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Graham EL, Weir TL, Gentile CL. Exploring the Impact of Intermittent Fasting on Vascular Function and the Immune System: A Narrative Review and Novel Perspective. Arterioscler Thromb Vasc Biol 2025; 45:654-668. [PMID: 40177772 PMCID: PMC12018117 DOI: 10.1161/atvbaha.125.322692] [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] [Indexed: 04/05/2025]
Abstract
Vascular function is a critical determinant of cardiovascular health and all-cause mortality. Recent studies have suggested that intermittent fasting, a popular dietary strategy, elicits beneficial effects on vascular function. These studies also suggest that fasting-mediated improvements in vascular function coincide with reductions in systemic inflammation. However, the mechanisms that connect fasting, the immune system, and vascular function remain largely underexplored. The current review summarizes the effects of different intermittent fasting modalities on vascular health, focusing on endothelial dysfunction and arterial stiffness, 2 critical indices of vascular function. Improvements in vascular function are associated with reduced inflammation and are mechanistically linked to decreased circulating immune cells and their accumulation within the vascular wall and perivascular tissue. Recent data show that fasting redistributes circulating and tissue-resident immune cells to the bone marrow, affecting their inflammatory actions. However, there is no direct evidence relating immune cell redistribution to cardiovascular health. By relating fasting-induced immune cell redistribution to reduced inflammation and improved vascular function, we propose an exciting avenue of further exploration is determining whether fasting-induced immune cell redistribution impacts cardiovascular health.
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Affiliation(s)
- Elliot L. Graham
- Integrative Cardiovascular Physiology Laboratory, Intestinal Health Laboratory, Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, United States
| | - Tiffany L. Weir
- Integrative Cardiovascular Physiology Laboratory, Intestinal Health Laboratory, Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, United States
| | - Christopher L. Gentile
- Integrative Cardiovascular Physiology Laboratory, Intestinal Health Laboratory, Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, United States
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Xiong R, Hu Y, Wang M, Han T, Hu Y, Ma C, Li B. Peripheral CD4 + T cells mediate the destructive effects of maternal separation on prefrontal myelination and cognitive functions. Proc Natl Acad Sci U S A 2025; 122:e2412995122. [PMID: 40238461 PMCID: PMC12037062 DOI: 10.1073/pnas.2412995122] [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: 06/29/2024] [Accepted: 03/12/2025] [Indexed: 04/18/2025] Open
Abstract
Maternal separation (MS), a chronic stress event in early life, impairs myelination in the prefrontal cortex (PFC) and leads to PFC cognitive disorders. It remains largely unclear how such deficits are mediated. Here, we show that peripheral CD4+ T cells play an essential role in mediating the destructive effects of MS on medial prefrontal cortical (mPFC) myelination and cognitive functions in mice. Offspring mice with MS experience (MS mice) exhibited an increase in CD4+ T cells and xanthine levels in peripheral blood and a severe deficit in mPFC-dependent cognitive functions such as working memory, social interaction, and anxiety/depression emotion regulation, along with a decrease in oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLs) in the mPFC. These phenotypes were rescued upon treatment with the antibody neutralizing peripheral CD4+ T cells. Rag1-/- immunodeficient mice receiving transplantation of CD4+ T cells isolated from the peripheral blood of MS mice showed similar phenotypes as observed in MS mice. Immunofluorescence staining revealed a rich expression of adenosine receptor A1 (A1) in OPCs in the mPFC, and the A1-expressing OPCs decreased in the Rag1-/- mice receiving CD4+ T cell transplantation. The present study demonstrates a causal link between peripheral CD4+ T cells and MS-induced prefrontal cortical hypomyelination and cognitive dysfunction, and such a link is probably mediated via xanthine-adenosine receptor A1 signaling in OPCs.
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Affiliation(s)
- Rui Xiong
- Institute of Life Science and School of Life Science, Nanchang University, Nanchang330031, China
| | - Yinyin Hu
- Institute of Life Science and School of Life Science, Nanchang University, Nanchang330031, China
| | - Menghan Wang
- Institute of Life Science and School of Life Science, Nanchang University, Nanchang330031, China
| | - Ting Han
- Institute of Life Science and School of Life Science, Nanchang University, Nanchang330031, China
| | - Yuying Hu
- Institute of Life Science and School of Life Science, Nanchang University, Nanchang330031, China
| | - Chaolin Ma
- Institute of Life Science and School of Life Science, Nanchang University, Nanchang330031, China
| | - Baoming Li
- Institute of Life Science and School of Life Science, Nanchang University, Nanchang330031, China
- Institute of Brain Science, School of Basic Medical Science, Hangzhou Normal University, Hangzhou311121, China
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Han M, Ha JW, Jung I, Kim CY, Ahn SS. Incidence of systemic vasculitides after Mycobacterium tuberculosis infection: a population-based cohort study in Korea. Rheumatology (Oxford) 2025; 64:1400-1408. [PMID: 38507705 DOI: 10.1093/rheumatology/keae185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 02/17/2024] [Accepted: 03/15/2024] [Indexed: 03/22/2024] Open
Abstract
BACKGROUND Tuberculosis (TB) is a highly prevalent disease associated with significant morbidity and mortality globally and is reported to be associated with the onset of autoimmunity. This study investigated the association between TB and the incidence of systemic vasculitides (SV). METHODS Data were obtained from the South Korean National Claims database to identify patients with TB and controls (who had undergone appendectomy). The overall occurrence of SV and disease subtypes during the observation period was compared between the two groups. Adjusted Cox proportional hazards regression and Kaplan-Meier analysis were performed to identify the relationship between TB and SV and to compare SV incidence. RESULTS We identified 418 677 patients with TB and 160 289 controls. The overall SV incidence rate was 192/1 000 000 person-years during a mean follow-up of 7.5 years and was higher in patients with TB than controls. Cox regression revealed that the risk of SV was elevated in the TB group independently (adjusted hazard ratio [aHR]: 1.72, 95% confidence interval [CI]: 1.45-2.05). Furthermore, the risk of SV was significantly higher in extrapulmonary TB (aHR: 4.28, 95% CI: 3.52-5.21) when the TB group was categorized into pulmonary and extrapulmonary TB. The findings remained identical even after applying a stabilized inverse probability of treatment weighting analysis. CONCLUSIONS Patients with TB have an increased risk of SV, which is prominent in extrapulmonary TB. As well as confirming TB is associated with an increased incidence of immune-related vasculitis, our findings highlight the need for clinical vigilance for early diagnosis and initiation of treatment.
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Affiliation(s)
- Minkyung Han
- Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jang Woo Ha
- Division of Rheumatology, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Gyeonggi-do, Republic of Korea
| | - Inkyung Jung
- Division of Biostatistics, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Chi Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung Soo Ahn
- Division of Rheumatology, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Gyeonggi-do, Republic of Korea
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Bhuia MS, Chowdhury R, Hasan R, Hasan MSA, Ansari SA, Ansari IA, Mubarak MS, Coutinho HDM, Domiciano CB, Islam MT. trans-Ferulic Acid Antagonizes the Anti-Inflammatory Activity of Etoricoxib: Possible Interaction of COX-1 and NOS. Biotechnol Appl Biochem 2025. [PMID: 39985155 DOI: 10.1002/bab.2739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 02/06/2025] [Indexed: 02/24/2025]
Abstract
This study emphasizes to investigate the modulatory activity of trans-ferulic acid (TFA) on anti-inflammatory activity of etoricoxib (ETO) and underlying mechanisms via formalin-induced licking and paw edema model and in silico study. Inflammation was induced by injecting formalin (50 µL) into the right hind paw of mice. The animals were treated with different doses of TFA (25, 50, and 75 mg/kg, p.o.). The vehicle and ETO (35 mg/kg, p.o.) were provided as positive and negative control, respectively. ETO also served combined with TFA to evaluate the modulatory activity. The licking behavior was counted for the early and late phases, whereas the paw edema diameter was measured by using a slide caliper. All treatment was continued for 7 days until the edema was totally minimized to determine the inflammation's recovery capability for a specific group. Different computed and web tools were used to estimate molecular binding affinity, binding interactions, and pharmacokinetics. The findings demonstrated that TFA significantly (p < 0.05) enhanced the onset of licking and reduced the number of licks compared to vehicle group. TFA also showed a significant (p < 0.05) diminished in paw edema and complete recovered of the edema after 5 days of treatment indicating the anti-inflammatory effects. However, TFA with ETO notably diminished the anti-inflammatory effects of ETO by enhancing paw edema diameter and licking number. TFA also expressed elevated binding affinity of -7.5 and -6.5 kcal/mol toward nitric oxide (NO) synthase and COX-1, respectively. In conclusion, TFA exerted anti-inflammatory effects and reduces anti-inflammatory capability of ETO.
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Affiliation(s)
- Md Shimul Bhuia
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
- BioLuster Research Center Ltd., Gopalganj, Bangladesh
| | - Raihan Chowdhury
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
- BioLuster Research Center Ltd., Gopalganj, Bangladesh
| | - Rubel Hasan
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
- BioLuster Research Center Ltd., Gopalganj, Bangladesh
| | - Md Sakib Al Hasan
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
| | - Siddique Akber Ansari
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Irfan Aamer Ansari
- Department of Drug Science and Technology, University of Turin, Turin, Italy
| | - Mohammad S Mubarak
- Department of Chemistry, The University of Jordan, Amman, Jordan
- Department of Chemistry, Indiana University, Bloomington, Indiana, USA
| | | | | | - Muhammad Torequl Islam
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
- BioLuster Research Center Ltd., Gopalganj, Bangladesh
- Pharmacy Discipline, Khulna University, Khulna, Bangladesh
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Gergely TG, Drobni ZD, Sayour NV, Ferdinandy P, Varga ZV. Molecular fingerprints of cardiovascular toxicities of immune checkpoint inhibitors. Basic Res Cardiol 2025; 120:187-205. [PMID: 39023770 PMCID: PMC11790702 DOI: 10.1007/s00395-024-01068-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/09/2024] [Accepted: 07/10/2024] [Indexed: 07/20/2024]
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by unleashing the power of the immune system against malignant cells. However, their use is associated with a spectrum of adverse effects, including cardiovascular complications, which can pose significant clinical challenges. Several mechanisms contribute to cardiovascular toxicity associated with ICIs. First, the dysregulation of immune checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1) and its ligand (PD-L1), and molecular mimicry with cardiac autoantigens, leads to immune-related adverse events, including myocarditis and vasculitis. These events result from the aberrant activation of T cells against self-antigens within the myocardium or vascular endothelium. Second, the disruption of immune homeostasis by ICIs can lead to autoimmune-mediated inflammation of cardiac tissues, manifesting as cardiac dysfunction and heart failure, arrhythmias, or pericarditis. Furthermore, the upregulation of inflammatory cytokines, particularly tumor necrosis factor-alpha, interferon-γ, interleukin-1β, interleukin-6, and interleukin-17 contributes to cardiac and endothelial dysfunction, plaque destabilization, and thrombosis, exacerbating cardiovascular risk on the long term. Understanding the intricate mechanisms of cardiovascular side effects induced by ICIs is crucial for optimizing patient care and to ensure the safe and effective integration of immunotherapy into a broader range of cancer treatment protocols. The clinical implications of these mechanisms underscore the importance of vigilant monitoring and early detection of cardiovascular toxicity in patients receiving ICIs. Future use of these key pathological mediators as biomarkers may aid in prompt diagnosis of cardiotoxicity and will allow timely interventions.
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Affiliation(s)
- Tamás G Gergely
- Center for Pharmacology and Drug Research & Development, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- HCEMM-SU Cardiometabolic Immunology Research Group, Budapest, Hungary
- MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Budapest, Hungary
| | - Zsófia D Drobni
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Nabil V Sayour
- Center for Pharmacology and Drug Research & Development, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- HCEMM-SU Cardiometabolic Immunology Research Group, Budapest, Hungary
- MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Budapest, Hungary
| | - Péter Ferdinandy
- Center for Pharmacology and Drug Research & Development, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- Pharmahungary Group, Szeged, Hungary
| | - Zoltán V Varga
- Center for Pharmacology and Drug Research & Development, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
- HCEMM-SU Cardiometabolic Immunology Research Group, Budapest, Hungary.
- MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Budapest, Hungary.
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Hu X, Xu Lou I, Chen Q. Integrated bioinformatic analysis of the shared molecular mechanisms between ANCA-associated vasculitis and atherosclerosis. Arthritis Res Ther 2024; 26:223. [PMID: 39702436 DOI: 10.1186/s13075-024-03448-w] [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: 08/02/2024] [Accepted: 11/29/2024] [Indexed: 12/21/2024] Open
Abstract
BACKGROUND AND OBJECTIVE Accumulated evidence supports the tendency of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis(AAV) to coexist with atherosclerosis (AS). However, the common etiology of these two diseases remains unclear. This study aims to explore the mechanisms underlying the concurrent occurrence of ANCA and AS. METHODS Microarray data of AAV and AS were examined in a comprehensive gene expression database. Weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis (GEO2R) were performed to identify common genes between AAV and AS. Based on the co-expressed genes, functional enrichment analysis, protein-protein interaction (PPI) network analysis, and identification of hub genes (HGs) were conducted. Subsequently, co-expression analysis of HGs was performed, and their expression and diagnostic value were validated. We further explored immune cell infiltration and analyzed the correlation between HGs and infiltrating immune cells. Finally, the reliability of the selected pathways was verified. RESULTS The results of the common gene analysis suggest that immune and inflammatory responses may be common features in the pathophysiology of AAV and AS. Through the interaction of different analysis results, we confirmed five HGs (CYBB, FCER1G, TYROBP, IL10RA, CSF1R). The CytoHubba plugin and HG validation demonstrated the reliability of the selected five HGs. Co-expression network analysis revealed that these five HGs could influence monocyte migration. Analysis of immune cell infiltration showed that monocytes in ANCA and M0 macrophages in AS constituted a higher proportion of all infiltrating immune cells, with significant differences in infiltration. We also found significant positive correlations between CYBB, FCER1G, TYROBP, IL10RA, CSF1R, and monocytes/M0 macrophages in AAV, as well as between CYBB, FCER1G, TYROBP, IL10RA, CSF1R, and M0 macrophages in AS. CONCLUSION These five HGs can promote monocyte differentiation into macrophages, leading to the concurrent occurrence of AAV and AS. Our study provides insights into the mechanisms underlying the coexistence of AAV and AS.
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Affiliation(s)
- Xun Hu
- Hangzhou Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
- Department of Cardiology, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310025, China
| | - Inmaculada Xu Lou
- Department of Cardiology, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310025, China
| | - Qilan Chen
- Department of Cardiology, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310025, China.
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Magnusen AF, Pandey MK. Complement System and Adhesion Molecule Skirmishes in Fabry Disease: Insights into Pathogenesis and Disease Mechanisms. Int J Mol Sci 2024; 25:12252. [PMID: 39596318 PMCID: PMC11594573 DOI: 10.3390/ijms252212252] [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: 09/12/2024] [Revised: 11/05/2024] [Accepted: 11/11/2024] [Indexed: 11/28/2024] Open
Abstract
Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene, resulting in the accumulation of globotriaosylceramide (Gb3) and its deacetylated form, globotriaosylsphingosine (Lyso-Gb3) in various tissues and fluids throughout the body. This pathological accumulation triggers a cascade of processes involving immune dysregulation and complement system activation. Elevated levels of complement 3a (C3a), C5a, and their precursor C3 are observed in the plasma, serum, and tissues of patients with Fabry disease, correlating with significant endothelial cell abnormalities and vascular dysfunction. This review elucidates how the complement system, particularly through the activation of C3a and C5a, exacerbates disease pathology. The activation of these pathways leads to the upregulation of adhesion molecules, including vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1), platelet and endothelial cell adhesion molecule 1 (PECAM1), and complement receptor 3 (CR3) on leukocytes and endothelial cells. This upregulation promotes the excessive recruitment of leukocytes, which in turn exacerbates disease pathology. Targeting complement components C3a, C5a, or their respective receptors, C3aR (C3a receptor) and C5aR1 (C5a receptor 1), could potentially reduce inflammation, mitigate tissue damage, and improve clinical outcomes for individuals with Fabry disease.
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Affiliation(s)
- Albert Frank Magnusen
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA;
| | - Manoj Kumar Pandey
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA;
- Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA
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Padmanaban AM, Ganesan K, Ramkumar KM. A Co-Culture System for Studying Cellular Interactions in Vascular Disease. Bioengineering (Basel) 2024; 11:1090. [PMID: 39593750 PMCID: PMC11591305 DOI: 10.3390/bioengineering11111090] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 10/17/2024] [Accepted: 10/21/2024] [Indexed: 11/28/2024] Open
Abstract
Cardiovascular diseases (CVDs) are leading causes of morbidity and mortality globally, characterized by complications such as heart failure, atherosclerosis, and coronary artery disease. The vascular endothelium, forming the inner lining of blood vessels, plays a pivotal role in maintaining vascular homeostasis. The dysfunction of endothelial cells contributes significantly to the progression of CVDs, particularly through impaired cellular communication and paracrine signaling with other cell types, such as smooth muscle cells and macrophages. In recent years, co-culture systems have emerged as advanced in vitro models for investigating these interactions and mimicking the pathological environment of CVDs. This review provides an in-depth analysis of co-culture models that explore endothelial cell dysfunction and the role of cellular interactions in the development of vascular diseases. It summarizes recent advancements in multicellular co-culture models, their physiological and therapeutic relevance, and the insights they provide into the molecular mechanisms underlying CVDs. Additionally, we evaluate the advantages and limitations of these models, offering perspectives on how they can be utilized for the development of novel therapeutic strategies and drug testing in cardiovascular research.
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Affiliation(s)
- Abirami M. Padmanaban
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India;
| | - Kumar Ganesan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong 999077, China;
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603 203, Tamil Nadu, India;
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Liu Z, Zhang L, Sun B, Ding Y. Association of cardiovascular risk factors and intraplaque neovascularization in symptomatic carotid plaque. Front Neurol 2024; 15:1442656. [PMID: 39253361 PMCID: PMC11381375 DOI: 10.3389/fneur.2024.1442656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 08/15/2024] [Indexed: 09/11/2024] Open
Abstract
Background and purpose Cardiovascular risk factors are known to contribute to the formation of atherosclerotic plaques, which can result in carotid stenosis. However, the extent to which these factors are associated with intraplaque neovascularization, a key indicator of plaque vulnerability, remains unclear. To investigate this relationship, a study was conducted utilizing contrast-enhanced ultrasound (CEUS) to assess intraplaque neovascularization in symptomatic patients. Methods A cohort of 157 symptomatic patients underwent evaluation using Contrast-Enhanced Ultrasound (CEUS) imaging to assess carotid intraplaque neovascularization, which was quantified based on the degree of plaque enhancement. The collected data encompassed baseline patient characteristics, results from biochemical examinations, cardiovascular risk factors, and medication usage history. Regression analyses were conducted to elucidate the relationship between carotid plaque neovascularization and various cardiovascular risk factors. Results Patients with intraplaque neovascularization were more prone to have diabetes mellitus (OR 3.81, 95% CI 1.94-7.46, p < 0.001), dyslipidemia (OR 2.36, 95% CI 1.22-4.55, p = 0.011) and hypertension (OR 2.92, 95% CI 1.50-5.71, p = 0.002). Smoking increased the risk of having intraplaque neovascularization (OR 2.25, 95% CI 1.12-4.54, p = 0.023). Treatment with statins was significantly lower in patients with intraplaque neovascularization (OR 0.37, 95% CI 0.19-0.72, p = 0.003). In the multivariate analysis, diabetes mellitus (OR 3.27, 95% CI 1.10-9.78, p = 0.034) was independently related to the presence of intraplaque neovascularization. Meanwhile, compared to the patients in the first tertile of serum glucose (< 6.20 mmol/L), the patients in the third tertile (> 13.35 mmol/L) had the most significance of intraplaque neovascularization (OR 5.55, 95% CI 1.85-16.66, p = 0.002). Conclusion The findings indicated that diabetes mellitus is a significant cardiovascular risk factor that is strongly associated with carotid intraplaque neovascularization.
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Affiliation(s)
- Zehao Liu
- Department of Neurosurgery, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China
| | - Lianlian Zhang
- Department of Ultrasonography, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng, China
| | - Bing Sun
- Department of Neurosurgery, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China
| | - Yasuo Ding
- Department of Neurosurgery, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, China
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Chen J, Liu Y, Zhan P, Gao T, Zuo J, Li X, Zhang F, Wang H, Fu S. Bayesian-based analysis of the causality between 731 immune cells and erectile dysfunction: a two-sample, bidirectional, and multivariable Mendelian randomization study. Sex Med 2024; 12:qfae062. [PMID: 39315306 PMCID: PMC11416910 DOI: 10.1093/sexmed/qfae062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 08/20/2024] [Accepted: 09/03/2024] [Indexed: 09/25/2024] Open
Abstract
Background The causal relationship between certain immune cells and erectile dysfunction (ED) is still uncertain. Aim The study sought to investigate the causal effect of 731 types of immune cells on ED through Mendelian randomization (MR) using genome-wide association studies (GWAS). Methods Genetic instruments for 731 immune cells were identified through GWAS, and ED data were obtained from the FinnGen database. Univariable and multivariable bidirectional MR studies were conducted to explore potential causal relationships between these immune cells and ED. The inverse-variance weighted method was primarily used, with Cochran's Q test and MR-Egger intercept test assessing pleiotropy and heterogeneity. Bayesian weighted Mendelian randomization (BWMR) was also employed. Outcomes Six immune cells were identified as related to ED. CD45 on Natural Killer (NK) cells, CD33dim HLA DR+ CD11b + Absolute Count, CD19 on IgD- CD38dim B cells, and CD3 on CD39+ resting CD4 regulatory T cells were identified as risk factors, whereas CD20 on IgD+ CD38dim B cells and Activated & resting CD4 regulatory T cell %CD4+ T cells were protective factors. Further multivariable MR analysis confirmed that 5 of these immune cells independently impacted ED, except for CD45 on NK cells. Reverse MR analysis indicated that ED occurrence decreases certain immune cell counts, but BWMR found no causal relationship for CD20 on IgD+ CD38dim B cells. Results Our MR analysis confirmed a potential bidirectional causal relationship between immune cells and ED, providing new insights into potential mechanisms and therapeutic strategies. Clinical Translation This study provides evidence for the impact of certain immune cells on the development of ED and suggests potential therapeutic targets. Strengths and Limitations We performed both univariable and multivariable MR to strengthen the causal relationship between exposures and outcomes. However, the population in this study was limited to European ancestry. Conclusion Our MR analysis confirmed a potential bidirectional causal relationship between immune cells and ED. This provides new insights into potential mechanisms of pathogenesis and subsequent therapeutic strategies.
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Affiliation(s)
- Junhao Chen
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Wuhua District, Kunming, 650032, Yunnan, China
| | - Yidao Liu
- Department of Urology, Dehong People's Hospital, Mangshi City, Dehong, Yunnan Province, 678499, China
| | - Peiqin Zhan
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Wuhua District, Kunming, 650032, Yunnan, China
| | - Tianci Gao
- The Second Hospital of Jilin University, Nanguan District, Changchun City, Jilin Province, China
- College of Clinical Medicine, Jiamusi University, Xiangyang District, Jiamusi City, Heilongjiang Province
| | - Jieming Zuo
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Wuhua District, Kunming, 650032, Yunnan, China
| | - Xiangyun Li
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Wuhua District, Kunming, 650032, Yunnan, China
| | - Fangfei Zhang
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226United States
| | - Haifeng Wang
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Wuhua District, Kunming, 650032, Yunnan, China
| | - Shi Fu
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Wuhua District, Kunming, 650032, Yunnan, China
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Yennemadi AS, Jordan N, Diong S, Keane J, Leisching G. The Link Between Dysregulated Immunometabolism and Vascular Damage: Implications for the Development of Atherosclerosis in Systemic Lupus Erythematosus and Other Rheumatic Diseases. J Rheumatol 2024; 51:234-241. [PMID: 38224981 DOI: 10.3899/jrheum.2023-0833] [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] [Accepted: 11/30/2023] [Indexed: 01/17/2024]
Abstract
A bimodal pattern of mortality in systemic lupus erythematosus (SLE) exists. Early-stage deaths are predominantly caused by infection, whereas later-stage deaths are mainly caused by atherosclerotic disease. Further, although SLE-related mortality has reduced considerably in recent years, cardiovascular (CV) events remain one of the leading causes of death in people with SLE. Accelerated atherosclerosis in SLE is attributed to both an increase in traditional CV risk factors and the inflammatory effects of SLE itself. Many of these changes occur within the microenvironment of the vascular-immune interface, the site of atherosclerotic plaque development. Here, an intimate interaction between endothelial cells, vascular smooth muscle cells, and immune cells dictates physiological vs pathological responses to a chronic type 1 interferon environment. Low-density neutrophils (LDNs) have also been implicated in eliciting vasculature-damaging effects at such lesion sites. These changes are thought to be governed by dysfunctional metabolism of immune cells in this niche due at least in part to the chronic induction of type 1 interferons. Understanding these novel pathophysiological mechanisms and metabolic pathways may unveil potential innovative pharmacological targets and therapeutic opportunities for atherosclerosis, as well as shed light on the development of premature atherosclerosis in patients with SLE who develop CV events.
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Affiliation(s)
- Anjali S Yennemadi
- A.S. Yennemadi, MSc, J. Keane, MD, G. Leisching, PhD, TB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, School of Medicine, Trinity College Dublin, University of Dublin
| | - Natasha Jordan
- N. Jordan, PhD, Department of Rheumatology, St. James's Hospital
| | - Sophie Diong
- S. Diong, MD, Department of Dermatology, St. James's Hospital, Dublin, Ireland
| | - Joseph Keane
- A.S. Yennemadi, MSc, J. Keane, MD, G. Leisching, PhD, TB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, School of Medicine, Trinity College Dublin, University of Dublin
| | - Gina Leisching
- A.S. Yennemadi, MSc, J. Keane, MD, G. Leisching, PhD, TB Immunology Group, Department of Clinical Medicine, Trinity Translational Medicine Institute, School of Medicine, Trinity College Dublin, University of Dublin;
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Duarte da Silva KC, Carneiro WF, Virote BDCR, Santos MDF, de Oliveira JPL, Castro TFD, Bertolucci SKV, Murgas LDS. Evaluation of the Anti-Inflammatory and Antioxidant Potential of Cymbopogon citratus Essential Oil in Zebrafish. Animals (Basel) 2024; 14:581. [PMID: 38396549 PMCID: PMC10886050 DOI: 10.3390/ani14040581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 12/24/2023] [Accepted: 01/03/2024] [Indexed: 02/25/2024] Open
Abstract
This study explored the protective capacity of the essential oil (EO) of Cymbopogon citratus against oxidative stress induced by hydrogen peroxide (H2O2) and the inflammatory potential in zebrafish. Using five concentrations of EO (0.39, 0.78, 1.56, 3.12, and 6.25 μg/mL) in the presence of 7.5 mM H2O2, we analyzed the effects on neutrophil migration, caudal fin regeneration, cellular apoptosis, production of reactive oxygen species (ROS), and activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione S-transferase (GST) after 96 h of exposure. A significant decrease in neutrophil migration was observed in all EO treatments compared to the control. Higher concentrations of EO (3.12 and 6.25 μg/mL) resulted in a significant decrease in caudal fin regeneration compared to the control. SOD activity was reduced at all EO concentrations, CAT activity significantly decreased at 3.12 μg/mL, and GST activity increased at 0.78 μg/mL and 1.56 μg/mL, compared to the control group. No significant changes in ROS production were detected. A reduction in cellular apoptosis was evident at all EO concentrations, suggesting that C. citratus EO exhibits anti-inflammatory properties, influences regenerative processes, and protects against oxidative stress and apoptosis.
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Affiliation(s)
- Kiara Cândido Duarte da Silva
- Faculty of Animal Science and Veterinary Medicine (FZMV), Department of Veterinary Medicine, Federal University of Lavras, Lavras 37200-900, Minas Gerais, Brazil; (K.C.D.d.S.); (W.F.C.); (B.d.C.R.V.)
| | - William Franco Carneiro
- Faculty of Animal Science and Veterinary Medicine (FZMV), Department of Veterinary Medicine, Federal University of Lavras, Lavras 37200-900, Minas Gerais, Brazil; (K.C.D.d.S.); (W.F.C.); (B.d.C.R.V.)
| | - Bárbara do Carmo Rodrigues Virote
- Faculty of Animal Science and Veterinary Medicine (FZMV), Department of Veterinary Medicine, Federal University of Lavras, Lavras 37200-900, Minas Gerais, Brazil; (K.C.D.d.S.); (W.F.C.); (B.d.C.R.V.)
| | - Maria de Fátima Santos
- School of Agricultural Sciences of Lavras (ESAL), Department of Agriculture, Federal University of Lavras, Lavras 37200-900, Minas Gerais, Brazil; (M.d.F.S.); (J.P.L.d.O.); (S.K.V.B.)
| | - João Paulo Lima de Oliveira
- School of Agricultural Sciences of Lavras (ESAL), Department of Agriculture, Federal University of Lavras, Lavras 37200-900, Minas Gerais, Brazil; (M.d.F.S.); (J.P.L.d.O.); (S.K.V.B.)
| | - Tássia Flávia Dias Castro
- Institute of Biomedical Sciences II (ICBII), Universidade de São Paulo, São Paulo 05508-000, São Paulo, Brazil;
| | - Suzan Kelly Vilela Bertolucci
- School of Agricultural Sciences of Lavras (ESAL), Department of Agriculture, Federal University of Lavras, Lavras 37200-900, Minas Gerais, Brazil; (M.d.F.S.); (J.P.L.d.O.); (S.K.V.B.)
| | - Luis David Solis Murgas
- Faculty of Animal Science and Veterinary Medicine (FZMV), Department of Veterinary Medicine, Federal University of Lavras, Lavras 37200-900, Minas Gerais, Brazil; (K.C.D.d.S.); (W.F.C.); (B.d.C.R.V.)
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Lintermans LL, Stegeman CA, Muñoz-Elías EJ, Tarcha EJ, Iadonato SP, Rutgers A, Heeringa P, Abdulahad WH. Kv1.3 blockade by ShK186 modulates CD4+ effector memory T-cell activity of patients with granulomatosis with polyangiitis. Rheumatology (Oxford) 2024; 63:198-208. [PMID: 37086441 PMCID: PMC10765141 DOI: 10.1093/rheumatology/kead192] [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: 10/10/2022] [Revised: 03/21/2023] [Accepted: 04/18/2023] [Indexed: 04/23/2023] Open
Abstract
OBJECTIVES Granulomatosis with polyangiitis (GPA) is a chronic relapsing systemic autoimmune vasculitis. Current treatment of GPA is unsatisfactory, as it relies on strong immunosuppressive regimens, with either CYC or rituximab, which reduce the immunogenicity of several vaccines and are risk factors for a severe form of COVID-19. This emphasizes the need to identify new drug targets and to develop treatment strategies with less harmful side effects. Since CD4+ effector memory T cells (TEM) play a key role in the pathogenesis of GPA, we aimed in this study to modulate CD4+TEM cell activity via Kv1.3 blockade using the specific peptide inhibiter, ShK-186. METHODS Peripheral blood samples from 27 patients with GPA in remission and 16 age- and sex-matched healthy controls (HCs) were pre-incubated in vitro in the presence or absence of ShK-186, followed by stimulation with phorbol myristate acetate, calcium ionophore and brefeldin-A. The effect of ShK-186 on the cytokine production (IFNγ, TNFα, IL-4, IL-17, IL-21) within total and subsets of CD4+ T helper (CD4+TH) cells were assessed using flow cytometry. RESULTS ShK-186 reduced the expression level of IFNγ, TNFα, IL-4, IL-17 and IL-21 in CD4+TH cells from patients with GPA in vitro. Further analysis performed on sorted CD4+T cell subsets, revealed that ShK-186 predominantly inhibited the cytokine production of CD4+TEM cells. ShK-186 treatment reduced the production of the pro-inflammatory cytokines to the level seen in CD4+ TH cells from HCs. CONCLUSIONS Modulation of cellular effector function by ShK-186 may constitute a novel treatment strategy for GPA with high specificity and less harmful side effects.
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Affiliation(s)
- Lucas L Lintermans
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Coen A Stegeman
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | | | | | - Abraham Rutgers
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Peter Heeringa
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Wayel H Abdulahad
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Adebiyi OE, Bynoe MS. Roles of Adenosine Receptor (subtypes A 1 and A 2A) in Cuprizone-Induced Hippocampal Demyelination. Mol Neurobiol 2023; 60:5878-5890. [PMID: 37358743 DOI: 10.1007/s12035-023-03440-6] [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: 02/15/2023] [Accepted: 06/10/2023] [Indexed: 06/27/2023]
Abstract
Hippocampal demyelination in multiple sclerosis (MS) has been linked with cognitive deficits, however, patients could benefit from treatment that induces oligodendroglial cell function and promotes remyelination. We investigated the role of A1 and A2A adenosine receptors (AR) in regulating oligodendrocyte precursor cells (OPCs) and myelinating oligodendrocyte (OL) in the demyelinated hippocampus using the cuprizone model of MS. Spatial learning and memory were assessed in wild type C57BL/6 mice (WT) or C57BL/6 mice with global deletion of A1 (A1AR-/-) or A2A AR (A2AAR-/-) fed standard or cuprizone diet (CD) for four weeks. Histology, immunofluorescence, Western blot and TUNEL assays were performed to evaluate the extent of demyelination and apoptosis in the hippocampus. Deletion of A1 and A2A AR alters spatial learning and memory. In A1AR-/- mice, cuprizone feeding led to severe hippocampal demyelination, A2AAR-/- mice had a significant increase in myelin whereas WT mice had intermediate demyelination. The A1AR-/- CD-fed mice displayed significant astrocytosis and decreased expression of NeuN and MBP, whereas these proteins were increased in the A2AAR-/- CD mice. Furthermore, Olig2 was upregulated in A1AR-/- CD-fed mice compared to WT mice fed the standard diet. TUNEL staining of brain sections revealed a fivefold increase in the hippocampus of A1AR-/- CD-fed mice. Also, WT mice fed CD showed a significant decrease expression of A1 AR. A1 and A2A AR are involved in OPC/OL functions with opposing roles in myelin regulation in the hippocampus. Thus, the neuropathological findings seen in MS may be connected to the depletion of A1 AR.
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Affiliation(s)
- Olamide E Adebiyi
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
- Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Nigeria.
| | - Margaret S Bynoe
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
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Gao R, Wu Z, Xu X, Pu J, Pan S, Zhang Y, Zhuang S, Yang L, Liang Y, Song J, Tang J, Wang X. Predictors of poor prognosis in ANCA-associated vasculitis (AAV): a single-center prospective study of inpatients in China. Clin Exp Med 2023; 23:1331-1343. [PMID: 36244021 PMCID: PMC10390347 DOI: 10.1007/s10238-022-00915-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 10/06/2022] [Indexed: 12/01/2022]
Abstract
To identify potential predictors by assessing adverse outcomes in ANCA-associated vasculitis (AAV) patients. Eighty-nine untreated AAV patients were followed up to January 31, 2022, death, or loss of follow-up. Clinical characteristics, laboratory tests, treatment, and progress were collected, and disease activity was evaluated via Birmingham Vasculitis Activity Score (BVAS). We determined risk factors of high-risk events, defined as developing tumors, renal replacement therapy (RRT), and death. Patients and renal survivals were computed by the Kaplan-Meier curve analysis. Cox regression analysis was performed for assessing variables for predicting death. During 267 person-years follow-up, 46 patients occurred high-risk events, including 20 patients receiving RRT, 12 patients developing tumors, and 29 patients who died mostly from organ failure and infection. Decreased estimated glomerular filtration rate (eGFR) (P < 0.001) and complement 3 levels (P = 0.019) were associated with high-risk events. Patients with lower serum potassium tended to develop tumors (P = 0.033); with higher BVAS (HR = 1.290, 95%CI 1.075-1.549, P = 0.006) and lower eGFR (HR = 0.782, 95%CI 0.680-0.901, P = 0.001) were more likely to undergo RRT. Patients with cardio and renal involvement exhibited a lower frequency of renal survival and all-cause mortality. Through multivariate COX analysis, age (HR = 1.016, 95%CI 1.016-1.105, P = 0.006) and eGFR (HR = 0.982, 95%CI 0.968-0.997, P = 0.018) predicted death in AAV, separately. The BVAS and eGFR could be a great prognosticator for RRT, while age and eGFR can independently predict the death. Serum potassium level and immunoglobulins should be focused on their predictor value in development of cancer and renal outcomes in AAV patients.
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Affiliation(s)
- Ronglin Gao
- Department of Rheumatology and Immunology, Tongji Hospital, School of Medicine, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China
| | - Zhenzhen Wu
- Department of Rheumatology and Immunology, Tongji Hospital, School of Medicine, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China
| | - Xianghuai Xu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China
| | - Jincheng Pu
- Department of Rheumatology and Immunology, Tongji Hospital, School of Medicine, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China
| | - Shengnan Pan
- Department of Rheumatology and Immunology, Tongji Hospital, School of Medicine, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China
| | - Youwei Zhang
- Department of Rheumatology and Immunology, Tongji Hospital, School of Medicine, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China
| | - Shuqi Zhuang
- Department of Rheumatology and Immunology, Tongji Hospital, School of Medicine, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China
| | - Lufei Yang
- Department of Rheumatology and Immunology, Tongji Hospital, School of Medicine, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China
| | - Yuanyuan Liang
- Department of Rheumatology and Immunology, Tongji Hospital, School of Medicine, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China
| | - Jiamin Song
- Department of Rheumatology and Immunology, Tongji Hospital, School of Medicine, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China
| | - Jianping Tang
- Department of Rheumatology and Immunology, Tongji Hospital, School of Medicine, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China.
| | - Xuan Wang
- Department of Rheumatology and Immunology, Tongji Hospital, School of Medicine, Tongji University, No. 389 Xincun Road, Shanghai, 200065, China.
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Lin W, Liu S, Huang Z, Li H, Lu T, Luo Y, Zhong J, Xu Z, Liu Y, Li Y, Li P, Xu Q, Cai J, Li H, Chen XL. Mass cytometry and single-cell RNA sequencing reveal immune cell characteristics of active and inactive phases of Crohn's disease. Front Med (Lausanne) 2023; 9:1064106. [PMID: 36714133 PMCID: PMC9878392 DOI: 10.3389/fmed.2022.1064106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 12/14/2022] [Indexed: 01/13/2023] Open
Abstract
Objectives For Crohn's disease (CD), the alternation of the active phase and inactive phase may be related to humoral immunity and cellular immunity. This study aims to understand the characteristics of immune cells in patients with active CD (CDa) and inactive CD (CDin). Methods Mass cytometry (CyTOF) and single-cell RNA sequencing (scRNA-seq) data about CDa, CDin, and healthy control (HC) were included. CyTOF analysis was performed to capture gated subsets, including T cells, T regulatory (Treg) cells, B cells, innate immune cells, and natural killer (NK) cells. Differential analysis was used to identify different immune cell subsets among CDa, CDin, and HC. ScRNA-seq analysis was used to verify the results of CyTOF. CD-related signaling pathways were obtained using KEGG pathway enrichment analysis. CellChat analysis was used to infer the cell communication network among immune cell subsets. Results Compared to patients with CDin, patients with CDa had higher abundances of CD16+CD38+CD4+CXCR3+CCR6+ naive T cells, HLA-DR+CD38+IFNγ+TNF+ effector memory (EM) T cells, HLA-DR+IFNγ+ naive B cells, and CD14++CD11C+IFNγ+IL1B+ monocytes. KEGG analysis showed the similarity of pathway enrichment for the earlier four subsets, such as thermogenesis, oxidative phosphorylation, and metabolic pathways. The patients with CDin were characterized by an increased number of CD16+CD56dimCD44+HLA-DR+IL22+ NK cells. Compared to HC, patients with CDa demonstrated a low abundance of HLA-DR+CCR6+ NK cells and a high abundance of FOXP3+CD44+ EM Tregs. CellChat analysis revealed the interaction network of cell subsets amplifying in CDa compared with CDin. Conclusion Some immune subsets cells were identified for CDa and CDin. These cells may be related to the occurrence and development of CD and may provide assistance in disease diagnosis and treatment.
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Affiliation(s)
- Wenjia Lin
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shiying Liu
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhuojian Huang
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Haiwen Li
- Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
| | - Tianyu Lu
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yongxin Luo
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiamin Zhong
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zewen Xu
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yu Liu
- Department of Medical Statistics, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Yanwu Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China,Pi-Wei Institute, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Peiwu Li
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qian Xu
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiazhong Cai
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China,Pi-Wei Institute, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Huibiao Li
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xin-lin Chen
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China,*Correspondence: Xin-lin Chen,
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Kovoor E, Chauhan SK, Hajrasouliha A. Role of inflammatory cells in pathophysiology and management of diabetic retinopathy. Surv Ophthalmol 2022; 67:1563-1573. [PMID: 35914582 PMCID: PMC11082823 DOI: 10.1016/j.survophthal.2022.07.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 07/18/2022] [Accepted: 07/25/2022] [Indexed: 02/05/2023]
Abstract
Diabetic retinopathy (DR) is a sight-threatening complication of diabetes mellitus. Several inflammatory cells and proteins, including macrophages and microglia, cytokines, and vascular endothelial growth factors, are found to play a significant role in the development and progression of DR. Inflammatory cells play a significant role in the earliest changes seen in DR including the breakdown of the blood retinal barrier leading to leakage of blood into the retina. They also have an important role in the pathogenesis of more advanced stage of proliferative diabetic retinopathy, leading to neovascularization, vitreous hemorrhage, and tractional retinal detachment. In this review, we examine the function of numerous inflammatory cells involved in the pathogenesis, progression, and role as a potential therapeutic target in DR. Additionally, we explore the role of inflammation following treatment of DR.
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Affiliation(s)
- Elias Kovoor
- Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Sunil K Chauhan
- Schepens Eye Institute, Harvard Medical School, Boston, MA, USA
| | - Amir Hajrasouliha
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
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Hu X, Shen C, Meng T, Ooi JD, Eggenhuizen PJ, Zhou YO, Luo H, Chen JB, Lin W, Gong Y, Xiong Q, Xu J, Liu N, Xiao X, Tang R, Zhong Y. Clinical features and prognosis of MPO-ANCA and anti-GBM double-seropositive patients. Front Immunol 2022; 13:991469. [PMID: 36389826 PMCID: PMC9648717 DOI: 10.3389/fimmu.2022.991469] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 10/07/2022] [Indexed: 10/03/2023] Open
Abstract
BACKGROUND Several lines of evidence implicate that there are distinct differences between patients with myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane (GBM) antibody double-seropositive patients (DPPs) and single-positive patients. Hence, we conducted a retrospective study from a single center in China to analyze the clinical and pathological features, and prognosis of DPPs. METHODS 109 patients with MPO-ANCA-associated vasculitis (MPO-AAV), 20 DPPs and 23 patients diagnosed with anti-GBM disease from a large center in China were included in this study. The ratio of patients with renal biopsy in three groups were 100%, 50% and 100%, respectively. Their clinical and pathological characteristics, and outcomes were analyzed. The intensity of immune deposits in the kidney at diagnosis was detected by immunofluorescence (IF). Furthermore, multivariate Cox hazard model analysis was used to assess the clinical and histological predictors of end-stage renal disease (ESRD) and death for DPPs. RESULTS In our study, we found that patients in the DPPs group were older than the other two groups (p = 0.007, MPO-AAV vs. DPPs; p < 0.001, DPPs vs. anti-GBM). The DPPs group had a higher value of serum creatinine (p = 0.041) and lower estimated glomerular filtration rate (eGFR) (p = 0.032) compared with MPO-AAV patients. On the contrary, the DPPs group had a lower serum creatinine (p = 0.003) compared with patients with anti-GBM group. The proportion of patients with cardiac system involvement in the DPPs group was higher than anti-GBM patients (p = 0.014). Cellular crescents could be generally observed in renal biopsy of DPPs and patients with anti-GBM glomerulonephritis. In addition, Bowman's capsule rupture was more common in DPPs than MPO-AAV patients (p = 0.001). MPO-AAV had a better renal and overall survival outcome than DPPs (p < 0.001). There was no significant difference of renal and overall survival outcome between DPPs and patients with anti-GBM disease. The incidence of ESRD in DPPs was negatively associated with lymphocyte count (HR 0.153, 95% CI 0.027 to 0.872, p = 0.034) and eGFR (HR 0.847, 95% CI 0.726 to 0.989, p = 0.036). Elevated serum creatinine was confirmed as a risk factor of both renal (HR 1.003, 95% CI 1.000 to 1.005, p = 0.019) and patient survival in DPPs (HR1.461, 95% CI 1.050 to 2.033, p = 0.024). CONCLUSION In summary, compared with anti-GBM disease, DPPs tended to involve multi-organ damage rather than limited to the kidney. It is highlighted that serologic DPPs have a worse renal and patient prognosis than MPO-AAV. Moreover, we found that the risk factors of renal survival of DPPs include low lymphocyte count, elevated serum creatinine and reduced eGFR, and serum creatinine can predict patient survival.
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Affiliation(s)
- Xueling Hu
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya Hospital, Central South University, Changsha, China
| | - Chanjuan Shen
- Department of Hematology, The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, China
| | - Ting Meng
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya Hospital, Central South University, Changsha, China
| | - Joshua D. Ooi
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya Hospital, Central South University, Changsha, China
- Centre for Inflammatory Diseases, Department of Medicine, Monash Medical Centre, Monash University, Clayton, VIC, Australia
| | - Peter J. Eggenhuizen
- Centre for Inflammatory Diseases, Department of Medicine, Monash Medical Centre, Monash University, Clayton, VIC, Australia
| | - Ya-ou Zhou
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, China
| | - Hui Luo
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, China
| | - Jin-biao Chen
- Department of Medical Records and Information, Xiangya Hospital, Central South University, Changsha, China
| | - Wei Lin
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Yizi Gong
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya Hospital, Central South University, Changsha, China
| | - Qi Xiong
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya Hospital, Central South University, Changsha, China
| | - Jia Xu
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya Hospital, Central South University, Changsha, China
| | - Ning Liu
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya Hospital, Central South University, Changsha, China
| | - Xiangcheng Xiao
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya Hospital, Central South University, Changsha, China
| | - Rong Tang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya Hospital, Central South University, Changsha, China
| | - Yong Zhong
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya Hospital, Central South University, Changsha, China
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Goyal S, Sood A, Gautam I, Pradhan S, Mondal P, Singh G, Jaura RS, Singh TG, Sibia RS. Serum protease-activated receptor (PAR-1) levels as a potential biomarker for diagnosis of inflammation in type 2 diabetic patients. Inflammopharmacology 2022; 30:1843-1851. [PMID: 35974263 DOI: 10.1007/s10787-022-01049-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/03/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Inflammation is a prominent clinical manifestation in type 2 diabetes mellitus (T2DM) patients, often associated with insulin resistance, metabolic dysregulation, and other complications. AIM OF THE STUDY The present study has been designed to check the serum levels of PAR-1 and correlate with various clinical manifestations and inflammatory cytokines levels in type 2 diabetic subjects. MATERIAL AND METHODS The study population was divided into two groups, healthy volunteers (n = 15): normal glycated hemoglobin (HbA1c) (4.26 ± 0.55) and type 2 diabetic subjects (n = 30): HbA1c levels (7.80 ± 2.41). The serum levels of PAR-1 (ELISA method) were studied in both groups and correlated with demographic parameters age, weight, body mass index (BMI), and conventional inflammation biomarkers like C-reactive protein (CRP), interleukin 6 (IL-6), interleukin 8 (IL-8), and tumour necrosis factor-alpha (TNF-α). RESULTS The demographic variables including the body weight (77.38 ± 10.00 vs. controls 55.26 ± 6.99), BMI (29.39 ± 3.61 vs. controls 25.25 ± 4.01), glycemic index HbA1c (7.80 ± 2.41 vs. controls 4.26 ± 0.55) were found to be statistically increased in T2DM subjects than the healthy control group. The levels of various inflammatory biomarkers and PAR-1 were significantly elevated in T2DM groups in comparison to healthy volunteers. The univariate and multivariate regression analysis revealed that elevated PAR-1 levels positively correlated with increased body weight, BMI, HbA1c, and inflammatory cytokines. CONCLUSION Our findings indicate that the elevated serum PAR-1 levels serve as an independent predictor of inflammation in T2DM subjects and might have prognostic value for determining T2DM progression.
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Affiliation(s)
- Sanjay Goyal
- Government Medical College, Patiala, Punjab, India
| | - Ankita Sood
- Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala National Highway (NH-64), Tehsil, Rajpura District, Patiala, 140401, Punjab, India
| | - Isha Gautam
- Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala National Highway (NH-64), Tehsil, Rajpura District, Patiala, 140401, Punjab, India
| | - Soumyadip Pradhan
- Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala National Highway (NH-64), Tehsil, Rajpura District, Patiala, 140401, Punjab, India
| | - Puskar Mondal
- Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala National Highway (NH-64), Tehsil, Rajpura District, Patiala, 140401, Punjab, India
| | - Gaaminepreet Singh
- Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala National Highway (NH-64), Tehsil, Rajpura District, Patiala, 140401, Punjab, India.
| | - Ravinder Singh Jaura
- Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala National Highway (NH-64), Tehsil, Rajpura District, Patiala, 140401, Punjab, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Chandigarh-Patiala National Highway (NH-64), Tehsil, Rajpura District, Patiala, 140401, Punjab, India
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20
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Jeucken KCM, van Rooijen CCN, Kan YY, Kocken LA, Jongejan A, van Steen ACI, van Buul JD, Olsson HK, van Hamburg JP, Tas SW. Differential Contribution of NF-κB Signaling Pathways to CD4+ Memory T Cell Induced Activation of Endothelial Cells. Front Immunol 2022; 13:860327. [PMID: 35769477 PMCID: PMC9235360 DOI: 10.3389/fimmu.2022.860327] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 05/12/2022] [Indexed: 11/21/2022] Open
Abstract
Endothelial cells (ECs) are important contributors to inflammation in immune-mediated inflammatory diseases (IMIDs). In this study, we examined whether CD4+ memory T (Tm) cells can drive EC inflammatory responses. Human Tm cells produced ligands that induced inflammatory responses in human umbilical vein EC as exemplified by increased expression of inflammatory mediators including chemokines and adhesion molecules. NF-κB, a key regulator of EC activation, was induced by Tm cell ligands. We dissected the relative contribution of canonical and non-canonical NF-κB signaling to Tm induced EC responses using pharmacological small molecule inhibitors of IKKβ (iIKKβ) or NF-κB inducing kinase (iNIK). RNA sequencing revealed substantial overlap in IKKβ and NIK regulated genes (n=549) that were involved in inflammatory and immune responses, including cytokines (IL-1β, IL-6, GM-CSF) and chemokines (CXCL5, CXCL1). NIK regulated genes were more restricted, as 332 genes were uniquely affected by iNIK versus 749 genes by iIKKβ, the latter including genes involved in metabolism, proliferation and leukocyte adhesion (VCAM-1, ICAM-1). The functional importance of NIK and IKKβ in EC activation was confirmed by transendothelial migration assays with neutrophils, demonstrating stronger inhibitory effects of iIKKβ compared to iNIK. Importantly, iIKKβ – and to some extent iNIK - potentiated the effects of currently employed therapies for IMIDs, like JAK inhibitors and anti-IL-17 antibodies, on EC inflammatory responses. These data demonstrate that inhibition of NF-κB signaling results in modulation of Tm cell-induced EC responses and highlight the potential of small molecule NF-κB inhibitors as a novel treatment strategy to target EC inflammatory responses in IMIDs.
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Affiliation(s)
- Kim C. M. Jeucken
- Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
| | - Charlotte C. N. van Rooijen
- Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
| | - Yik Y. Kan
- Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
| | - Lotte A. Kocken
- Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
| | - Aldo Jongejan
- Department of Epidemiology and Data Science, Bioinformatics Laboratory, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Abraham C. I. van Steen
- Molecular Cell Biology Lab at Dept. Molecular Hematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, Netherlands
| | - Jaap D. van Buul
- Molecular Cell Biology Lab at Dept. Molecular Hematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, Netherlands
- Leeuwenhoek Centre for Advanced Microscopy (LCAM), Section Molecular Cytology, Swammerdam Institute for Life Sciences (SILS), University of Amsterdam, Amsterdam, Netherlands
| | - Henric K. Olsson
- Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Jan Piet van Hamburg
- Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
| | - Sander W. Tas
- Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- *Correspondence: Sander W. Tas,
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21
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Gopaluni S, Smith R, Goymer D, Cahill H, Broadhurst E, Wallin E, McClure M, Chaudhry A, Jayne D. Alemtuzumab for refractory primary systemic vasculitis-a randomised controlled dose ranging clinical trial of efficacy and safety (ALEVIATE). Arthritis Res Ther 2022; 24:81. [PMID: 35365179 PMCID: PMC8972754 DOI: 10.1186/s13075-022-02761-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/06/2022] [Indexed: 12/21/2022] Open
Abstract
Background Primary systemic vasculitis (PSV) is a heterogeneous group of autoimmune conditions. There is an unmet need for alternative therapies that lead to sustained remission in patients with refractory disease. Alemtuzumab, an anti-CD52 antibody, depletes lymphocytes for prolonged periods and, in retrospective studies, has induced sustained, treatment-free remissions in patients with refractory/relapsing vasculitis but has raised safety concerns of infection and secondary autoimmunity. This phase IIb clinical trial aimed to assess the efficacy and safety of alemtuzumab, at two different doses, in inducing remission in refractory vasculitis patients. Methods The ALEVIATE trial was a randomised, prospective, open-label, dose ranging clinical trial. Patients with refractory ANCA-associated vasculitis (AAV) or Behçet’s disease (BD) were randomised to receive either 60 mg or 30 mg alemtuzumab. Treatments were administered at baseline and 6 months or earlier where clinically appropriate. A maximum of three treatments were allowed within the 12-month study period. Results Twenty-three patients received at least one dose of alemtuzumab. Twelve had AAV, and 11 a diagnosis of BD. The median age was 40 years (range 28–44), with a prior disease duration of 61 months (42–103). Sixteen (70%) achieved either complete (6/23, 26%) or partial (10/23, 44%) response at 6 months. Eight (35%) maintained remission to the end of the trial without relapse. Ten severe adverse events were observed in 7 (30%) patients; 4 were related to alemtuzumab. There were no differences in clinical endpoints between the 60 and 30 mg alemtuzumab treatment groups. Conclusion In a selected group of refractory vasculitis patients, alemtuzumab led to remission in two thirds of patients at 6 months. Remission was maintained to 12 months in a third of the patients, and the safety profile was acceptable. Trial registration ClinicalTrials.gov identifier: NCT01405807, EudraCT Number: 2009-017087-17. Registered on April 07, 2011. Supplementary Information The online version contains supplementary material available at 10.1186/s13075-022-02761-6.
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Affiliation(s)
- Seerapani Gopaluni
- University of Cambridge, Box 118, Addenbrooke's Hospital, Hills Road, Cambridge, CB20QQ, UK.
| | - Rona Smith
- University of Cambridge, Box 118, Addenbrooke's Hospital, Hills Road, Cambridge, CB20QQ, UK.,Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Donna Goymer
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Hugh Cahill
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | | | - Elizabeth Wallin
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Mark McClure
- University of Cambridge, Box 118, Addenbrooke's Hospital, Hills Road, Cambridge, CB20QQ, UK.,Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Afzal Chaudhry
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - David Jayne
- University of Cambridge, Box 118, Addenbrooke's Hospital, Hills Road, Cambridge, CB20QQ, UK.,Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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22
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Caliz AD, Vertii A, Fisch V, Yoon S, Yoo HJ, Keaney JF, Kant S. Mitogen-activated protein kinase kinase 7 in inflammatory, cancer, and neurological diseases. Front Cell Dev Biol 2022; 10:979673. [PMID: 36340039 PMCID: PMC9630596 DOI: 10.3389/fcell.2022.979673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 10/10/2022] [Indexed: 11/13/2022] Open
Abstract
Stress-activated mitogen-activated protein kinase kinase 7 (MKK7) is a member of the dual-specificity mitogen-activated protein kinase family. In the human body, MKK7 controls essential physiological processes, including but not limited to proliferation and differentiation in multiple tissues and organs. MKK7, along with the MKK4 pathway, has been implicated in stress-activated activities and biological events that are mediated by c-Jun N-terminal kinase (JNK) signaling. Although numerous studies have been performed to identify the role of JNK in multiple biological processes, there are limited publications that focus on dissecting the independent role of MKK7. Recent research findings have spurred testing via in vivo genetically deficient models, uncovering previously undocumented JNK-independent functions of MKK7. Here we discuss both JNK-dependent and-independent functions of MKK7 in vivo. This review summarizes the role of MKK7 in inflammation, cytokine production, cancer, and neurological diseases.
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Affiliation(s)
- Amada D Caliz
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Anastassiia Vertii
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, United States
| | - Vijay Fisch
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Soonsang Yoon
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Hyung-Jin Yoo
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - John F Keaney
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Shashi Kant
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
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23
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Sciascia S, Ponticelli C, Roccatello D. Pathogenesis-based new perspectives of management of ANCA-associated vasculitis. Autoimmun Rev 2021; 21:103030. [PMID: 34971805 DOI: 10.1016/j.autrev.2021.103030] [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: 12/05/2021] [Accepted: 12/25/2021] [Indexed: 11/28/2022]
Abstract
While the pathogenesis of anti-neutrophil cytoplasmic autoantibody associated vasculitis (AAV) is still not fully elucidated, there is a mounting evidence that it is initiated by inflammation and activation of innate immunity in the presence of predisposing factors, innate immunity, aberrant responses of the adaptive immune system, and complement system activation. Biologics targeting inflammation-related molecules in the immune system have been explored to treat AVV, and these treatments have provided revolutionary advances. When focusing on the pathogenic mechanisms of AVV, this review presents the new findings regarding novel therapeutic approaches for the management of these conditions.
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Affiliation(s)
- Savino Sciascia
- CMID-Nephrology and Dialysis Unit (ERK-net Member), Center of Research of Immunopathology and Rare Diseases- Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, Department of Clinical and Biological Sciences, University of Turin and S. Giovanni Bosco Hub Hospital, Turin, Italy
| | | | - Dario Roccatello
- CMID-Nephrology and Dialysis Unit (ERK-net Member), Center of Research of Immunopathology and Rare Diseases- Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, Department of Clinical and Biological Sciences, University of Turin and S. Giovanni Bosco Hub Hospital, Turin, Italy.
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24
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Goswami KK, Bose A, Baral R. Macrophages in tumor: An inflammatory perspective. Clin Immunol 2021; 232:108875. [PMID: 34740843 DOI: 10.1016/j.clim.2021.108875] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 10/07/2021] [Accepted: 10/27/2021] [Indexed: 01/08/2023]
Abstract
Inflammation is a part of carefully co-ordinated healing immune exercise to eliminate injurious stimuli. However, in substantial number of cancer types, it contributes in shaping up of robust tumor microenvironment (TME). Solid TME promotes infiltration of tumor associated macrophages (TAMs) that contributes to cancer promotion. TAMs are functionally heterogeneous and display an extraordinary degree of plasticity, which allow 'Switching' of macrophages into an 'M2', phenotype, linked with immunosuppression, advancement of tumor angiogenesis with metastatic consequences. In contrary to the classical M1 macrophages, these M2 TAMs are high-IL-10, TGF-β secreting-'anti-inflammatory'. In this review, we will discuss the modes of infiltration and switching of TAMs into M2 anti-inflammatory state in the TME to promote immunosuppression and inflammation-driven cancer.
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Affiliation(s)
- Kuntal Kanti Goswami
- Department of Microbiology, Asutosh College, 92, S. P. Mukherjee Road, Kolkata 700026, India.
| | - Anamika Bose
- Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India
| | - Rathindranath Baral
- Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India
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25
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Tylek K, Trojan E, Leśkiewicz M, Regulska M, Bryniarska N, Curzytek K, Lacivita E, Leopoldo M, Basta-Kaim A. Time-Dependent Protective and Pro-Resolving Effects of FPR2 Agonists on Lipopolysaccharide-Exposed Microglia Cells Involve Inhibition of NF-κB and MAPKs Pathways. Cells 2021; 10:cells10092373. [PMID: 34572022 PMCID: PMC8472089 DOI: 10.3390/cells10092373] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/01/2021] [Accepted: 09/07/2021] [Indexed: 02/07/2023] Open
Abstract
Prolonged or excessive microglial activation may lead to disturbances in the resolution of inflammation (RoI). The importance of specialized pro-resolving lipid mediators (SPMs) in RoI has been highlighted. Among them, lipoxins (LXA4) and aspirin-triggered lipoxin A4 (AT-LXA4) mediate beneficial responses through the activation of N-formyl peptide receptor-2 (FPR2). We aimed to shed more light on the time-dependent protective and anti-inflammatory impact of the endogenous SPMs, LXA4, and AT-LXA4, and of a new synthetic FPR2 agonist MR-39, in lipopolysaccharide (LPS)-exposed rat microglial cells. Our results showed that LXA4, AT-LXA4, and MR-39 exhibit a protective and pro-resolving potential in LPS-stimulated microglia, even if marked differences were apparent regarding the time dependency and efficacy of inhibiting particular biomarkers. The LXA4 action was found mainly after 3 h of LPS stimulation, and the AT-LXA4 effect was varied in time, while MR-39′s effect was mainly observed after 24 h of stimulation by endotoxin. MR-39 was the only FPR2 ligand that attenuated LPS-evoked changes in the mitochondrial membrane potential and diminished the ROS and NO release. Moreover, the LPS-induced alterations in the microglial phenotype were modulated by LXA4, AT-LXA4, and MR-39. The anti-inflammatory effect of MR-39 on the IL-1β release was mediated through FPR2. All tested ligands inhibited TNF-α production, while AT-LXA4 and MR-39 also diminished IL-6 levels in LPS-stimulated microglia. The favorable action of LXA4 and MR-39 was mediated through the inhibition of ERK1/2 phosphorylation. AT-LXA4 and MR39 diminished the phosphorylation of the transcription factor NF-κB, while AT-LXA4 also affected p38 kinase phosphorylation. Our results suggest that new pro-resolving synthetic mediators can represent an attractive treatment option for the enhancement of RoI, and that FPR2 can provide a perspective as a target in immune-related brain disorders.
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Affiliation(s)
- Kinga Tylek
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, Poland; (K.T.); (E.T.); (M.L.); (M.R.); (N.B.); (K.C.)
| | - Ewa Trojan
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, Poland; (K.T.); (E.T.); (M.L.); (M.R.); (N.B.); (K.C.)
| | - Monika Leśkiewicz
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, Poland; (K.T.); (E.T.); (M.L.); (M.R.); (N.B.); (K.C.)
| | - Magdalena Regulska
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, Poland; (K.T.); (E.T.); (M.L.); (M.R.); (N.B.); (K.C.)
| | - Natalia Bryniarska
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, Poland; (K.T.); (E.T.); (M.L.); (M.R.); (N.B.); (K.C.)
| | - Katarzyna Curzytek
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, Poland; (K.T.); (E.T.); (M.L.); (M.R.); (N.B.); (K.C.)
| | - Enza Lacivita
- Department of Pharmacy—Drug Sciences, University of Bari, Via Orabona 4, 70125 Bari, Italy; (E.L.); (M.L.)
| | - Marcello Leopoldo
- Department of Pharmacy—Drug Sciences, University of Bari, Via Orabona 4, 70125 Bari, Italy; (E.L.); (M.L.)
| | - Agnieszka Basta-Kaim
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, Poland; (K.T.); (E.T.); (M.L.); (M.R.); (N.B.); (K.C.)
- Correspondence: ; Tel.: +48-12-662-32-73
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Ortega MA, Fraile-Martínez O, García-Montero C, Álvarez-Mon MA, Chaowen C, Ruiz-Grande F, Pekarek L, Monserrat J, Asúnsolo A, García-Honduvilla N, Álvarez-Mon M, Bujan J. Understanding Chronic Venous Disease: A Critical Overview of Its Pathophysiology and Medical Management. J Clin Med 2021; 10:3239. [PMID: 34362022 PMCID: PMC8348673 DOI: 10.3390/jcm10153239] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/19/2021] [Accepted: 07/20/2021] [Indexed: 01/19/2023] Open
Abstract
Chronic venous disease (CVD) is a multifactorial condition affecting an important percentage of the global population. It ranges from mild clinical signs, such as telangiectasias or reticular veins, to severe manifestations, such as venous ulcerations. However, varicose veins (VVs) are the most common manifestation of CVD. The explicit mechanisms of the disease are not well-understood. It seems that genetics and a plethora of environmental agents play an important role in the development and progression of CVD. The exposure to these factors leads to altered hemodynamics of the venous system, described as ambulatory venous hypertension, therefore promoting microcirculatory changes, inflammatory responses, hypoxia, venous wall remodeling, and epigenetic variations, even with important systemic implications. Thus, a proper clinical management of patients with CVD is essential to prevent potential harms of the disease, which also entails a significant loss of the quality of life in these individuals. Hence, the aim of the present review is to collect the current knowledge of CVD, including its epidemiology, etiology, and risk factors, but emphasizing the pathophysiology and medical care of these patients, including clinical manifestations, diagnosis, and treatments. Furthermore, future directions will also be covered in this work in order to provide potential fields to explore in the context of CVD.
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Affiliation(s)
- Miguel A. Ortega
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain; (M.A.O.); (O.F.-M.); (C.G.-M.); (C.C.); (L.P.); (J.M.); (N.G.-H.); (M.Á.-M.); (J.B.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain;
- Cancer Registry and Pathology Department, Hospital Universitario Principe de Asturias, 28806 Alcalá de Henares, Spain
| | - Oscar Fraile-Martínez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain; (M.A.O.); (O.F.-M.); (C.G.-M.); (C.C.); (L.P.); (J.M.); (N.G.-H.); (M.Á.-M.); (J.B.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain;
| | - Cielo García-Montero
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain; (M.A.O.); (O.F.-M.); (C.G.-M.); (C.C.); (L.P.); (J.M.); (N.G.-H.); (M.Á.-M.); (J.B.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain;
| | - Miguel A. Álvarez-Mon
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain; (M.A.O.); (O.F.-M.); (C.G.-M.); (C.C.); (L.P.); (J.M.); (N.G.-H.); (M.Á.-M.); (J.B.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain;
| | - Chen Chaowen
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain; (M.A.O.); (O.F.-M.); (C.G.-M.); (C.C.); (L.P.); (J.M.); (N.G.-H.); (M.Á.-M.); (J.B.)
| | - Fernando Ruiz-Grande
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain;
- Department of Vascular Surgery, Príncipe de Asturias Hospital, 28801 Alcalá de Henares, Spain
| | - Leonel Pekarek
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain; (M.A.O.); (O.F.-M.); (C.G.-M.); (C.C.); (L.P.); (J.M.); (N.G.-H.); (M.Á.-M.); (J.B.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain;
| | - Jorge Monserrat
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain; (M.A.O.); (O.F.-M.); (C.G.-M.); (C.C.); (L.P.); (J.M.); (N.G.-H.); (M.Á.-M.); (J.B.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain;
| | - Angel Asúnsolo
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain;
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain;
- Department of Epidemiology and Biostatistics, Graduate School of Public Health and Health Policy, The City University of New York, New York, NY 10027, USA
| | - Natalio García-Honduvilla
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain; (M.A.O.); (O.F.-M.); (C.G.-M.); (C.C.); (L.P.); (J.M.); (N.G.-H.); (M.Á.-M.); (J.B.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain;
| | - Melchor Álvarez-Mon
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain; (M.A.O.); (O.F.-M.); (C.G.-M.); (C.C.); (L.P.); (J.M.); (N.G.-H.); (M.Á.-M.); (J.B.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain;
- Immune System Diseases—Rheumatology and Internal Medicine Service, University Hospital Príncipe de Asturias, (CIBEREHD), 28806 Alcalá de Henares, Spain
| | - Julia Bujan
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain; (M.A.O.); (O.F.-M.); (C.G.-M.); (C.C.); (L.P.); (J.M.); (N.G.-H.); (M.Á.-M.); (J.B.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain;
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Liao Z, Tang J, Luo L, Deng S, Luo L, Wang F, Yuan X, Hu X, Feng J, Li X. Altered circulating CCR6 +and CXCR3 + T cell subsets are associated with poor renal prognosis in MPO-ANCA-associated vasculitis. Arthritis Res Ther 2021; 23:194. [PMID: 34289887 PMCID: PMC8293504 DOI: 10.1186/s13075-021-02576-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 05/26/2021] [Indexed: 11/15/2022] Open
Abstract
Background Effector memory T cells are pivotal effectors of adaptive immunity with enhanced migration characteristics and are involved in the pathogenesis of ANCA-associated vasculitis (AAV). The diversity of effector memory T cells in chemokine receptor expression has been well studied in proteinase 3 (PR3)-AAV. However, few studies have been conducted in myeloperoxidase (MPO)-AAV. Here, we characterized chemokine receptor expression on effector memory T cells from patients with active MPO-AAV. Methods Clinical data from newly diagnosed MPO-AAV patients and healthy subjects were collected and analyzed. Human peripheral blood mononuclear cells (PBMCs) isolated from patients with active MPO-AAV were analyzed by flow cytometry. The production of effector memory T cell-related chemokines in serum was assessed by ELISA. Results We observed decreased percentages of CD4+ and CD8+ T cells in the peripheral blood, accompanied by a significant decrease in CCR6-expressing T cells but an increase in CXCR3+ T cells, in active MPO-AAV. Furthermore, the decrease in CCR6 and increase in CXCR3 expression were mainly limited to effector memory T cells. Consistent with this finding, the serum level of CCL20 was increased. In addition, a decreasing trend in the TEM17 cell frequency, with concomitant increases in the frequencies of CD4+ TEM1 and CD4+ TEM17.1 cells, was observed when T cell functional subsets were defined by chemokine receptor expression. Moreover, the proportions of peripheral CD8+ T cells and CD4+ TEM subsets were correlated with renal prognosis and inflammatory markers. Conclusions Our data indicate that dysregulated chemokine receptor expression on CD4+ and CD8+ effector memory T cells and aberrant distribution of functional CD4+ T cell subsets in patients with active MPO-AAV have critical roles related to kidney survival.
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Affiliation(s)
- Zhonghua Liao
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Jiale Tang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Liying Luo
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Shuanglinzi Deng
- Department of Respiratory and Critical Care Medicine, Key Cite of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Lisa Luo
- Department of Respiratory and Critical Care Medicine, Key Cite of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Fangyuan Wang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Xiangning Yuan
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Xinyue Hu
- Department of Respiratory and Critical Care Medicine, Key Cite of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Juntao Feng
- Department of Respiratory and Critical Care Medicine, Key Cite of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Xiaozhao Li
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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Tesser A, Pin A, Mencaroni E, Gulino V, Tommasini A. Vasculitis, Autoimmunity, and Cytokines: How the Immune System Can Harm the Brain. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:5585. [PMID: 34073717 PMCID: PMC8197198 DOI: 10.3390/ijerph18115585] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/14/2021] [Accepted: 05/19/2021] [Indexed: 02/06/2023]
Abstract
More and more findings suggest that neurological disorders could have an immunopathological cause. Thus, immune-targeted therapies are increasingly proposed in neurology (even if often controversial), as anakinra, inhibiting IL-1 for febrile inflammatory illnesses, and JAK inhibitors for anti-interferons treatment. Precision medicine in neurology could be fostered by a better understanding of the disease machinery, to develop a rational use of immuno-modulators in clinical trials. In this review, we focus on monogenic disorders with neurological hyper-inflammation/autoimmunity as simplified "models" to correlate immune pathology and targeted treatments. The study of monogenic models yields great advantages for the elucidation of the pathogenic mechanisms that can be reproduced in cellular/animal models, overcoming the limitations of biological samples to study. Moreover, monogenic disorders provide a unique tool to study the mechanisms of neuroinflammatory and autoimmune brain damage, in all their manifestations. The insight of clinical, pathological, and therapeutic aspects of the considered monogenic models can impact knowledge about brain inflammation and can provide useful hints to better understand and cure some neurologic multifactorial disorders.
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Affiliation(s)
- Alessandra Tesser
- Department of Pediatrics, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (A.T.); (A.T.)
| | - Alessia Pin
- Department of Pediatrics, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (A.T.); (A.T.)
| | - Elisabetta Mencaroni
- Department of Pediatrics, Ospedale Santa Maria Misericordia, 06123 Perugia, Italy;
| | - Virginia Gulino
- Family Pediatrician, Valnerina District, UslUmbria2, 06046 Norcia, Italy;
| | - Alberto Tommasini
- Department of Pediatrics, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (A.T.); (A.T.)
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149 Trieste, Italy
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Ahn SS, Han M, Yoo J, Park YB, Jung I, Lee SW. Risk of Stroke in Systemic Necrotizing Vasculitis: A Nationwide Study Using the National Claims Database. Front Immunol 2021; 12:629902. [PMID: 33868249 PMCID: PMC8046646 DOI: 10.3389/fimmu.2021.629902] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 03/16/2021] [Indexed: 11/29/2022] Open
Abstract
Objective Evidences indicate that the risk of stroke is increased in autoimmune rheumatic diseases. This study aimed to investigate the incidence of stroke in patients with systemic necrotizing vasculitis (SNV) using the national health database. Methods Data were obtained from the Korean National Claims database between 2010 and 2018 to identify incident SNV [anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and polyarteritis nodosa (PAN)] cases. The standardized incidence ratio (SIR) and incidence rate ratio (IRR) were calculated to estimate the risk of stroke in patients with SNV compared to the general population and among disease subgroups. Time-dependent Cox's regression analysis was performed to identify risk factors for stroke. Results Among 2644 incident SNV cases, 159 patients (6.0%) were affected by stroke. The overall risk of stroke was significantly higher in patients with SNV compared to the general population (SIR 8.42). Stroke event rates were the highest within the first year of SNV diagnosis (67.3%). Among disease subgroups, patients with microscopic polyangiitis (MPA) exhibited higher IRR compared to PAN (adjusted IRR 1.98). In Cox's hazard analysis, older age and MPA were associated with higher risk of stroke [hazard ratio (HR) 1.05 and 1.88], whereas the administration of cyclophosphamide, azathioprine/mizoribine, methotrexate, and statins were protective in stroke (HR 0.26, 0.34, 0.49, and 0.50, respectively). Conclusion A considerable number of SNV patients experienced stroke, especially in the early phase of disease. Older age and MPA diagnosis were associated with elevated risk of stroke, while the administration of immunosuppressive agents and statins was beneficial in preventing stroke.
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Affiliation(s)
- Sung Soo Ahn
- Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, South Korea
| | - Minkyung Han
- Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, South Korea
| | - Juyoung Yoo
- Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Yong-Beom Park
- Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea
| | - Inkyung Jung
- Division of Biostatistics, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, South Korea
| | - Sang-Won Lee
- Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea
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Microbial Lipid A Remodeling Controls Cross-Presentation Efficiency and CD8 T Cell Priming by Modulating Dendritic Cell Function. Infect Immun 2021; 89:IAI.00335-20. [PMID: 33257533 DOI: 10.1128/iai.00335-20] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Accepted: 11/10/2020] [Indexed: 12/18/2022] Open
Abstract
The majority of Gram-negative bacteria elicit a potent immune response via recognition of lipid A expressed on the outer bacterial membrane by the host immune receptor Toll-like receptor 4 (TLR4). However, some Gram-negative bacteria evade detection by TLR4 or alter the outcome of TLR4 signaling by modification of lipid A species. Although the role of lipid A modifications on host innate immunity has been examined in some detail, it is currently unclear how lipid A remodeling influences host adaptive immunity. One prototypic Gram-negative bacterium that modifies its lipid A structure is Porphyromonas gingivalis, an anaerobic pathobiont that colonizes the human periodontium and induces chronic low-grade inflammation that is associated with periodontal disease as well as a number of systemic inflammatory disorders. P. gingivalis produces dephosphorylated and deacylated lipid A structures displaying altered activities at TLR4. Here, we explored the functional role of P. gingivalis lipid A modifications on TLR4-dependent innate and adaptive immune responses in mouse bone marrow-derived dendritic cells (BMDCs). We discovered that lipid A 4'-phosphate removal is required for P. gingivalis to evade BMDC-dependent proinflammatory cytokine responses and markedly limits the bacterium's capacity to induce beta interferon (IFN-β) production. In addition, lipid A 4'-phosphatase activity prevents canonical bacterium-induced delay in antigen degradation, which leads to inefficient antigen cross-presentation and a failure to cross-prime CD8 T cells specific for a P. gingivalis-associated antigen. We propose that lipid A modifications produced by this bacterium alter host TLR4-dependent adaptive immunity to establish chronic infections associated with a number of systemic inflammatory disorders.
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Trojan E, Bryniarska N, Leśkiewicz M, Regulska M, Chamera K, Szuster-Głuszczak M, Leopoldo M, Lacivita E, Basta-Kaim A. The Contribution of Formyl Peptide Receptor Dysfunction to the Course of Neuroinflammation: A Potential Role in the Brain Pathology. Curr Neuropharmacol 2020; 18:229-249. [PMID: 31629396 PMCID: PMC7327951 DOI: 10.2174/1570159x17666191019170244] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 08/01/2019] [Accepted: 10/15/2019] [Indexed: 12/27/2022] Open
Abstract
Chronic inflammatory processes within the central nervous system (CNS) are in part responsible for the development of neurodegenerative and psychiatric diseases. These processes are associated with, among other things, the increased and disturbed activation of microglia and the elevated production of proinflammatory factors. Recent studies indicated that the disruption of the process of resolution of inflammation (RoI) may be the cause of CNS disorders. It is shown that the RoI is regulated by endogenous molecules called specialized pro-resolving mediators (SPMs), which interact with specific membrane receptors. Some SPMs activate formyl peptide receptors (FPRs), which belong to the family of seven-transmembrane G protein-coupled receptors. These receptors take part not only in the proinflammatory response but also in the resolution of the inflammation process. Therefore, the activation of FPRs might have complex consequences. This review discusses the potential role of FPRs, and in particular the role of FPR2 subtype, in the brain under physiological and pathological conditions and their involvement in processes underlying neurodegenerative and psychiatric disorders as well as ischemia, the pathogenesis of which involves the dysfunction of inflammatory processes.
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Affiliation(s)
- Ewa Trojan
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna St. 31-343 Krakow, Poland
| | - Natalia Bryniarska
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna St. 31-343 Krakow, Poland
| | - Monika Leśkiewicz
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna St. 31-343 Krakow, Poland
| | - Magdalena Regulska
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna St. 31-343 Krakow, Poland
| | - Katarzyna Chamera
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna St. 31-343 Krakow, Poland
| | - Magdalena Szuster-Głuszczak
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna St. 31-343 Krakow, Poland
| | - Marcello Leopoldo
- Department of Pharmacy - Drug Sciences, University of Bari, via Orabona 4, 70125 Bari, Italy
| | - Enza Lacivita
- Department of Pharmacy - Drug Sciences, University of Bari, via Orabona 4, 70125 Bari, Italy
| | - Agnieszka Basta-Kaim
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna St. 31-343 Krakow, Poland
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Jung JH, Jeong HS, Choi SJ, Song GG, Kim JH, Lee TH, Han Y. Associations between interleukin 18 gene polymorphisms and susceptibility to vasculitis: A meta-analysis. SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES 2020; 37:203-211. [PMID: 33093784 PMCID: PMC7569561 DOI: 10.36141/svdld.v37i2.9399] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 06/15/2020] [Indexed: 11/24/2022]
Abstract
Interleukin 18 (IL18), a pro-inflammatory cytokine, affects the development and progress of vasculitis. The production, expression, and function of this cytokine are affected by polymorphisms of promoter region of the IL18 gene. In this study, a meta-analysis of the associations between several IL18 polymorphisms and susceptibility to vasculitis was performed. Published literature from PubMed and Embase were retrieved. In total, nine studies comprising 1006 patients with vasculitis and 1499 controls combined, and the investigating the rs187238, rs194618, and rs360719 polymorphisms of the promoter region of the IL18 gene, were included in the meta-analysis. Pooled odds ratios (OR) and 95% confidence intervals (CI) were estimated with fixed-effects model or random-effects model. The recessive model of the rs194618 polymorphism was found to be significantly associated with a high susceptibility to vasculitis (OR = 1.54, 95% CI = 1.02–2.33, P = 0.04), especially in the Mongoloid race, where the A allele of rs194618 was associated with a low risk of the disease (OR = 0.77, 95% CI = 0.62–0.95, P = 0.01). By contrast, the rs187238 and rs360719 polymorphisms were not associated with this inflammatory condition. This meta-analysis showed that some IL18 polymorphisms are associated with susceptibility to vasculitis. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 203-211)
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Affiliation(s)
- Jae Hyun Jung
- Korea University College of Medicine, 73 Goryeodae-ro, Seongbuk-gu, Seoul, 02841, Korea.,Division of Rheumatology, Department of Internal Medicine, Korea University Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan-si, Gyeonggi-do, 15355, Korea
| | - Han Saem Jeong
- Heart Disease Research Institute, Dr. Jeong's Heart Clinic, 224 Baekje-daero, Wansan-gu, Jeonju-si, Jeollabuk-do, 54985, Korea
| | - Sung Jae Choi
- Korea University College of Medicine, 73 Goryeodae-ro, Seongbuk-gu, Seoul, 02841, Korea.,Division of Rheumatology, Department of Internal Medicine, Korea University Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan-si, Gyeonggi-do, 15355, Korea
| | - Gwan Gyu Song
- Korea University College of Medicine, 73 Goryeodae-ro, Seongbuk-gu, Seoul, 02841, Korea.,Division of Rheumatology, Department of Internal Medicine, Korea University Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Korea
| | - Jong-Ho Kim
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, 73 Goryeodae-ro, Seongbuk-gu, Seoul, 02841, Korea
| | - Tae Hyub Lee
- College of Medicine, Chung-Ang University, 84 Heukseouk-ro, Donjak-gu, Seoul 06974, Korea
| | - Youngjin Han
- Division of Vascular Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
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Ahn SS, Han M, Yoo J, Park YB, Jung I, Lee SW. Incidence of Tuberculosis in Systemic Necrotizing Vasculitides: A Population-Based Study From an Intermediate-Burden Country. Front Med (Lausanne) 2020; 7:550004. [PMID: 33195300 PMCID: PMC7649822 DOI: 10.3389/fmed.2020.550004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 09/16/2020] [Indexed: 11/13/2022] Open
Affiliation(s)
- Sung Soo Ahn
- Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, South Korea
| | - Minkyung Han
- Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, South Korea
| | - Juyoung Yoo
- Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Yong-Beom Park
- Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea
| | - Inkyung Jung
- Division of Biostatistics, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, South Korea
- *Correspondence: Inkyung Jung
| | - Sang-Won Lee
- Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea
- Sang-Won Lee
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Liu Y, Yang Z, Lai P, Huang Z, Sun X, Zhou T, He C, Liu X. Bcl-6-directed follicular helper T cells promote vascular inflammatory injury in diabetic retinopathy. Am J Cancer Res 2020; 10:4250-4264. [PMID: 32226551 PMCID: PMC7086358 DOI: 10.7150/thno.43731] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 02/19/2020] [Indexed: 12/21/2022] Open
Abstract
Diabetic retinopathy (DR) is a vision-threatening complication of diabetes mellitus characterized by chronic retinal microvascular inflammation. The involvement of CD4+ T cells in retinal vascular inflammation has been considered, but the specific subset and mechanism of T cell-mediated response during the process remains unclear. Here, we aim to investigate the potential role of follicular helper T (Tfh) cells, a newly identified subset of CD4+ T cells in retinal vascular inflammation in DR. Methods: Patients with DR were enrolled and the PD-1+CXCR5+CD4+ Tfh cells were detected in the peripheral blood by flow cytometry. The streptozotocin (STZ)-induced DR model and oxygen-induced retinopathy (OIR) model were established, and 79-6, an inhibitor of Bcl-6, was injected intraperitoneally to suppress Tfh cells. The Tfh cells-related genes were investigated in the spleen, lymph nodes, and retina of mice by flow cytometry, immunofluorescence, and qPCR. Results: The Tfh cells expanded in the circulation of patients with DR and also increased in circulation, lymph nodes and retinal tissues from the STZ-induced DR mice and OIR mice. Notably, inhibition of Bcl-6, a critical transcription factor for Tfh cells development, prevented upregulation of Tfh cells and its typical IL-21 cytokine, and ameliorated vascular leakage in DR mice or retinal angiogenesis in OIR mice, indicating that Bcl-6-directed Tfh cells could promote vascular inflammation and angiogenesis. Conclusions: Our results suggested that excessive Bcl-6-directed Tfh cells represent an unrecognized feature of DR and be responsible for the retinal vascular inflammation and angiogenesis, providing opportunities for new therapeutic approaches to DR.
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Sangolli PM, Lakshmi DV. Vasculitis: A Checklist to Approach and Treatment Update for Dermatologists. Indian Dermatol Online J 2019; 10:617-626. [PMID: 31807439 PMCID: PMC6859757 DOI: 10.4103/idoj.idoj_248_18] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Vasculitis poses a great diagnostic, investigative and therapeutic challenge to the treating physician. The classification of vasculitides itself still eludes universal acceptance. Comprehensive management comprises establishing the diagnosis of true vasculitis after ruling out vasculitis mimics, finding the etiology if feasible, assessing the caliber of the vessels involved, deciphering the pathological process of vessel damage, investigating for the existence and extent of systemic involvement and finally planning the therapy in the background of co-morbidities. Successful management also entails regular monitoring to foresee complications arising from the disease process itself as well as complications of immunosuppressive treatment. Although steroids remain first line drug, biologics are emerging as popular agents in the treatment of immune-mediated vasculitis. Triphasic treatment is the best plan of action comprising induction, maintenance of remission and treatment of relapses.
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Curcumin Nanoparticles Enhance Mycobacterium bovis BCG Vaccine Efficacy by Modulating Host Immune Responses. Infect Immun 2019; 87:IAI.00291-19. [PMID: 31481412 PMCID: PMC6803339 DOI: 10.1128/iai.00291-19] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 08/22/2019] [Indexed: 12/20/2022] Open
Abstract
Tuberculosis (TB) is one of the deadliest diseases, causing ∼2 million deaths annually worldwide. Mycobacterium bovis bacillus Calmette-Guérin (BCG), the only TB vaccine in common use, is effective against disseminated and meningeal TB in young children but is not effective against adult pulmonary TB. Tuberculosis (TB) is one of the deadliest diseases, causing ∼2 million deaths annually worldwide. Mycobacterium bovis bacillus Calmette-Guérin (BCG), the only TB vaccine in common use, is effective against disseminated and meningeal TB in young children but is not effective against adult pulmonary TB. T helper 1 (Th1) cells producing interferon gamma (IFN-γ) and Th17 cells producing interleukin-17 (IL-17) play key roles in host protection against TB, whereas Th2 cells producing IL-4 and regulatory T cells (Tregs) facilitate TB disease progression by inhibiting protective Th1 and Th17 responses. Furthermore, the longevity of vaccine efficacy critically depends on the magnitude of long-lasting central memory T (TCM) cell responses. Hence, immunomodulators that promote TCM responses of the Th1 and Th17 cell lineages may improve BCG vaccine efficacy. Here, we show that curcumin nanoparticles enhance various antigen-presenting cell (APC) functions, including autophagy, costimulatory activity, and the production of inflammatory cytokines and other mediators. We further show that curcumin nanoparticles enhance the capacity of BCG to induce TCM cells of the Th1 and Th17 lineages, which augments host protection against TB infection. Thus, curcumin nanoparticles hold promise for enhancing the efficacy of TB vaccines.
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Fan Z, Lu X, Long H, Li T, Zhang Y. The association of hemocyte profile and obstructive sleep apnea. J Clin Lab Anal 2018; 33:e22680. [PMID: 30246267 DOI: 10.1002/jcla.22680] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 08/20/2018] [Accepted: 08/27/2018] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND The hemocyte profile is one of the most frequently requested clinical laboratory tests. However, the analysis of blood cell indexes of obstructive sleep apnea (OSA) patients in previous studies was not comprehensive. And, this study aimed to fully analyze the blood routine in OSA patients. METHODS A retrospective study was conducted on 1087 male patients, who were admitted to the sleep center of Nanfang Hospital from May 2013 to February 2018. According to the apnea hypopnea index (AHI), patients were divided into four groups: control group (AHI < 5, n = 135), mild OSA (5 ≦ AHI < 15, n = 185), moderate OSA (15 ≦ AHI < 30, n = 171), and severe OSA (AHI ≧ 30, n = 596). Data collected included sleep parameters, complete blood routine, body mass index (BMI), age, and comorbidities. RESULTS In our study, leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils, erythrocytes, hemoglobin, hematocrit, platelets, MPV, and PDW-SD were statistically significant among the four groups based on AHI (P < 0.05), but no significant differences were found in MCV, RDW-SD, N/L, and P/L ratio (P > 0.05). Neutrophils, lymphocytes, monocytes, eosinophils, basophils, hemoglobin, hematocrit, platelets, and MPV were significantly correlated with AHI. Moreover, multiple linear regression analysis demonstrated that hematocrit (β = 73.254, P = 0.001), neutrophils (β = 1.414, P = 0.012), and lymphocytes (β = 4.228, P < 0.001) were independently associated with AHI. CONCLUSION Neutrophils, lymphocytes, and hematocrit were independently associated with OSA severity. And combining these three blood cell indicators could contribute to the diagnosis of OSA.
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Affiliation(s)
- Zeqin Fan
- Sleep Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoxia Lu
- Sleep Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hong Long
- Sleep Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Taoping Li
- Sleep Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanhong Zhang
- Health Care Center, Guangdong Entry-exit Inspection and Quarantine Bureau, Guangzhou, China
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Mir SM, Ravuri HG, Pradhan RK, Narra S, Kumar JM, Kuncha M, Kanjilal S, Sistla R. Ferulic acid protects lipopolysaccharide-induced acute kidney injury by suppressing inflammatory events and upregulating antioxidant defenses in Balb/c mice. Biomed Pharmacother 2018; 100:304-315. [DOI: 10.1016/j.biopha.2018.01.169] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 01/27/2018] [Accepted: 01/29/2018] [Indexed: 12/16/2022] Open
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Hid Cadena R, Abdulahad WH, Hospers GAP, Wind TT, Boots AMH, Heeringa P, Brouwer E. Checks and Balances in Autoimmune Vasculitis. Front Immunol 2018. [PMID: 29520282 PMCID: PMC5827159 DOI: 10.3389/fimmu.2018.00315] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Age-associated changes in the immune system including alterations in surface protein expression are thought to contribute to an increased susceptibility for autoimmune diseases. The balance between the expression of coinhibitory and costimulatory surface protein molecules, also known as immune checkpoint molecules, is crucial in fine-tuning the immune response and preventing autoimmunity. The activation of specific inhibitory signaling pathways allows cancer cells to evade recognition and destruction by the host immune system. The use of immune checkpoint inhibitors (ICIs) to treat cancer has proven to be effective producing durable antitumor responses in multiple cancer types. However, one of the disadvantages derived from the use of these agents is the appearance of inflammatory manifestations termed immune-related adverse events (irAEs). These irAEs are often relatively mild, but more severe irAEs have been reported as well including several forms of vasculitis. In this article, we argue that age-related changes in expression and function of immune checkpoint molecules lead to an unstable immune system, which is prone to tolerance failure and autoimmune vasculitis development. The topic is introduced by a case report from our hospital describing a melanoma patient treated with ICIs and who subsequently developed biopsy-proven giant cell arteritis. Following this case report, we present an in-depth review on the role of immune checkpoint pathways in the development and progression of autoimmune vasculitis and its relation with an aging immune system.
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Affiliation(s)
- Rebeca Hid Cadena
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Wayel H Abdulahad
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.,Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - G A P Hospers
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - T T Wind
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Annemieke M H Boots
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Peter Heeringa
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Elisabeth Brouwer
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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41
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Dincer Z, Piccicuto V, Walker UJ, Mahl A, McKeag S. Spontaneous and Drug-induced Arteritis/Polyarteritis in the Göttingen Minipig—Review. Toxicol Pathol 2018; 46:121-130. [DOI: 10.1177/0192623318754791] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Arteritis/polyarteritis occurs spontaneously in many species used in preclinical toxicology studies. In Göttingen minipigs, arteritis/polyarteritis is an occasionally observed background change. In the minipig, this finding differs in frequency and nature from age-related polyarteritis nodosa in rats or monkeys, and Beagle pain syndrome in dogs. In minipigs, it can be present in a single small- or medium-sized artery of an organ or a few organs and is most commonly recorded in the cardiac and extracardiac blood vessels, vagina, oviduct, rectum, epididymis, spinal cord, pancreas, urinary bladder, kidneys, and stomach. The etiology is unknown although it has been considered in minipigs as well as in rats, dogs, and monkeys to be possibly immune mediated. This background change is important with respect to its nature and distribution in the minipig in order to distinguish it from drug-induced vascular changes, which might occur in similar locations and have similar morphologic features. This review summarizes the morphology, incidence, and predilection sites of arteritis as a spontaneously occurring background change and as a drug-induced vasculopathy in the minipig, and also describes the main aspects to consider when evaluating vascular changes in Göttingen minipig toxicity studies and their human relevance.
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Affiliation(s)
- Zuhal Dincer
- Pathology Department, Covance Laboratories Limited, Harrogate, United Kingdom
| | - Virginie Piccicuto
- Pathology Department, Covance Laboratories Limited, Harrogate, United Kingdom
| | - Ursula Junker Walker
- Preclinical Safety, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Andreas Mahl
- Preclinical Safety, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Sean McKeag
- Pathology Department, Covance Laboratories Limited, Harrogate, United Kingdom
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Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 2018. [PMID: 29467962 DOI: 10.1832/oncotarget.23208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2023] Open
Abstract
Inflammation is a biological response of the immune system that can be triggered by a variety of factors, including pathogens, damaged cells and toxic compounds. These factors may induce acute and/or chronic inflammatory responses in the heart, pancreas, liver, kidney, lung, brain, intestinal tract and reproductive system, potentially leading to tissue damage or disease. Both infectious and non-infectious agents and cell damage activate inflammatory cells and trigger inflammatory signaling pathways, most commonly the NF-κB, MAPK, and JAK-STAT pathways. Here, we review inflammatory responses within organs, focusing on the etiology of inflammation, inflammatory response mechanisms, resolution of inflammation, and organ-specific inflammatory responses.
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Affiliation(s)
- Linlin Chen
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
| | - Huidan Deng
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
| | - Hengmin Cui
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China.,Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
| | - Jing Fang
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China.,Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
| | - Zhicai Zuo
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China.,Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
| | - Junliang Deng
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China.,Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
| | - Yinglun Li
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China.,Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
| | - Xun Wang
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China.,Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
| | - Ling Zhao
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China.,Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
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Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 2018; 9:7204-7218. [PMID: 29467962 PMCID: PMC5805548 DOI: 10.18632/oncotarget.23208] [Citation(s) in RCA: 2763] [Impact Index Per Article: 394.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 11/03/2017] [Indexed: 02/07/2023] Open
Abstract
Inflammation is a biological response of the immune system that can be triggered by a variety of factors, including pathogens, damaged cells and toxic compounds. These factors may induce acute and/or chronic inflammatory responses in the heart, pancreas, liver, kidney, lung, brain, intestinal tract and reproductive system, potentially leading to tissue damage or disease. Both infectious and non-infectious agents and cell damage activate inflammatory cells and trigger inflammatory signaling pathways, most commonly the NF-κB, MAPK, and JAK-STAT pathways. Here, we review inflammatory responses within organs, focusing on the etiology of inflammation, inflammatory response mechanisms, resolution of inflammation, and organ-specific inflammatory responses.
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Affiliation(s)
- Linlin Chen
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
| | - Huidan Deng
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
| | - Hengmin Cui
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
- Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
| | - Jing Fang
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
- Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
| | - Zhicai Zuo
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
- Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
| | - Junliang Deng
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
- Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
| | - Yinglun Li
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
- Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
| | - Xun Wang
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
- Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
| | - Ling Zhao
- College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China
- Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China
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Baragetti A, Ramirez GA, Magnoni M, Garlaschelli K, Grigore L, Berteotti M, Scotti I, Bozzolo E, Berti A, Camici PG, Catapano AL, Manfredi AA, Ammirati E, Norata GD. Disease trends over time and CD4 +CCR5 + T-cells expansion predict carotid atherosclerosis development in patients with systemic lupus erythematosus. Nutr Metab Cardiovasc Dis 2018; 28:53-63. [PMID: 29150407 DOI: 10.1016/j.numecd.2017.09.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 09/07/2017] [Accepted: 09/09/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Patients with Systemic Lupus Erythematosus (SLE) present increased cardiovascular mortality compared to the general population. Few studies have assessed the long-term development and progression of carotid atherosclerotic plaque in SLE patients. Our aim was to investigate the association of clinical and laboratory markers of disease activity and classical cardiovascular risk factors (CVRF) with carotid atherosclerosis development in SLE patients in a prospective 5-year study. METHODS AND RESULTS Clinical history and information on principal CVRFs were collected at baseline and after 5 years in 40 SLE patients (36 women, mean age 42 ± 9 years; 14.4 ± 7 years of mean disease duration) and 50 age-matched controls. Carotid Doppler ultrasonography was employed to quantify the atherosclerotic burden at baseline and at follow up. Clinimetrics were applied to assess SLE activity over time (SLEDAI). The association between basal circulating T cell subsets (including CD4+CCR5+; CD4+CXCR3+; CD4+HLADR+; CD4+CD45RA+RO-, CD4+CD45RO+RA- and their subsets) and atherosclerosis development was evaluated. During the 5-year follow up, 32% of SLE patients, developed carotid atherosclerosis compared to 4% of controls. Furthermore, considering SLEDAI changes over time, patients within the highest tertile were those with increased incidence of carotid atherosclerosis independently of CVRF. In addition, increased levels of CD4+CCR5+ T cells were independently associated with the development of carotid atherosclerosis in SLE patients. CONCLUSION Serial clinical evaluations over time, rather than a single point estimation of disease activity or CVRF burden, are required to define the risk of carotid atherosclerosis development in SLE patients. Specific T cell subsets are associated with long-term atherosclerotic progression and may further be of help in predicting vascular disease progression.
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Affiliation(s)
- A Baragetti
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy; Center for the Study of Atherosclerosis - Bassini Hospital, Cinisello Balsamo, Italy
| | - G A Ramirez
- Università Vita-Salute San Raffaele, Milan, Italy; Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - M Magnoni
- Department of Thoracic and Cardiovascular Surgery, Università Vita-Salute San Raffaele Scientific Institute Milan, Italy
| | - K Garlaschelli
- Center for the Study of Atherosclerosis - Bassini Hospital, Cinisello Balsamo, Italy
| | - L Grigore
- Center for the Study of Atherosclerosis - Bassini Hospital, Cinisello Balsamo, Italy; IRCCS - Multimedica Hospital, Sesto San Giovanni, Italy
| | - M Berteotti
- Department of Thoracic and Cardiovascular Surgery, Università Vita-Salute San Raffaele Scientific Institute Milan, Italy
| | - I Scotti
- Department of Thoracic and Cardiovascular Surgery, Università Vita-Salute San Raffaele Scientific Institute Milan, Italy
| | - E Bozzolo
- Università Vita-Salute San Raffaele, Milan, Italy
| | - A Berti
- Università Vita-Salute San Raffaele, Milan, Italy; Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - P G Camici
- Department of Thoracic and Cardiovascular Surgery, Università Vita-Salute San Raffaele Scientific Institute Milan, Italy
| | - A L Catapano
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy; IRCCS - Multimedica Hospital, Sesto San Giovanni, Italy
| | - A A Manfredi
- Università Vita-Salute San Raffaele, Milan, Italy; Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - E Ammirati
- Niguarda Ca' Granda Hospital, Milan, Italy
| | - G D Norata
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy; Center for the Study of Atherosclerosis - Bassini Hospital, Cinisello Balsamo, Italy; School of Biomedical Sciences, Curtin Health Innovation Research Institute, Faculty of Health Science, Curtin University, Perth, Western Australia, Australia.
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Weyand CM, Berry GJ, Goronzy JJ. The immunoinhibitory PD-1/PD-L1 pathway in inflammatory blood vessel disease. J Leukoc Biol 2017; 103:565-575. [PMID: 28848042 DOI: 10.1189/jlb.3ma0717-283] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 08/03/2017] [Indexed: 12/16/2022] Open
Abstract
Because of their vital function, the wall structures of medium and large arteries are immunoprivileged and protected from inflammatory attack. That vascular immunoprivilege is broken in atherosclerosis and in vasculitis, when wall-invading T cells and macrophages (Mϕ) promote tissue injury and maladaptive repair. Historically, tissue-residing T cells were studied for their antigen specificity, but recent progress has refocused attention to antigen-nonspecific regulation, which determines tissue access, persistence, and functional differentiation of T cells. The coinhibitory receptor PD-1, expressed on T cells, delivers negative signals when engaged by its ligand PD-L1, expressed on dendritic cells, Mϕ, and endothelial cells to attenuate T cell activation, effector functions, and survival. Through mitigating signals, the PD-1 immune checkpoint maintains tissue tolerance. In line with this concept, dendritic cells and Mϕs from patients with the vasculitic syndrome giant cell arteritis (GCA) are PD-L1lo ; including vessel-wall-embedded DCs that guard the vascular immunoprivilege. GCA infiltrates in the arterial walls are filled with PD-1+ T cells that secrete IFN-γ, IL-17, and IL-21; drive inflammation-associated angiogenesis; and facilitate intimal hyperplasia. Conversely, chronic tissue inflammation in the atherosclerotic plaque is associated with an overreactive PD-1 checkpoint. Plaque-residing Mϕs are PD-L1hi , a defect induced by their addiction to glucose and glycolytic breakdown. PD-L1hi Mϕs render patients with coronary artery disease immunocompromised and suppress antiviral immunity, including protective anti-varicella zoster virus T cells. Thus, immunoinhibitory signals affect several domains of vascular inflammation; failing PD-L1 in vasculitis enables unopposed immunostimulation and opens the flood gates for polyfunctional inflammatory T cells, and excess PD-L1 in the atherosclerotic plaque disables tissue-protective T cell immunity.
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Affiliation(s)
- Cornelia M Weyand
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Gerald J Berry
- Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
| | - Jörg J Goronzy
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
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46
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Changes in CD73, CD39 and CD26 expression on T-lymphocytes of ANCA-associated vasculitis patients suggest impairment in adenosine generation and turn-over. Sci Rep 2017; 7:11683. [PMID: 28916770 PMCID: PMC5601951 DOI: 10.1038/s41598-017-12011-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 08/31/2017] [Indexed: 01/03/2023] Open
Abstract
Extracellular adenosine, generated via the concerted action of CD39 and CD73, contributes to T-cell differentiation and function. Adenosine concentrations are furthermore influenced by adenosine deaminase binding protein CD26. Because aberrant T-cell phenotypes had been reported in anti-neutrophil cytoplasmic auto-antibody (ANCA)-associated vasculitis (AAV) patients, an impaired expression of these molecules on T-cells of AAV patients was hypothesized in the present study. While in AAV patients (n = 29) CD26 was increased on CD4+ lymphocytes, CD39 and CD73 were generally reduced on patients’ T-cells. In CD4+ cells significant differences in CD73 expression were confined to memory CD45RA- cells, while in CD4- lymphocytes differences were significant in both naïve CD45RA+ and memory CD45RA- cells. The percentage of CD4-CD73+ cells correlated with micro-RNA (miR)−31 expression, a putative regulator of factor inhibiting hypoxia-inducible factor 1 alpha (FIH-1), inversely with serum C-reactive protein (CRP) and positively with estimated glomerular filtration rate (eGFR). No correlation with disease activity, duration, and ANCA profile was found. It remains to be assessed if a decreased CD73 and CD39 expression underlies functional impairment of lymphocytes in AAV patients. Likewise, the relations between frequencies of CD4-CD73+ cells and serum CRP or eGFR require further functional elucidation.
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Venom-derived peptide inhibitors of voltage-gated potassium channels. Neuropharmacology 2017; 127:124-138. [PMID: 28689025 DOI: 10.1016/j.neuropharm.2017.07.002] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 07/02/2017] [Accepted: 07/04/2017] [Indexed: 12/11/2022]
Abstract
Voltage-gated potassium channels play a key role in human physiology and pathology. Reflecting their importance, numerous channelopathies have been characterised that arise from mutations in these channels or from autoimmune attack on the channels. Voltage-gated potassium channels are also the target of a broad range of peptide toxins from venomous organisms, including sea anemones, scorpions, spiders, snakes and cone snails; many of these peptides bind to the channels with high potency and selectivity. In this review we describe the various classes of peptide toxins that block these channels and illustrate the broad range of three-dimensional structures that support channel blockade. The therapeutic opportunities afforded by these peptides are also highlighted. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.'
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Ohanyan V, Yin L, Bardakjian R, Kolz C, Enrick M, Hakobyan T, Luli J, Graham K, Khayata M, Logan S, Kmetz J, Chilian WM. Kv1.3 channels facilitate the connection between metabolism and blood flow in the heart. Microcirculation 2017; 24:10.1111/micc.12334. [PMID: 28504408 PMCID: PMC5433265 DOI: 10.1111/micc.12334] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Revised: 10/23/2016] [Accepted: 11/01/2016] [Indexed: 12/17/2022]
Abstract
The connection between metabolism and flow in the heart, metabolic dilation, is essential for cardiac function. We recently found redox-sensitive Kv1.5 channels play a role in coronary metabolic dilation; however, more than one ion channel likely plays a role in this process as animals null for these channels still showed limited coronary metabolic dilation. Accordingly, we examined the role of another Kv1 family channel, the energetically linked Kv1.3 channel, in coronary metabolic dilation. We measured myocardial blood flow (contrast echocardiography) during norepinephrine-induced increases in cardiac work (heart rate x mean arterial pressure) in WT, WT mice given correolide (preferential Kv1.3 antagonist), and Kv1.3-null mice (Kv1.3-/- ). We also measured relaxation of isolated small arteries mounted in a myograph. During increased cardiac work, myocardial blood flow was attenuated in Kv1.3-/- and in correolide-treated mice. In isolated vessels from Kv1.3-/- mice, relaxation to H2 O2 was impaired (vs WT), but responses to adenosine and acetylcholine were equivalent to WT. Correolide reduced dilation to adenosine and acetylcholine in WT and Kv1.3-/- , but had no effect on H2 O2 -dependent dilation in vessels from Kv1.3-/- mice. We conclude that Kv1.3 channels participate in the connection between myocardial blood flow and cardiac metabolism.
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Affiliation(s)
- Vahagn Ohanyan
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Liya Yin
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | | | - Christopher Kolz
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Molly Enrick
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Tatevik Hakobyan
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Jordan Luli
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Kathleen Graham
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | | | - Suzanna Logan
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | - John Kmetz
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | - William M Chilian
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
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Shaw MK, Tse KY, Zhao X, Welch K, Eitzman DT, Thipparthi RR, Montgomery PC, Thummel R, Tse HY. T-Cells Specific for a Self-Peptide of ApoB-100 Exacerbate Aortic Atheroma in Murine Atherosclerosis. Front Immunol 2017; 8:95. [PMID: 28280493 PMCID: PMC5322236 DOI: 10.3389/fimmu.2017.00095] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 01/19/2017] [Indexed: 12/31/2022] Open
Abstract
On the basis of mouse I-Ab-binding motifs, two sequences of the murine apolipoprotein B-100 (mApoB-100), mApoB-1003501–3515 (designated P3) and mApoB-100978–992 (designated P6), were found to be immunogenic. In this report, we show that P6 is also atherogenic. Immunization of Apoe−/− mice fed a high-fat diet (HFD) with P6 resulted in enhanced development of aortic atheroma as compared to control mice immunized with an irrelevant peptide MOG35–55 or with complete Freund’s adjuvant alone. Adoptive transfer of lymph node cells from P6-immunized donor mice to recipients fed an HFD caused exacerbated aortic atheromas, correlating P6-primed cells with disease development. Finally, P6-specific T cell clones were generated and adoptive transfer of T cell clones into recipients fed an HFD led to significant increase in aortic plaque coverage when compared to control animals receiving a MOG35–55-specific T cell line. Recipient mice not fed an HFD, however, did not exhibit such enhancement, indicating that an inflammatory environment facilitated the atherogenic activity of P6-specific T cells. That P6 is identical to or cross-reacts with a naturally processed peptide of ApoB-100 is evidenced by the ability of P6 to stimulate the proliferation of T cells in the lymph node of mice primed by full-length human ApoB-100. By identifying an atherogenic T cell epitope of ApoB-100 and establishing specific T cell clones, our studies open up new and hitherto unavailable avenues to study the nature of atherogenic T cells and their functions in the atherosclerotic disease process.
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Affiliation(s)
- Michael K Shaw
- Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI, USA; Department of Research and Clinical Trials, St. John-Providence Health System, Macomb-Oakland Hospital, Warren, MI, USA
| | - Kevin Y Tse
- Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, University of California at San Diego Medical Center, La Jolla, CA, USA; Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
| | - Xiaoqing Zhao
- Department of Immunology and Microbiology, Wayne State University School of Medicine , Detroit, MI , USA
| | - Kathryn Welch
- Department of Immunology and Microbiology, Wayne State University School of Medicine , Detroit, MI , USA
| | - Daniel T Eitzman
- Cardiovascular Medicine, University of Michigan Cardiovascular Center , Ann Arbor, MI , USA
| | - Raghavendar R Thipparthi
- Department of Immunology and Microbiology, Wayne State University School of Medicine , Detroit, MI , USA
| | - Paul C Montgomery
- Department of Immunology and Microbiology, Wayne State University School of Medicine , Detroit, MI , USA
| | - Ryan Thummel
- Department of Anatomy and Cell Biology, Wayne State University School of Medicine , Detroit, MI , USA
| | - Harley Y Tse
- Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI, USA; Cardiovascular Research Institute, Wayne State University School of Medicine, Detroit, MI, USA
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Sawyer DM, Pace LA, Pascale CL, Kutchin AC, O'Neill BE, Starke RM, Dumont AS. Lymphocytes influence intracranial aneurysm formation and rupture: role of extracellular matrix remodeling and phenotypic modulation of vascular smooth muscle cells. J Neuroinflammation 2016; 13:185. [PMID: 27416931 PMCID: PMC4946206 DOI: 10.1186/s12974-016-0654-z] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 07/06/2016] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Intracranial aneurysms (IA) are increasingly recognized as a disease driven by chronic inflammation. Recent research has identified key mediators and processes underlying IA pathogenesis, but mechanistic understanding remains incomplete. Lymphocytic infiltrates have been demonstrated in patient IA tissue specimens and have also been shown to play an important role in abdominal aortic aneurysms (AAA) and related diseases such as atherosclerosis. However, no study has systematically examined the contribution of lymphocytes in a model of IA. METHODS Lymphocyte-deficient (Rag1) and wild-type (WT; C57BL/6 strain) mice were subjected to a robust IA induction protocol. Rates of IA formation and rupture were measured, and cerebral artery tissue was collected and utilized for histology and gene expression analysis. RESULTS At 2 weeks, the Rag1 group had significantly fewer IA formations and ruptures than the WT group. Histological analysis of unruptured IA tissue showed robust B and T lymphocyte infiltration in the WT group, while there were no differences in macrophage infiltration, IA diameter, and wall thickness. Significant differences in interleukin-6 (IL-6), matrix metalloproteinases 2 (MMP2) and 9 (MMP9), and smooth muscle myosin heavy chain (MHC) were observed between the groups. CONCLUSIONS Lymphocytes are key contributors to IA pathogenesis and provide a novel target for the prevention of IA progression and rupture in patients.
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Affiliation(s)
- David M Sawyer
- Department of Neurosurgery, Tulane Center for Clinical Neurosciences, Tulane University School of Medicine, 131 S. Robertson St. Ste. 1300, 8047, New Orleans, LA, 70112, USA
| | - Lauren A Pace
- Department of Neurosurgery, Tulane Center for Clinical Neurosciences, Tulane University School of Medicine, 131 S. Robertson St. Ste. 1300, 8047, New Orleans, LA, 70112, USA
| | - Crissey L Pascale
- Department of Neurosurgery, Tulane Center for Clinical Neurosciences, Tulane University School of Medicine, 131 S. Robertson St. Ste. 1300, 8047, New Orleans, LA, 70112, USA
| | - Alexander C Kutchin
- Department of Neurosurgery, Tulane Center for Clinical Neurosciences, Tulane University School of Medicine, 131 S. Robertson St. Ste. 1300, 8047, New Orleans, LA, 70112, USA
| | - Brannan E O'Neill
- Department of Neurosurgery, Tulane Center for Clinical Neurosciences, Tulane University School of Medicine, 131 S. Robertson St. Ste. 1300, 8047, New Orleans, LA, 70112, USA
| | - Robert M Starke
- Department of Neurosurgery, University of Miami, Miami, FL, USA
| | - Aaron S Dumont
- Department of Neurosurgery, Tulane Center for Clinical Neurosciences, Tulane University School of Medicine, 131 S. Robertson St. Ste. 1300, 8047, New Orleans, LA, 70112, USA.
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