithelium regulates the interaction between the noxious xenogenous, as well as the microbial environment and the immune system, not only by providing a barrier but also by expressing a number of immunoregulatory membrane receptors, and intracellular danger sensors and their downstream effectors. Amongst these are a number of inflammasome sensor subtypes, which have been initially characterized in myeloid cells and described to be activated upon assembly into multiprotein complexes by microbial and environmental triggers. This review compiles a vast amount of literature that supports a pivotal role for inflammasomes in the various epithelial barriers of the human body as essential factors maintaining immune signaling and homeostasis.
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Bertram A, Lovric S, Engel A, Beese M, Wyss K, Hertel B, Park JK, Becker JU, Kegel J, Haller H, Haubitz M, Kirsch T. Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis. J Am Soc Nephrol 2015; 26:2860-70. [PMID: 25788529 DOI: 10.1681/asn.2014050477] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Accepted: 01/04/2015] [Indexed: 12/14/2022] Open
Abstract
ANCA-associated vasculitides are characterized by inflammatory destruction of small vessels accompanied by enhanced cleavage of membrane-bound proteins. One of the main proteases responsible for ectodomain shedding is disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). Given its potential role in aggravating vascular dysfunction, we examined the role of ADAM17 in active proteinase-3 (PR3)-positive ANCA-associated vasculitis (AAV). ADAM17 concentration was significantly increased in plasma samples from patients with active PR3-AAV compared with samples from patients in remission or from other controls with renal nonvascular diseases. Comparably, plasma levels of the ADAM17 substrate syndecan-1 were significantly enhanced in active AAV. We also observed that plasma-derived ADAM17 retained its specific proteolytic activity and was partly located on extracellular microparticles. Transcript levels of ADAM17 were increased in blood samples of patients with active AAV, but those of ADAM10 or tissue inhibitor of metalloproteinases 3, which inhibits ADAMs, were not. We also performed a microRNA (miR) screen and identified miR-634 as significantly upregulated in blood samples from patients with active AAV. In vitro, miR-634 mimics induced a proinflammatory phenotype in monocyte-derived macrophages, with enhanced expression and release of ADAM17 and IL-6. These data suggest that ADAM17 has a prominent role in AAV and might account for the vascular complications associated with this disease.
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Affiliation(s)
- Anna Bertram
- Department of Nephrology and Hypertension, Center for Internal Medicine and
| | - Svjetlana Lovric
- Department of Nephrology and Hypertension, Center for Internal Medicine and
| | - Alissa Engel
- Department of Nephrology and Hypertension, Center for Internal Medicine and
| | - Michaela Beese
- Department of Nephrology and Hypertension, Center for Internal Medicine and
| | - Kristin Wyss
- Department of Nephrology and Hypertension, Center for Internal Medicine and
| | - Barbara Hertel
- Department of Nephrology and Hypertension, Center for Internal Medicine and
| | - Joon-Keun Park
- Department of Nephrology and Hypertension, Center for Internal Medicine and
| | - Jan U Becker
- Institute for Forensic Medicine, Hannover Medical School, Hannover, Germany; and
| | - Johanna Kegel
- Department of Nephrology and Hypertension, Center for Internal Medicine and
| | - Hermann Haller
- Department of Nephrology and Hypertension, Center for Internal Medicine and
| | - Marion Haubitz
- Department of Nephrology and Hypertension, Center for Internal Medicine and Medical Clinic III, Klinikum Fulda, Fulda, Germany
| | - Torsten Kirsch
- Department of Nephrology and Hypertension, Center for Internal Medicine and
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Fractalkine-CX3CR1-dependent recruitment and retention of human CD1c+ myeloid dendritic cells by in vitro-activated proximal tubular epithelial cells. Kidney Int 2015; 87:1153-63. [PMID: 25587706 DOI: 10.1038/ki.2014.407] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 10/23/2014] [Accepted: 10/30/2014] [Indexed: 12/24/2022]
Abstract
Chemokines play pivotal roles in tissue recruitment and retention of leukocytes, with CX3CR1 recently identified as a chemokine receptor that selectively targets mouse kidney dendritic cells (DCs). We have previously demonstrated increased tubulointerstitial recruitment of human transforming growth factor-β (TGF-β)-producing DCs in renal fibrosis and chronic kidney disease (CKD). However, little is known about the mechanism of human DC recruitment and retention within the renal interstitium. We identified CD1c+ DCs as the predominant source of profibrotic TGF-β and highest expressors of the fractalkine receptor CX3CR1 within the renal DC compartment. Immunohistochemical analysis of diseased human kidney biopsies showed colocalization of CD1c+ DCs with fractalkine-positive proximal tubular epithelial cells (PTECs). Human primary PTEC activation with interferon-γ and tumor necrosis factor-α induced both secreted and surface fractalkine expression. In line with this, we found fractalkine-dependent chemotaxis of CD1c+ DCs to supernatant from activated PTECs. Finally, in comparison with unactivated PTECs, we showed significantly increased adhesion of CD1c+ DCs to activated PTECs via a fractalkine-dependent mechanism. Thus, TGF-β-producing CD1c+ DCs are recruited and retained in the renal tubulointerstitium by PTEC-derived fractalkine. These cells are then positioned to play a role in the development of fibrosis and progression of chronic kidney disease.
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Ozbek E, Adas G, Otunctemur A, Duruksu G, Koc B, Polat EC, Kemik Sarvan A, Okcu A, Kamali G, Subasi C, Karaoz E. Role of Mesenchymal Stem Cells Transfected With Vascular Endothelial Growth Factor in Maintaining Renal Structure and Function in Rats with Unilateral Ureteral Obstruction. EXP CLIN TRANSPLANT 2014; 13:262-72. [PMID: 25542189 DOI: 10.6002/ect.2014.0080] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Mesenchymal stem cells hold promise for renal disease treatment. Vascular endothelial growth factor may heal tubule-interstitial fibrosis in unilateral ureteral obstruction by inhibiting epithelial-mesenchymal transition. We investigated the protective effect of vascular endothelial growth factor in transfected mesenchymal stem cells in unilateral ureteral obstruction-induced renal injury in rats. MATERIALS AND METHODS Male Wistar Albino rats (32 rats; weight, 250-300 g) were divided into 4 equal groups: group 1, control; group 2, unilateral ureteral obstruction; group 3, unilateral ureteral obstruction and mesenchymal stem cells; and group 4, unilateral ureteral obstruction and vascular endothelial growth factor-transfected mesenchymal stem cells. Vascular endothelial growth factor-transfected mesenchymal stem cells were administered intravenously before onset of unilateral ureteral obstruction. On day 14, the rats were killed and kidneys were retrieved. Tubular necrosis, mononuclear cell infiltration, and interstitial fibrosis were evaluated in paraffin blocks. We evaluated green fluorescent protein-positive and vascular endothelial growth factor-positive cells; anti-inflammatory (Prostaglandin E2 receptor) and interleukin 1 receptor antagonist), proinflammatory/anti-inflammatory (interleukin 6), and proinflammatory (MPO) cytokine expression levels; and levels of nitric oxide; transforming growth factor β1, E-cadherin, and hydroxyproline. RESULTS Green fluorescent protein-positive cells were negative in the renal parenchyma in groups 1 and 2 and positive in groups 3 and 4. Vascular endothelial growth factor levels were significantly higher in group 4. Transforming growth factor β1, nitric oxide, and E-cadherin levels were significantly higher in the unilateral ureteral obstruction than control group; however, in the study groups, these values were not significantly different from the unilateral ureteral obstruction group. In stem cell-transplanted tissue samples, EP3, interleukin 1 receptor antagonist, and interleukin 6 levels were elevated, but MPO expression levels were low. Although there were significant differences for tubular necrosis and fibrosis in group 2, there were significant reductions in tubular injury and fibrosis in groups 3 and 4. CONCLUSIONS Systemic stem cells transplanted into the kidney protected against unilateral ureteral obstruction-induced renal epithelial-mesenchymal transition and renal fibrosis.
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Affiliation(s)
- Emin Ozbek
- From the Okmeydani Training and Research Hospital, Department of Urology, Istanbul, Turkey
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Cessak G, Kuzawińska O, Burda A, Lis K, Wojnar M, Mirowska-Guzel D, Bałkowiec-Iskra E. TNF inhibitors – Mechanisms of action, approved and off-label indications. Pharmacol Rep 2014; 66:836-44. [DOI: 10.1016/j.pharep.2014.05.004] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2013] [Revised: 04/13/2014] [Accepted: 05/07/2014] [Indexed: 12/13/2022]
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Dimitrijevic I, Edvinsson L. Increased endothelin 1 type B receptors in nasal lesions of patients with granulomatosis with polyangiitis. Am J Rhinol Allergy 2014; 27:444-50. [PMID: 24274217 DOI: 10.2500/ajra.2013.27.3954] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Endothelin 1 (ET-1) is a locally produced vasoactive peptide with proinflammatory capabilities. Systemic levels of ET-1 seem elevated in granulomatosis with polyangiitis (GPA). The aim of this study was to examine the involvement of the endothelin system in patients with GPA using nasal mucosal biopsies. METHODS Formalin-fixed and paraffin-embedded nasal mucous membranes from eight patients with GPA and eight controls were analyzed for ET-1 type A receptor (ETAR) and type B receptor (ETBR) expression using immunohistochemistry. RESULT ETAR immunostaining was localized only to a few inflammatory cells and to multinucleate giant cells (MGCs) in the nasal mucosa in GPA subjects. Intense ETBR immunostaining was localized to lymphocytes and MGC in the nasal granulomatous lesions in GPA. CD3(+), CD4(+), CD8(+), and CD68(+) lymphocytes expressed ETBRs in GPA subjects. CONCLUSION This observation shows that ETBR(+) lymphocyte expression predominates in nasal granulomatous lesions in GPA compared with ETAR. ETBR immunostaining is located to T cells, CD68(+) cells, and MGCs. ETBR may play an active role in the progression of granulomatous lesions in GPA.
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Affiliation(s)
- Ivan Dimitrijevic
- Department of Medicine, Institute of Clinical Sciences Lund University, Lund, Sweden
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Hilhorst M, Shirai T, Berry G, Goronzy JJ, Weyand CM. T cell-macrophage interactions and granuloma formation in vasculitis. Front Immunol 2014; 5:432. [PMID: 25309534 PMCID: PMC4162471 DOI: 10.3389/fimmu.2014.00432] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 08/23/2014] [Indexed: 12/18/2022] Open
Abstract
Granuloma formation, bringing into close proximity highly activated macrophages and T cells, is a typical event in inflammatory blood vessel diseases, and is noted in the name of several of the vasculitides. It is not known whether specific properties of the microenvironment in the blood vessel wall or the immediate surroundings of blood vessels contribute to granuloma formation and, in some cases, generation of multinucleated giant cells. Granulomas provide a specialized niche to optimize macrophage-T cell interactions, strongly activating both cell types. This is mirrored by the intensity of the systemic inflammation encountered in patients with vasculitis, often presenting with malaise, weight loss, fever, and strongly upregulated acute phase responses. As a sophisticated and highly organized structure, granulomas can serve as an ideal site to induce differentiation and maturation of T cells. The granulomas possibly seed aberrant Th1 and Th17 cells into the circulation, which are known to be the main pathogenic cells in vasculitis. Through the induction of memory T cells, aberrant innate immune responses can imprint the host immune system for decades to come and promote chronicity of the disease process. Improved understanding of T cell-macrophage interactions will redefine pathogenic models in the vasculitides and provide new avenues for immunomodulatory therapy.
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Affiliation(s)
- Marc Hilhorst
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University , Stanford, CA , USA
| | - Tsuyoshi Shirai
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University , Stanford, CA , USA
| | - Gerald Berry
- Department of Pathology, Stanford University , Stanford, CA , USA
| | - Jörg J Goronzy
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University , Stanford, CA , USA
| | - Cornelia M Weyand
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University , Stanford, CA , USA
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TNF receptors: signaling pathways and contribution to renal dysfunction. Kidney Int 2014; 87:281-96. [PMID: 25140911 DOI: 10.1038/ki.2014.285] [Citation(s) in RCA: 160] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 02/28/2014] [Accepted: 03/06/2014] [Indexed: 12/19/2022]
Abstract
Tumor necrosis factor (TNF), initially reported to induce tumor cell apoptosis and cachexia, is now considered a central mediator of a broad range of biological activities from cell proliferation, cell death and differentiation to induction of inflammation and immune modulation. TNF exerts its biological responses via interaction with two cell surface receptors: TNFR1 and TNFR2. (TNFRs). These receptors trigger shared and distinct signaling pathways upon TNF binding, which in turn result in cellular outputs that may promote tissue injury on one hand but may also induce protective, beneficial responses. Yet the role of TNF and its receptors specifically in renal disease is still not well understood. This review describes the expression of the TNFRs, the signaling pathways induced by them and the biological responses of TNF and its receptors in various animal models of renal diseases, and discusses the current outcomes from use of TNF biologics and TNF biomarkers in renal disorders.
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Zhang XH, Li ML, Wang B, Guo MX, Zhu RM. Caspase-1 inhibition alleviates acute renal injury in rats with severe acute pancreatitis. World J Gastroenterol 2014; 20:10457-10463. [PMID: 25132762 PMCID: PMC4130853 DOI: 10.3748/wjg.v20.i30.10457] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Revised: 11/04/2013] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the effect of inhibition of caspase-1 on acute renal injury in rats with severe acute pancreatitis (SAP).
METHODS: Forty-two Sprague-Dawley rats were randomly divided into three groups: healthy controls (HC, n = 6), SAP rats treated with saline (SAP-S, n = 18), or SAP rats treated with a caspase-1/interleukin (IL)-1β-converting-enzyme (ICE) inhibitor (SAP-I-ICE, n = 18). SAP was induced by retrograde infusion of 5% sodium taurocholate into the bile-pancreatic duct. HC rats were subjected to identical treatment and surgical procedures without sodium taurocholate. Rats received an intraperitoneal injection of isotonic saline (SAP-S) or the inhibitor (SAP-ICE-I) at 2 and 12 h after induction of acute pancreatitis. Surviving rats were sacrificed at different time points after SAP induction; all samples were obtained and stored for subsequent analyses. The levels of blood urea nitrogen (BUN) and creatinine (Cr) were measured using automatic methods, and serum IL-1β concentrations were measured by an enzyme-linked immunosorbent assay. Intrarenal expression of IL-1β, IL-18 and caspase-1 mRNAs was detected by RT-PCR. IL-1β protein expression and the pathologic changes in kidney tissues were observed by microscopy after immunohistochemical or hematoxylin and eosin staining, respectively.
RESULTS: The serum levels of BUN and Cr in the SAP-S group were 12.48 ± 2.30 mmol/L and 82.83 ± 13.89 μmol/L at 6 h, 23.53 ± 2.58 mmol/L and 123.67 ± 17.67 μmol/L at 12 h, and 23.60 ± 3.33 mmol/L and 125.33 ± 21.09 μmol/L at 18 h, respectively. All were significantly increased compared to HC rats (P < 0.01 for all). Levels in SAP-ICE-I rats were significantly decreased compared to SAP-S rats both at 12 and 18 h (P < 0.01 for all). Serum IL-1β levels in the SAP-S group were 276.77 ± 44.92 pg/mL at 6 h, 308.99 ± 34.95 pg/mL at 12 h, and 311.60 ± 46.51 pg/mL at 18 h; all significantly higher than those in the HC and SAP-ICE-I groups (P < 0.01 for all). Intrarenal expression of IL-1β mRNA was weak in HC rats, but increased significantly in SAP-S rats (P < 0.01). ICE inhibition significantly decreased the expression of IL-1β and IL-18 mRNAs (P < 0.05 for all vs SAP-S), whereas caspase-1 mRNA expression was not significantly different. Weak IL-1β immunostaining was observed in HC animals, and marked staining was found in the SAP-S group mainly in renal tubular epithelial cells. IL-1β immunostaining was significantly descended in SAP-ICE-I rats compared to SAP-S rats (P < 0.05). Caspase-1 inhibition had no effect on the severity of kidney tissue destruction.
CONCLUSION: The expression of caspase-1-activated cytokines IL-1β and IL-18 plays a pivotal role in acute renal injury in rats with experimental SAP. Caspase-1 inhibition improves renal function effectively.
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Abstract
Many types of kidney injury induce inflammation as a protective response. However, unresolved inflammation promotes progressive renal fibrosis, which can culminate in end-stage renal disease. Kidney inflammation involves cells of the immune system as well as activation of intrinsic renal cells, with the consequent production and release of profibrotic cytokines and growth factors that drive the fibrotic process. In glomerular diseases, the development of glomerular inflammation precedes interstitial fibrosis; although the mechanisms linking these events are poorly understood, an important role for tubular epithelial cells in mediating this link is gaining support. Data have implicated macrophages in promoting both glomerular and interstitial fibrosis, whereas limited evidence suggests that CD4(+) T cells and mast cells are involved in interstitial fibrosis. However, macrophages can also promote renal repair when the cause of renal injury can be resolved, highlighting their plasticity. Understanding the mechanisms by which inflammation drives renal fibrosis is necessary to facilitate the development of therapeutics to halt the progression of chronic kidney disease.
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Abstract
Vasculitis is a spectrum of clinicopathologic disorders defined by inflammation of arteries of veins of varying caliber with variable tissue injury. Headache may be an important clue to vasculitic involvement of central nervous system (CNS) vessels. CNS vasculitis may be primary, in which only intracranial vessels are involved in the inflammatory process, or secondary to another known disorder with overlapping systemic involvement. A suspicion of vasculitis based on the history, clinical examination, or laboratory studies warrants prompt evaluation and treatment to forestall progression and avert cerebral ischemia or infarction.
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You H, Gao T, Cooper TK, Brian Reeves W, Awad AS. Macrophages directly mediate diabetic renal injury. Am J Physiol Renal Physiol 2013; 305:F1719-27. [PMID: 24173355 DOI: 10.1152/ajprenal.00141.2013] [Citation(s) in RCA: 130] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Monocyte/macrophage recruitment correlates strongly with the progression of renal impairment in diabetic nephropathy (DN), yet their direct role is not clear. We hypothesized that macrophages contribute to direct podocyte injury and/or an abnormal podocyte niche leading to DN. Experiments were conducted in CD11b-DTR mice treated with diphtheria toxin (DT) to deplete macrophages after streptozotocin-induced diabetes. Additional experiments were conducted in bone marrow chimeric (CD11b-DTR→ C57BL6/J) mice. Diabetes was associated with an increase in the M1-to-M2 ratio by 6 wk after the induction of diabetes. Macrophage depletion in diabetic CD11b-DTR mice significantly attenuated albuminuria, kidney macrophage recruitment, and glomerular histological changes and preserved kidney nephrin and podocin expression compared with diabetic CD11b-DTR mice treated with mutant DT. These data were confirmed in chimeric mice indicating a direct role of bone marrow-derived macrophages in DN. In vitro, podocytes grown in high-glucose media significantly increased macrophage migration compared with podocytes grown in normal glucose media. In addition, classically activated M1 macrophages, but not M2 macrophages, induced podocyte permeability. These findings provide evidence showing that macrophages directly contribute to kidney injury in DN, perhaps by altering podocyte integrity through the proinflammatory M1 subset of macrophages. Attenuating the deleterious effects of macrophages on podocytes could provide a new therapeutic approach to the treatment of DN.
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Affiliation(s)
- Hanning You
- Penn State Univ., Hershey Medical Center, College of Medicine, Division of Nephrology, H040, 500 Univ. Drive, PO Box 850, BMR Bldg., C5830, Hershey, PA 17033.
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Silva-Fernández L, Loza E, Martínez-Taboada VM, Blanco R, Rúa-Figueroa I, Pego-Reigosa JM, Muñoz-Fernández S. Biological therapy for systemic vasculitis: a systematic review. Semin Arthritis Rheum 2013; 43:542-57. [PMID: 23978781 DOI: 10.1016/j.semarthrit.2013.07.010] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Revised: 07/08/2013] [Accepted: 07/09/2013] [Indexed: 11/27/2022]
Abstract
OBJECTIVE Relapses and failure are frequent in systemic vasculitis (SV) patients. Biological agents have been prescribed as rescue therapies. The aim of this systematic review is to analyze the current evidence on the therapeutic use of biological agents for SV. METHODS MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials were searched up to the end of April 2013. Systematic reviews and meta-analysis, clinical trials, cohort studies, and case series with >3 patients were included. Independent article review and study quality assessment was done by 2 investigators with consensus resolution of discrepancies. RESULTS Of 3447 citations, abstracts, and hand-searched studies screened, 90 were included. Most of the studies included ANCA-associated vasculitis (AAV) patients and only a few included large vessel vasculitis (LVV) patients. Rituximab was the most used agent, having demonstrated efficacy for remission induction in patients with AAV. A number of studies used different anti-TNFα agents with contrasting results. A few uncontrolled studies on the use of abatacept, alemtuzumab, mepolizumab, and tocilizumab were found. CONCLUSION Current evidence on the use of biological therapies for SV is mainly based on uncontrolled, observational data. Rituximab is not inferior to cyclophosphamide for remission induction in AAV and might be superior in relapsing disease. Infliximab and adalimumab are effective as steroid-sparing agents. Etanercept is not effective to maintain remission in patients with granulomatosis with polyangiitis, and serious adverse events have been reported. For LVV, both infliximab and etanercept had a role as steroid-sparing agents, and tocilizumab might be effective also for remission induction in LVV.
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Affiliation(s)
| | | | - Víctor M Martínez-Taboada
- Rheumatology Department, Hospital Universitario Marqués de Valdecilla, Facultad de Medicina, Universidad de Cantabria, Santander, Spain
| | - Ricardo Blanco
- Rheumatology Department, Hospital Universitario Marqués de Valdecilla, Facultad de Medicina, Universidad de Cantabria, Santander, Spain
| | - Iñigo Rúa-Figueroa
- Rheumatology Department, Hospital Universitario Doctor Negrín, Las Palmas de Gran Canaria, Spain
| | - José María Pego-Reigosa
- Rheumatology Department, Complejo Hospitalario Universitario de Vigo, Instituto de Investigación Biomédica de Vigo, Vigo, Spain
| | - Santiago Muñoz-Fernández
- Rheumatology Department, Hospital Universitario Infanta Sofía, San Sebastián de los Reyes, Spain
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Taubitz A, Schwarz M, Eltrich N, Lindenmeyer MT, Vielhauer V. Distinct contributions of TNF receptor 1 and 2 to TNF-induced glomerular inflammation in mice. PLoS One 2013; 8:e68167. [PMID: 23869211 PMCID: PMC3711912 DOI: 10.1371/journal.pone.0068167] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2013] [Accepted: 05/30/2013] [Indexed: 12/29/2022] Open
Abstract
TNF is an important mediator of glomerulonephritis. The two TNF-receptors TNFR1 and TNFR2 contribute differently to glomerular inflammation in vivo, but specific mechanisms of TNFR-mediated inflammatory responses in glomeruli are unknown. We investigated their expression and function in murine kidneys, isolated glomeruli ex vivo, and glomerular cells in vitro. In normal kidney TNFR1 and TNFR2 were preferentially expressed in glomeruli. Expression of both TNFRs and TNF-induced upregulation of TNFR2 mRNA was confirmed in murine glomerular endothelial and mesangial cell lines. In vivo, TNF exposure rapidly induced glomerular accumulation of leukocytes. To examine TNFR-specific inflammatory responses in intrinsic glomerular cells but not infiltrating leukocytes we performed microarray gene expression profiling on intact glomeruli isolated from wildtype and Tnfr-deficient mice following exposure to soluble TNF ex vivo. Most TNF-induced effects were exclusively mediated by TNFR1, including induced glomerular expression of adhesion molecules, chemokines, complement factors and pro-apoptotic molecules. However, TNFR2 contributed to TNFR1-dependent mRNA expression of inflammatory mediators in glomeruli when exposed to low TNF concentrations. Chemokine secretion was absent in TNF-stimulated Tnfr1-deficient glomeruli, but also significantly decreased in glomeruli lacking TNFR2. In vivo, TNF-induced glomerular leukocyte infiltration was abrogated in Tnfr1-deficient mice, whereas Tnfr2-deficiency decreased mononuclear phagocytes infiltrates, but not neutrophils. These data demonstrate that activation of intrinsic glomerular cells by soluble TNF requires TNFR1, whereas TNFR2 is not essential, but augments TNFR1-dependent effects. Previously described TNFR2-dependent glomerular inflammation may therefore require TNFR2 activation by membrane-bound, but not soluble TNF.
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MESH Headings
- Animals
- Cell Line
- Gene Deletion
- Gene Expression Profiling
- Kidney/metabolism
- Kidney/pathology
- Leukocytes/metabolism
- Leukocytes/pathology
- Leukocytes/physiology
- Male
- Mice
- Mice, Inbred C57BL
- Oligonucleotide Array Sequence Analysis
- Real-Time Polymerase Chain Reaction
- Receptors, Tumor Necrosis Factor, Type I/genetics
- Receptors, Tumor Necrosis Factor, Type I/metabolism
- Receptors, Tumor Necrosis Factor, Type I/physiology
- Receptors, Tumor Necrosis Factor, Type II/genetics
- Receptors, Tumor Necrosis Factor, Type II/metabolism
- Receptors, Tumor Necrosis Factor, Type II/physiology
- Transforming Growth Factors/pharmacology
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Affiliation(s)
- Anela Taubitz
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Martin Schwarz
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Nuru Eltrich
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany
| | | | - Volker Vielhauer
- Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany
- * E-mail:
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Kim KH, Park JH, Lee WR, Park JS, Kim HC, Park KK. The inhibitory effect of chimeric decoy oligodeoxynucleotide against NF-κB and Sp1 in renal interstitial fibrosis. J Mol Med (Berl) 2013; 91:573-586. [PMID: 23114611 DOI: 10.1007/s00109-012-0972-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2012] [Revised: 10/12/2012] [Accepted: 10/12/2012] [Indexed: 01/01/2023]
Abstract
The pathophysiology of chronic renal disease is characterized by a progressive loss of renal function and deposition of the extracellular matrix, leading to widespread tissue fibrosis. Much of the matrix in chronic renal disease is synthesized by interstitial myofibroblasts, recruited from resident fibroblasts and circulating precursors. These changes are believed to be derived from epithelial-mesenchymal transition (EMT) of tubuloepithelial cells. To develop a novel therapeutic approach for treating renal fibrosis, we examined the simultaneous inhibition of the transcription factors NF-κB and Sp1 in a mouse model of unilateral ureteral obstruction (UUO). To simultaneously inhibit both NF-κB and Sp1, we developed chimeric (Chi) decoy oligodeoxynucleotide (ODN) which contained binding sequences for both NF-κB and Sp1 in a single decoy molecule to enhance the effective use of decoy ODN strategy. Chi decoy ODN significantly attenuated tubulointerstitial fibrosis in a mouse model of UUO compared to scrambled decoy ODN, as demonstrated by the reduced interstitial volume, macrophage infiltration, and fibrosis-related gene expression. Interestingly, Chi decoy ODN also regulated EMT-related gene expression, leading to the inhibition of renal fibrotic changes in vivo and in vitro. The present study demonstrates the feasibility of Chi decoy ODN treatment for preventing renal fibrosis and EMT processes. This strategy might be useful to improve the clinical outcome after chronic renal disease.
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Affiliation(s)
- Kyung-Hyun Kim
- Department of Pathology, College of Medicine, Catholic University of Daegu, 3056-6 Daemyung 4-dong, Daegu, Nam-gu, 705-718, Republic of Korea
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Halbwachs L, Lesavre P. Endothelium-neutrophil interactions in ANCA-associated diseases. J Am Soc Nephrol 2012; 23:1449-61. [PMID: 22942199 DOI: 10.1681/asn.2012020119] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The two salient features of ANCA-associated vasculitis (AAV) are the restricted microvessel localization and the mechanism of inflammatory damage, independent of vascular immune deposits. The microvessel localization of the disease is due to the ANCA antigen accessibility, which is restricted to the membrane of neutrophils engaged in β2-integrin-mediated adhesion, while these antigens are cytoplasmic and inaccessible in resting neutrophils. The inflammatory vascular damage is the consequence of maximal proinflammatory responses of neutrophils, which face cumulative stimulations by TNF-α, β2-integrin engagement, C5a, and ANCA by the FcγRII receptor. This results in the premature intravascular explosive release by adherent neutrophils of all of their available weapons, normally designed to kill IgG-opsonized bacteria after migration in infected tissues.
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Affiliation(s)
- Lise Halbwachs
- Institut National de la Santé et de la Recherche Medicale INSERM U845, Université Paris Descartes, Sorbonne Paris Cité, France
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