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Song Y, Wang X, Tong D, Huang X, Jin X, Zhang C, Liu J, Guo B, Huang C, Lian J. Identification of Potential Biomarkers and Immune Cell Signatures in COVID-19 Myocarditis Through Bioinformatic Analysis. Cardiol Res Pract 2025; 2025:2349610. [PMID: 40230577 PMCID: PMC11996287 DOI: 10.1155/crp/2349610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 03/27/2024] [Accepted: 03/01/2025] [Indexed: 04/16/2025] Open
Abstract
Objective: The present study aims to elucidate the significance of immune cell infiltration in Coronavirus disease 2019 (COVID-19) myocarditis and identify potential diagnostic markers for this condition. Myocarditis, an inflammatory cardiac disease, primarily results from viral infections. Although the association between COVID-19 and myocarditis is well-established, the specific mechanism(s) underlying this relationship remain incompletely understood. Methods: The GSE53607 and GSE35182 datasets were obtained from the GEO database, which contains samples from a mouse model for viral myocarditis. Differentially expressed genes (DEGs) and candidate biomarkers were selected using the LASSO regression model and support vector machine recursive feature elimination (SVM-RFE) analysis. Subsequently, the diagnostic potential of these biomarkers was evaluated by calculating the area under the receiver operating characteristic curve (AUC). Further validation of the biomarkers was conducted using the GSE183850 dataset, which consists of samples from patients with COVID-19 myocarditis. In addition, CIBERSORT analysis was employed to estimate the compositional patterns of 22 types of immune cell fractions in merged cohorts. Results: Thirty genes were identified, with a significant proportion of the DEGs being associated with carbohydrate binding, endopeptidase activity, and pathogenic organisms such as Staphylococcus aureus and coronavirus disease. Importantly, gene sets related to the IL6-JAK-STAT3 signaling pathways, inflammatory response, and interferon response exhibited differential activation in viral myocarditis compared to the control group. In addition, in the context of COVID-19 myocarditis patients from the GSE183850 dataset, B2M and C3 were established as diagnostic markers that were subsequently validated (AUC = 0.978 and AUC = 0.956, respectively). Furthermore, analysis of immune cell infiltration revealed correlations between B2M and C3 expression levels and the activation of NK cells, dendritic cells, T cells CD4 memory resting, as well as eosinophils. Conclusion: B2M and C3 have been identified as potential biomarkers for viral myocarditis, providing valuable insights for future investigations into the pathogenesis of COVID-19-associated myocarditis.
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Affiliation(s)
- Yongfei Song
- Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
- Department of Cardiology, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Xiaofei Wang
- Biomedical Experimental Center, Xi'an Jiaotong University, Xian, Shaanxi, China
| | - Dongdong Tong
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xian, Shaanxi, China
- Key Laboratory of Environmentally and Genetically Associated Diseases, Xi'an Jiaotong University, Ministry of Education, Xian, Shaanxi, China
| | - Xiaoyan Huang
- Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
- Department of Cardiology, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Xiaojun Jin
- Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
- Department of Cardiology, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Chuanjing Zhang
- Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
- Department of Cardiology, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Jianhui Liu
- Department of Cardiology, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Bo Guo
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xian, Shaanxi, China
- Key Laboratory of Environmentally and Genetically Associated Diseases, Xi'an Jiaotong University, Ministry of Education, Xian, Shaanxi, China
| | - Chen Huang
- Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
- Department of Cardiology, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
- Biomedical Experimental Center, Xi'an Jiaotong University, Xian, Shaanxi, China
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xian, Shaanxi, China
- Key Laboratory of Environmentally and Genetically Associated Diseases, Xi'an Jiaotong University, Ministry of Education, Xian, Shaanxi, China
| | - Jiangfang Lian
- Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
- Department of Cardiology, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
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Cheng MZ, Luo JH, Li X, Liu FY, Zhou WJ. Zinc pretreatment for protection against intestinal ischemia-reperfusion injury. World J Gastrointest Surg 2024; 16:3843-3856. [PMID: 39734451 PMCID: PMC11650234 DOI: 10.4240/wjgs.v16.i12.3843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/01/2024] [Accepted: 10/28/2024] [Indexed: 11/27/2024] Open
Abstract
BACKGROUND Intestinal ischemia-reperfusion (I/R) injury (II/RI) is a critical condition that results in oxidative stress, inflammation, and damage to multiple organs. Zinc, an essential trace element, offers protective benefits in several tissues during I/R injury, but its effects on intestinal II/RI remain unclear. AIM To investigate the effects of zinc pretreatment on II/RI and associated multiorgan damage. METHODS C57BL/6 mice were pretreated with zinc sulfate (ZnSO4, 10 mg/kg) daily for three days before I/R injury was induced via superior mesenteric artery occlusion (SMAO) and abdominal aortic occlusion (AAO) models. Tissue and serum samples were collected to evaluate intestinal, liver, and kidney damage using Chiu's score, Suzuki score, and histopathological analysis. Caco-2 cells and intestinal organoids were used for in vitro hypoxia-reoxygenation injury models to measure reactive oxygen species (ROS) and superoxide dismutase (SOD) levels. RESULTS Zinc pretreatment significantly reduced intestinal damage in the SMAO and AAO models (P < 0.001). The serum levels of liver enzymes (alanine aminotransferase, aspartate aminotransferase) and kidney markers (creatinine and urea) were lower in the zinc-treated mice than in the control mice, indicating reduced hepatic and renal injury. In vitro, zinc decreased ROS levels and increased SOD activity in Caco-2 cells subject to hypoxia-reoxygenation injury. Intestinal organoids pretreated with zinc exhibited enhanced resilience to hypoxic injury compared to controls. CONCLUSION Zinc pretreatment mitigates II/RI and reduces associated multiorgan damage. These findings suggest that zinc has potential clinical applications in protecting against I/R injuries.
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Affiliation(s)
- Ming-Zhen Cheng
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Jia-Hao Luo
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Xin Li
- Department of Interventional Radiology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100071, China
| | - Feng-Yong Liu
- Department of Interventional Radiology, Senior Department of Oncology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100071, China
| | - Wei-Jie Zhou
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
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3
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Kaneko K, Tsai J, Meñez D, Oh B, Suh AJ, Bae S, Mizuno M, Umemoto A, Giannopoulou E, Fujii T, Zhang Y, Stein EM, Bockman RS, Park-Min KH. Cellular signatures in human blood track bone mineral density in postmenopausal women. JCI Insight 2024; 9:e178977. [PMID: 39576015 PMCID: PMC11601907 DOI: 10.1172/jci.insight.178977] [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: 01/03/2024] [Accepted: 10/08/2024] [Indexed: 11/29/2024] Open
Abstract
Osteoclasts are the sole bone-resorbing cells and are formed by the fusion of osteoclast precursor cells (OCPs) derived from myeloid lineage cells. Animal studies reveal that circulating OCPs (cOCPs) in blood travel to bone and fuse with bone-resident osteoclasts. However, the characteristics of human cOCPs and their association with bone diseases remain elusive. We have identified and characterized human cOCPs and found a positive association between cOCPs and osteoclast activity. Sorted cOCPs have a higher osteoclastogenic potential than other myeloid cells and effectively differentiate into osteoclasts. cOCPs exhibit distinct morphology and transcriptomic signatures. The frequency of cOCPs in the blood varies among treatment-naive postmenopausal women and has an inverse correlation with lumbar spine bone density and a positive correlation with serum CTX, a bone resorption marker. The increased cOCPs in treatment-naive patients with osteoporosis were significantly diminished by denosumab, a widely used antiresorptive therapy. Our study reveals the distinctive identity of human cOCPs and the potential link between the dynamic regulation of cOCPs and osteoporosis and its treatment. Taken together, our study enhances our understanding of human cOCPs and highlights a potential opportunity to measure cOCPs through a simple blood test, which could potentially identify high-risk individuals.
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Affiliation(s)
- Kaichi Kaneko
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA
- Division of Rheumatology, Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Chiba, Japan
| | - Jefferson Tsai
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA
| | - Deniece Meñez
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA
| | - Brian Oh
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA
| | - Andrew Junwoo Suh
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA
| | - Seyeon Bae
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA
| | - Masataka Mizuno
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA
- SUNY Downstate Health Sciences University, Brooklyn, New York, USA
| | - Akio Umemoto
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA
| | - Eugenia Giannopoulou
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA
- Biological Sciences Department, New York City College of Technology, City University of New York, Brooklyn, New York, USA
| | - Takayuki Fujii
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA
| | - Yaxia Zhang
- Pathology and Laboratory Medicine, Hospital for Special Surgery, New York, New York, USA
- Pathology and Clinical Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Emily M. Stein
- Endocrine Service, Hospital for Special Surgery, New York, New York, USA
- Department of Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Richard S. Bockman
- Endocrine Service, Hospital for Special Surgery, New York, New York, USA
- Department of Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Kyung-Hyun Park-Min
- Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA
- Department of Medicine, Weill Cornell Medical College, New York, New York, USA
- BCMB Allied Program, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA
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Mannes M, Savukoski S, Ignatius A, Halbgebauer R, Huber-Lang M. Crepuscular rays - The bright side of complement after tissue injury. Eur J Immunol 2024; 54:e2350848. [PMID: 38794857 DOI: 10.1002/eji.202350848] [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: 02/16/2024] [Revised: 05/10/2024] [Accepted: 05/11/2024] [Indexed: 05/26/2024]
Abstract
Acute injuries trigger an intense activation of the body's defense mechanisms aiming to limit damage and initiate healing. Among the crucial components of the intravascular immune system, the complement system plays a significant role in traumatic injuries, albeit often negatively. It has been suggested that excessive activation of the complement system, transitioning from a localized and timed response to a systemic one, can lead to a loss of its host-protective characteristics. Complement activation products have been associated with the severity of injuries, which sometimes serve as predictors for the onset of organ dysfunctions. Animal studies utilizing complement-targeting agents have provided the basis for considering complement in the management of traumatic injuries in humans. However, numerous studies suggest that the spatial and temporal aspects of complement inhibition are crucial for its efficacy. Understanding the underlying mechanism of the injury is essential to determine where, when, and whether complement inhibition is warranted. Despite the detrimental effects of uncontrolled complement activation, its regulated activation may contribute to essential aspects of healing, such as waste removal and regeneration. This review focuses on the beneficial roles of complement activation in trauma, which are often overlooked or given less consideration but are of immense importance.
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Affiliation(s)
- Marco Mannes
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Susa Savukoski
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Anita Ignatius
- Institute for Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
| | - Rebecca Halbgebauer
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
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Gedam M, Zheng H. Complement C3aR signaling: Immune and metabolic modulation and its impact on Alzheimer's disease. Eur J Immunol 2024; 54:e2350815. [PMID: 38778507 PMCID: PMC11305912 DOI: 10.1002/eji.202350815] [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: 01/27/2024] [Revised: 04/23/2024] [Accepted: 04/24/2024] [Indexed: 05/25/2024]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia among the elderly population. Despite its widespread prevalence, our comprehension of the intricate mechanisms governing the pathogenesis of the disease remains incomplete, posing a challenge for the development of efficient therapies. Pathologically characterized by the presence of amyloid β plaques and neurofibrillary tau tangles, AD is also accompanied by the hyperactivation of glial cells and the immune system. The complement cascade, the evolutionarily conserved innate immune pathway, has emerged as a significant contributor to AD. This review focuses on one of the complement components, the C3a receptor (C3aR), covering its structure, ligand-receptor interaction, intracellular signaling and its functional consequences. Drawing insights from cellular and AD mouse model studies, we present the multifaceted role of complement C3aR signaling in AD and attempt to convey to the readers that C3aR acts as a crucial immune and metabolic modulator to influence AD pathogenesis. Building on this framework, the objective of this review is to inform future research endeavors and facilitate the development of therapeutic strategies for this challenging condition.
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Affiliation(s)
- Manasee Gedam
- Department of Molecular and Human Genetics, Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA
| | - Hui Zheng
- Department of Molecular and Human Genetics, Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA
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Feng D, Zhao H, Wang Q, Wu J, Ouyang L, Jia S, Lu Q, Zhao M. Aberrant H3K4me3 modification of immune response genes in CD4 + T cells of patients with systemic lupus erythematosus. Int Immunopharmacol 2024; 130:111748. [PMID: 38432146 DOI: 10.1016/j.intimp.2024.111748] [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: 08/22/2023] [Revised: 01/17/2024] [Accepted: 02/21/2024] [Indexed: 03/05/2024]
Abstract
BACKGROUND Increasing evidence has highlighted the significant role of histone modifications in pathogenesis of systemic lupus erythematosus (SLE). However, few studies have comprehensively analyzed trimethylation of histone H3 lysine 4 (H3K4me3) features at specific immune gene loci in SLE patients. METHODS We conducted H3K4me3 chromatin immunoprecipitation sequencing (ChIP-seq) on CD4+ T cells from SLE patients and healthy controls (HC). Differential H3K4me3 peaks were identified, followed by enrichment analysis. We integrated online RNA-seq and DNA methylation datasets to explore the relationship between H3K4me3 modification, DNA methylation and gene expression. We validated several upregulated peak regions by ChIP-qPCR and confirmed their impact on gene expression using RT-qPCR. Finally, we investigated the impact of H3K4 methyltransferases KMT2A on the expression of immune response genes. RESULTS we identified 147 downregulated and 2701 upregulated H3K4me3 peaks in CD4+ T cells of SLE. The upregulated peaks primarily classified as gained peaks and enriched in immune response genes such as FCGR2A, C5AR1, SERPING1 and OASL. Genes with upregulated H3K4me3 and downregulated DNA methylations in the promoter were highly expressed in SLE patients. These genes, including OAS1, IFI27 and IFI44L, were enriched in immune response pathways. The IFI44L locus also showed increased H3K27ac modification, chromatin accessibility and chromatin interactions in SLE. Moreover, knockdown of KMT2A can downregulate the expression of immune response genes in T cells. CONCLUSION Our study uncovers dysregulated H3K4me3 modification patterns in immune response genes loci, which also exhibit downregulated DNA methylation and higher mRNA expression in CD4+ T cells of SLE patients.
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Affiliation(s)
- Delong Feng
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Hongjun Zhao
- Department of Rheumatology, Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Qian Wang
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Jiali Wu
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Lianlian Ouyang
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Sujie Jia
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, China
| | - Qianjin Lu
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China; Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China
| | - Ming Zhao
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China; Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China.
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Buelli S, Imberti B, Morigi M. The Complement C3a and C5a Signaling in Renal Diseases: A Bridge between Acute and Chronic Inflammation. Nephron Clin Pract 2024; 148:712-723. [PMID: 38452744 DOI: 10.1159/000538241] [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: 09/21/2023] [Accepted: 03/04/2024] [Indexed: 03/09/2024] Open
Abstract
The complement system, a cornerstone of the innate immune defense, typically confers protection against pathogens. However, in various clinical scenarios the complement's defensive actions can harm host cells, exacerbating immune and inflammatory responses. The central components C3 and C5 undergo proteolytic cleavage during complement activation, yielding small active fragments C3a and C5a anaphylatoxins. Traditionally, these fragments were associated with inflammation via the specific receptors C3a receptor (R), C5aR1 and C5aR2. Recent insights, however, spotlight the excessive C3a/C3aR and C5a/C5aR1 signaling as culprits in diverse disorders of inflammatory and autoimmune etiology. This is particularly true for several kidney diseases, where the potential involvement of anaphylatoxins in renal damage is supported by the enhanced renal expression of their receptors and the high levels of C3a and C5a in both plasma and urine. Furthermore, the production of complement proteins in the kidney, with different renal cells synthesizing C3 and C5, significantly contributes to local tissue injury. In the present review, we discuss the different aspects of C3a/C3aR and C5a/C5aR signaling in acute and chronic kidney diseases and explore the therapeutic potential of emerging targeted drugs for future clinical applications.
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Affiliation(s)
- Simona Buelli
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Barbara Imberti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Marina Morigi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
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Mastellos DC, Hajishengallis G, Lambris JD. A guide to complement biology, pathology and therapeutic opportunity. Nat Rev Immunol 2024; 24:118-141. [PMID: 37670180 DOI: 10.1038/s41577-023-00926-1] [Citation(s) in RCA: 89] [Impact Index Per Article: 89.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/20/2023] [Indexed: 09/07/2023]
Abstract
Complement has long been considered a key innate immune effector system that mediates host defence and tissue homeostasis. Yet, growing evidence has illuminated a broader involvement of complement in fundamental biological processes extending far beyond its traditional realm in innate immunity. Complement engages in intricate crosstalk with multiple pattern-recognition and signalling pathways both in the extracellular and intracellular space. Besides modulating host-pathogen interactions, this crosstalk guides early developmental processes and distinct cell trajectories, shaping tissue immunometabolic and regenerative programmes in different physiological systems. This Review provides a guide to the system-wide functions of complement. It highlights illustrative paradigm shifts that have reshaped our understanding of complement pathobiology, drawing examples from evolution, development of the central nervous system, tissue regeneration and cancer immunity. Despite its tight spatiotemporal regulation, complement activation can be derailed, fuelling inflammatory tissue pathology. The pervasive contribution of complement to disease pathophysiology has inspired a resurgence of complement therapeutics with major clinical developments, some of which have challenged long-held dogmas. We thus highlight major therapeutic concepts and milestones in clinical complement intervention.
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Affiliation(s)
| | - George Hajishengallis
- Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - John D Lambris
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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Yadav MK, Maharana J, Yadav R, Saha S, Sarma P, Soni C, Singh V, Saha S, Ganguly M, Li XX, Mohapatra S, Mishra S, Khant HA, Chami M, Woodruff TM, Banerjee R, Shukla AK, Gati C. Molecular basis of anaphylatoxin binding, activation, and signaling bias at complement receptors. Cell 2023; 186:4956-4973.e21. [PMID: 37852260 PMCID: PMC7615941 DOI: 10.1016/j.cell.2023.09.020] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 07/19/2023] [Accepted: 09/20/2023] [Indexed: 10/20/2023]
Abstract
The complement system is a critical part of our innate immune response, and the terminal products of this cascade, anaphylatoxins C3a and C5a, exert their physiological and pathophysiological responses primarily via two GPCRs, C3aR and C5aR1. However, the molecular mechanism of ligand recognition, activation, and signaling bias of these receptors remains mostly elusive. Here, we present nine cryo-EM structures of C3aR and C5aR1 activated by their natural and synthetic agonists, which reveal distinct binding pocket topologies of complement anaphylatoxins and provide key insights into receptor activation and transducer coupling. We also uncover the structural basis of a naturally occurring mechanism to dampen the inflammatory response of C5a via proteolytic cleavage of the terminal arginine and the G-protein signaling bias elicited by a peptide agonist of C3aR identified here. In summary, our study elucidates the innerworkings of the complement anaphylatoxin receptors and should facilitate structure-guided drug discovery to target these receptors in a spectrum of disorders.
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Affiliation(s)
- Manish K Yadav
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India
| | - Jagannath Maharana
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India
| | - Ravi Yadav
- Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA; The Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA
| | - Shirsha Saha
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India
| | - Parishmita Sarma
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India
| | - Chahat Soni
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India
| | - Vinay Singh
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India
| | - Sayantan Saha
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India
| | - Manisankar Ganguly
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India
| | - Xaria X Li
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Samanwita Mohapatra
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India
| | - Sudha Mishra
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India
| | - Htet A Khant
- USC Center of Excellence for Nano-Imaging, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA
| | - Mohamed Chami
- BioEM Lab, Biozentrum, Universität Basel, Basel, Switzerland
| | - Trent M Woodruff
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Ramanuj Banerjee
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
| | - Arun K Shukla
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
| | - Cornelius Gati
- Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA; The Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA; Department of Chemistry, Department of Quantitative and Computational Biology, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, USA.
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10
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Kareem S, Jacob A, Mathew J, Quigg RJ, Alexander JJ. Complement: Functions, location and implications. Immunology 2023; 170:180-192. [PMID: 37222083 PMCID: PMC10524990 DOI: 10.1111/imm.13663] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 05/09/2023] [Indexed: 05/25/2023] Open
Abstract
The complement system, an arm of the innate immune system plays a critical role in both health and disease. The complement system is highly complex with dual possibilities, helping or hurting the host, depending on the location and local microenvironment. The traditionally known functions of complement include surveillance, pathogen recognition, immune complex trafficking, processing and pathogen elimination. The noncanonical functions of the complement system include their roles in development, differentiation, local homeostasis and other cellular functions. Complement proteins are present in both, the plasma and on the membranes. Complement activation occurs both extra- and intracellularly, which leads to considerable pleiotropy in their activity. In order to design more desirable and effective therapies, it is important to understand the different functions of complement, and its location-based and tissue-specific responses. This manuscript will provide a brief overview into the complex nature of the complement cascade, outlining some of their complement-independent functions, their effects at different locale, and their implication in disease settings.
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Affiliation(s)
- Samer Kareem
- Department of Medicine, University at Buffalo, Buffalo, New York, United States
| | - Alexander Jacob
- Department of Medicine, University at Buffalo, Buffalo, New York, United States
| | - John Mathew
- Department of Rheumatology, Christian Medical College, Vellore, India
| | - Richard J Quigg
- Department of Medicine, University at Buffalo, Buffalo, New York, United States
| | - Jessy J Alexander
- Department of Medicine, University at Buffalo, Buffalo, New York, United States
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11
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Zarantonello A, Revel M, Grunenwald A, Roumenina LT. C3-dependent effector functions of complement. Immunol Rev 2023; 313:120-138. [PMID: 36271889 PMCID: PMC10092904 DOI: 10.1111/imr.13147] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
C3 is the central effector molecule of the complement system, mediating its multiple functions through different binding sites and their corresponding receptors. We will introduce the C3 forms (native C3, C3 [H2 O], and intracellular C3), the C3 fragments C3a, C3b, iC3b, and C3dg/C3d, and the C3 expression sites. To highlight the important role that C3 plays in human biological processes, we will give an overview of the diseases linked to C3 deficiency and to uncontrolled C3 activation. Next, we will present a structural description of C3 activation and of the C3 fragments generated by complement regulation. We will proceed by describing the C3a interaction with the anaphylatoxin receptor, followed by the interactions of opsonins (C3b, iC3b, and C3dg/C3d) with complement receptors, divided into two groups: receptors bearing complement regulatory functions and the effector receptors without complement regulatory activity. We outline the molecular architecture of the receptors, their binding sites on the C3 activation fragments, the cells expressing them, the diversity of their functions, and recent advances. With this review, we aim to give an up-to-date analysis of the processes triggered by C3 activation fragments on different cell types in health and disease contexts.
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Affiliation(s)
- Alessandra Zarantonello
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France
| | - Margot Revel
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France
| | - Anne Grunenwald
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France
| | - Lubka T Roumenina
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France
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12
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Zhao SJ, Wu KY, Min XY, Wang CX, Cao B, Ma N, Yang XL, Zhu ZR, Fu RG, Zhou W, Yang JR, Li K. Protective role for C3aR in experimental chronic pyelonephritis. FASEB J 2022; 36:e22599. [PMID: 36250902 DOI: 10.1096/fj.202201007r] [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: 06/30/2022] [Revised: 09/05/2022] [Accepted: 09/26/2022] [Indexed: 11/11/2022]
Abstract
Emerging evidence suggest that C3aR plays important roles in homeostasis, host defense and disease. Although it is known that C3aR is protective in several models of acute bacterial infections, the role for C3aR in chronic infection is largely unknown. Here we show that C3aR is protective in experimental chronic pyelonephritis. Global C3aR deficient (C3ar-/- ) mice had higher renal bacterial load, more pronounced renal histological lesions, increased renal apoptotic cell accumulation, tissue inflammation and extracellular matrix deposition following renal infection with uropathogenic E. coli (UPEC) strain IH11128, compared to WT control mice. Myeloid C3aR deficient (Lyz2-C3ar-/- ) mice exhibited a similar disease phenotype to global C3ar-/- mice. Pharmacological treatment with a C3aR agonist reduced disease severity in experimental chronic pyelonephritis. Furthermore, macrophages of C3ar-/- mice exhibited impaired ability to phagocytose UPEC. Our data clearly demonstrate a protective role for C3aR against experimental chronic pyelonephritis, macrophage C3aR plays a major role in the protection, and C3aR is necessary for phagocytosis of UPEC by macrophages. Our observation that C3aR agonist curtailed the pathology suggests a therapeutic potential for activation of C3aR in chronic infection.
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Affiliation(s)
- Shu-Juan Zhao
- Core Research Laboratory, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Kun-Yi Wu
- Core Research Laboratory, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Xiao-Yun Min
- Core Research Laboratory, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Chun-Xuan Wang
- Department of Nephrology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bo Cao
- Core Research Laboratory, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Ning Ma
- Core Research Laboratory, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Xue-Ling Yang
- Department of Nephrology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhuo-Ran Zhu
- Core Research Laboratory, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Rong-Guo Fu
- Department of Nephrology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wuding Zhou
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King's College, London, UK
| | - Ju-Rong Yang
- Department of Nephrology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ke Li
- Core Research Laboratory, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
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13
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Shende R, Wong SSW, Meitei HT, Lal G, Madan T, Aimanianda V, Pal JK, Sahu A. Protective role of host complement system in Aspergillus fumigatus infection. Front Immunol 2022; 13:978152. [PMID: 36211424 PMCID: PMC9539816 DOI: 10.3389/fimmu.2022.978152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 09/05/2022] [Indexed: 11/25/2022] Open
Abstract
Invasive aspergillosis (IA) is a life-threatening fungal infection for immunocompromised hosts. It is, therefore, necessary to understand the immune pathways that control this infection. Although the primary infection site is the lungs, aspergillosis can disseminate to other organs through unknown mechanisms. Herein we have examined the in vivo role of various complement pathways as well as the complement receptors C3aR and C5aR1 during experimental systemic infection by Aspergillus fumigatus, the main species responsible for IA. We show that C3 knockout (C3-/-) mice are highly susceptible to systemic infection of A. fumigatus. Intriguingly, C4-/- and factor B (FB)-/- mice showed susceptibility similar to the wild-type mice, suggesting that either the complement pathways display functional redundancy during infection (i.e., one pathway compensates for the loss of the other), or complement is activated non-canonically by A. fumigatus protease. Our in vitro study substantiates the presence of C3 and C5 cleaving proteases in A. fumigatus. Examination of the importance of the terminal complement pathway employing C5-/- and C5aR1-/- mice reveals that it plays a vital role in the conidial clearance. This, in part, is due to the increased conidial uptake by phagocytes. Together, our data suggest that the complement deficiency enhances the susceptibility to systemic infection by A. fumigatus.
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Affiliation(s)
- Rajashri Shende
- Complement Biology Laboratory, National Centre for Cell Science, Savitribai Phule (S. P.) Pune University Campus, Pune, India
- Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pune, India
| | - Sarah Sze Wah Wong
- Institut Pasteur, Université Paris Cité, CNRS UMR2000, Unité Mycologie Moléculaire, Department of Mycology, Paris, France
| | - Heikrujam Thoihen Meitei
- Laboratory of Autoimmunity and Tolerance, National Centre for Cell Science, Savitribai Phule (S. P.) Pune University Campus, Pune, India
| | - Girdhari Lal
- Laboratory of Autoimmunity and Tolerance, National Centre for Cell Science, Savitribai Phule (S. P.) Pune University Campus, Pune, India
| | - Taruna Madan
- Department of Innate Immunity, ICMR – National Institute for Research in Reproductive and Child Health, Mumbai, India
| | - Vishukumar Aimanianda
- Institut Pasteur, Université Paris Cité, CNRS UMR2000, Unité Mycologie Moléculaire, Department of Mycology, Paris, France
- *Correspondence: Arvind Sahu, ; Vishukumar Aimanianda,
| | - Jayanta Kumar Pal
- Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pune, India
| | - Arvind Sahu
- Complement Biology Laboratory, National Centre for Cell Science, Savitribai Phule (S. P.) Pune University Campus, Pune, India
- *Correspondence: Arvind Sahu, ; Vishukumar Aimanianda,
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14
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Krieg C, Weber LM, Fosso B, Marzano M, Hardiman G, Olcina MM, Domingo E, El Aidy S, Mallah K, Robinson MD, Guglietta S. Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy. J Immunother Cancer 2022; 10:e004717. [PMID: 36137652 PMCID: PMC9511657 DOI: 10.1136/jitc-2022-004717] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/29/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND AND AIMS The role of inflammatory immune responses in colorectal cancer (CRC) development and response to therapy is a matter of intense debate. While inflammation is a known driver of CRC, inflammatory immune infiltrates are a positive prognostic factor in CRC and predispose to response to immune checkpoint blockade (ICB) therapy. Unfortunately, over 85% of CRC cases are primarily unresponsive to ICB due to the absence of an immune infiltrate, and even the cases that show an initial immune infiltration can become refractory to ICB. The identification of therapy supportive immune responses in the field has been partially hindered by the sparsity of suitable mouse models to recapitulate the human disease. In this study, we aimed to understand how the dysregulation of the complement anaphylatoxin C3a receptor (C3aR), observed in subsets of patients with CRC, affects the immune responses, the development of CRC, and response to ICB therapy. METHODS We use a comprehensive approach encompassing analysis of publicly available human CRC datasets, inflammation-driven and newly generated spontaneous mouse models of CRC, and multiplatform high-dimensional analysis of immune responses using microbiota sequencing, RNA sequencing, and mass cytometry. RESULTS We found that patients' regulation of the complement C3aR is associated with epigenetic modifications. Specifically, downregulation of C3ar1 in human CRC promotes a tumor microenvironment characterized by the accumulation of innate and adaptive immune cells that support antitumor immunity. In addition, in vivo studies in our newly generated mouse model revealed that the lack of C3a in the colon activates a microbiota-mediated proinflammatory program which promotes the development of tumors with an immune signature that renders them responsive to the ICB therapy. CONCLUSIONS Our findings reveal that C3aR may act as a previously unrecognized checkpoint to enhance antitumor immunity in CRC. C3aR can thus be exploited to overcome ICB resistance in a larger group of patients with CRC.
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Affiliation(s)
- Carsten Krieg
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
- Hollings Cancer Center Charleston, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Lukas M Weber
- Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
- SIB Swiss Institute of Bioinformatics, University of Zurich, Zurich, Switzerland
| | - Bruno Fosso
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, Bari, Italy
| | - Marinella Marzano
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, Bari, Italy
| | - Gary Hardiman
- School of Biological Sciences and Institute for Global Food Security, Queens University of Belfast, Belfast, UK
| | - Monica M Olcina
- Institute of Radiation Oncology, Medical Research Council Oxford Institute for Radiation Oncology, Oxford, UK
| | - Enric Domingo
- Institute of Radiation Oncology, Medical Research Council Oxford Institute for Radiation Oncology, Oxford, UK
| | - Sahar El Aidy
- Host-microbe Metabolic Interactions, Microbiology, University of Groningen, Groningen, The Netherlands
| | - Khalil Mallah
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Mark D Robinson
- Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
- SIB Swiss Institute of Bioinformatics, University of Zurich, Zurich, Switzerland
| | - Silvia Guglietta
- Hollings Cancer Center Charleston, Medical University of South Carolina, Charleston, South Carolina, USA
- Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, USA
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
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15
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The Complement System, Aging, and Aging-Related Diseases. Int J Mol Sci 2022; 23:ijms23158689. [PMID: 35955822 PMCID: PMC9369321 DOI: 10.3390/ijms23158689] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/03/2022] [Accepted: 08/03/2022] [Indexed: 12/10/2022] Open
Abstract
The complement system is a part of the immune system and consists of multiple complement components with biological functions such as defense against pathogens and immunomodulation. The complement system has three activation pathways: the classical pathway, the lectin pathway, and the alternative pathway. Increasing evidence indicates that the complement system plays a role in aging. Complement plays a role in inflammatory processes, metabolism, apoptosis, mitochondrial function, and Wnt signaling pathways. In addition, the complement system plays a significant role in aging-related diseases, including Alzheimer’s disease, age-related macular degeneration, and osteoarthritis. However, the effect of complement on aging and aging-related diseases is still unclear. Thus, a better understanding of the potential relationship between complement, aging, and aging-related diseases will provide molecular targets for treating aging, while focusing on the balance of complement in during treatment. Inhibition of a single component does not result in a good outcome. In this review, we discussed the research progress and effects of complement in aging and aging-related diseases.
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16
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Abstract
Activation of the complement pathway results in the production of bioactive C3a, a product of C3 cleavage, which interacts with membrane-bound receptor C3aR to regulate innate immune cell function and outcome of bacterial infection. Specifically, previous research has identified mechanistically distinct and cell type–specific roles for C3aR in regulating innate immune cell inflammatory state, antimicrobial killing capacity, and metabolism. Historically, the production of C3a has been relegated to the serum; however, recent studies have provided evidence that various cell types can produce intracellular C3a that stimulates intracellular C3aR. In light of these new results, it is imperative that we revisit previous studies regarding the role of C3aR in controlling bacterial infections and analyze these results in the context of both extracellular and intracellular C3a production and C3aR activation. Thus, this review will cover specific roles of C3aR in driving cell type–specific and tissue specific responses during bacterial infections and emphasize the contribution of the C3a–C3aR axis in regulating host resistance to bacterial infection.
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Affiliation(s)
- Jesse A. Corcoran
- Department of Biology and Center for Life in Extreme Environments, Portland State University, Portland, Oregon, United States of America
| | - Brooke A. Napier
- Department of Biology and Center for Life in Extreme Environments, Portland State University, Portland, Oregon, United States of America
- * E-mail:
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17
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Schanzenbacher J, Köhl J, Karsten CM. Anaphylatoxins spark the flame in early autoimmunity. Front Immunol 2022; 13:958392. [PMID: 35958588 PMCID: PMC9358992 DOI: 10.3389/fimmu.2022.958392] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 06/29/2022] [Indexed: 11/13/2022] Open
Abstract
The complement system (CS) is an ancient and highly conserved part of the innate immune system with important functions in immune defense. The multiple fragments bind to specific receptors on innate and adaptive immune cells, the activation of which translates the initial humoral innate immune response (IR) into cellular innate and adaptive immunity. Dysregulation of the CS has been associated with the development of several autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ANCA-associated vasculitis, and autoimmune bullous dermatoses (AIBDs), where complement drives the inflammatory response in the effector phase. The role of the CS in autoimmunity is complex. On the one hand, complement deficiencies were identified as risk factors to develop autoimmune disorders. On the other hand, activation of complement can drive autoimmune responses. The anaphylatoxins C3a and C5a are potent mediators and regulators of inflammation during the effector phase of autoimmunity through engagement of specific anaphylatoxin receptors, i.e., C3aR, C5aR1, and C5aR2 either on or in immune cells. In addition to their role in innate IRs, anaphylatoxins regulate humoral and cellular adaptive IRs including B-cell and T-cell activation, differentiation, and survival. They regulate B- and T-lymphocyte responses either directly or indirectly through the activation of anaphylatoxin receptors via dendritic cells that modulate lymphocyte function. Here, we will briefly review our current understanding of the complex roles of anaphylatoxins in the regulation of immunologic tolerance and the early events driving autoimmunity and the implications of such regulation for therapeutic approaches that target the CS.
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Affiliation(s)
- Jovan Schanzenbacher
- Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
| | - Jörg Köhl
- Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
- Division of Immunobiology, Cincinnati Childrens Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Christian M. Karsten
- Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
- *Correspondence: Christian M. Karsten,
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18
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Zhang L, Li W, Gong M, Zhang Z, Xue X, Mao J, Zhang H, Li S, Liu X, Wu F, Shi J, Fu G. C-reactive protein inhibits C3a/C3aR-dependent podocyte autophagy in favor of diabetic kidney disease. FASEB J 2022; 36:e22332. [PMID: 35503088 DOI: 10.1096/fj.202200198r] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/28/2022] [Accepted: 04/18/2022] [Indexed: 12/24/2022]
Abstract
Numerous studies have reported the pathogenic roles of C-reactive protein (CRP) and complement activation in diabetic kidney disease (DKD) individually. However, considering the potent regulatory effect of CRP on complement activation, it remains unclear whether CRP participates in DKD pathogenesis by regulating complement activation. Moreover, this work focuses on complement activation in rats, which aims at settling the dispute that whether rat CRP can activate the complement system. To address this question, the complement effectors C3a, C5a, and C5b-9 were examined in human patients with diabetic nephropathy (DN) and wt, Crp-/- , and huCRPtg rats with STZ-diabetic DKD. The Crp-/- rats showed more C3a accumulation in blood and glomeruli than wt and huCRPtg rats. The balance between autophagy and apoptosis was evaluated in DKD rats, and Crp-/- rats showed increased podocyte autophagy compared with wt and huCRPtg rats. Meanwhile, stable CRP-overexpression and CRP-knockout cell lines were established and used to demonstrate that CRP suppresses C3a-induced podocyte autophagy under high-glucose conditions. We further verified that the inhibition of C3a-induced podocyte autophagy by CRP was dependent on C3aR expression and that this effect could be reversed with a C3aR antagonist and agonist. Therefore, our findings provide evidence that CRP suppresses podocyte autophagy to accelerate the development of DKD by inhibiting C3a/C3aR axis signaling, which may help in the development of a new therapeutic strategy for the management of podocyte autophagy and DKD. In addition, rat CRP has been shown to be identical to human CRP in the activation of autologous complement and interspecific complement.
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Affiliation(s)
- Lin Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Wei Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Minjie Gong
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Zeyu Zhang
- School of Basic Medicine, Xizang Minzu University, Xianyang, China
| | - Xiaodong Xue
- School of Computer Science, National University of Singapore, Singapore, Singapore
| | - Jiarong Mao
- Department of pathology, Shaanxi Provincial Hospital of Chinese Medicine, Xi'an, China
| | - Haibao Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Siqi Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Xiawan Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Feng Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Jingming Shi
- School of Basic Medicine, Xizang Minzu University, Xianyang, China
| | - Guorong Fu
- Department of Nephrology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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19
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Qiao P, Zhi D, Yu C, Zhang C, Wu K, Fang H, Shao S, Yin W, Dang E, Li K, Wang G. Activation of the C3a anaphylatoxin receptor inhibits keratinocyte proliferation by regulating keratin 6, keratin 16, and keratin 17 in psoriasis. FASEB J 2022; 36:e22322. [PMID: 35429062 DOI: 10.1096/fj.202101458r] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 03/29/2022] [Accepted: 04/07/2022] [Indexed: 11/11/2022]
Affiliation(s)
- Pei Qiao
- Department of Dermatology Xijing Hospital Fourth Military Medical University Xi'an China
- Department of Transfusion Medicine Xijing Hospital Fourth Military Medical University Xi'an China
| | - Dalong Zhi
- Department of Dermatology Xijing Hospital Fourth Military Medical University Xi'an China
| | - Chen Yu
- Department of Dermatology Xijing Hospital Fourth Military Medical University Xi'an China
| | - Chen Zhang
- Department of Dermatology Xijing Hospital Fourth Military Medical University Xi'an China
| | - Kunyi Wu
- Core Research Laboratory The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University Xi'an China
| | - Hui Fang
- Department of Dermatology Xijing Hospital Fourth Military Medical University Xi'an China
| | - Shuai Shao
- Department of Dermatology Xijing Hospital Fourth Military Medical University Xi'an China
| | - Wen Yin
- Department of Transfusion Medicine Xijing Hospital Fourth Military Medical University Xi'an China
| | - Erle Dang
- Department of Dermatology Xijing Hospital Fourth Military Medical University Xi'an China
| | - Ke Li
- Core Research Laboratory The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University Xi'an China
| | - Gang Wang
- Department of Dermatology Xijing Hospital Fourth Military Medical University Xi'an China
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20
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Liao S, Luo J, Kadier T, Ding K, Chen R, Meng Q. Mitochondrial DNA Release Contributes to Intestinal Ischemia/Reperfusion Injury. Front Pharmacol 2022; 13:854994. [PMID: 35370747 PMCID: PMC8966724 DOI: 10.3389/fphar.2022.854994] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 03/02/2022] [Indexed: 12/12/2022] Open
Abstract
Mitochondria release many damage-associated molecular patterns (DAMPs) when cells are damaged or stressed, with mitochondrial DNA (mtDNA) being. MtDNA activates innate immune responses and induces inflammation through the TLR-9, NLRP3 inflammasome, and cGAS-STING signaling pathways. Released inflammatory factors cause damage to intestinal barrier function. Many bacteria and endotoxins migrate to the circulatory system and lymphatic system, leading to systemic inflammatory response syndrome (SIRS) and even damaging the function of multiple organs throughout the body. This process may ultimately lead to multiple organ dysfunction syndrome (MODS). Recent studies have shown that various factors, such as the release of mtDNA and the massive infiltration of inflammatory factors, can cause intestinal ischemia/reperfusion (I/R) injury. This destroys intestinal barrier function, induces an inflammatory storm, leads to SIRS, increases the vulnerability of organs, and develops into MODS. Mitophagy eliminates dysfunctional mitochondria to maintain cellular homeostasis. This review discusses mtDNA release during the pathogenesis of intestinal I/R and summarizes methods for the prevention or treatment of intestinal I/R. We also discuss the effects of inflammation and increased intestinal barrier permeability on drugs.
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Affiliation(s)
- Shishi Liao
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jie Luo
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Tulanisa Kadier
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ke Ding
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Rong Chen
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.,Department of Anesthesiology, East Hospital, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qingtao Meng
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.,Department of Anesthesiology, East Hospital, Renmin Hospital of Wuhan University, Wuhan, China
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21
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Torp MK, Ranheim T, Schjalm C, Hjorth M, Heiestad C, Dalen KT, Nilsson PH, Mollnes TE, Pischke SE, Lien E, Vaage J, Yndestad A, Stensløkken KO. Intracellular Complement Component 3 Attenuated Ischemia-Reperfusion Injury in the Isolated Buffer-Perfused Mouse Heart and Is Associated With Improved Metabolic Homeostasis. Front Immunol 2022; 13:870811. [PMID: 35432387 PMCID: PMC9011808 DOI: 10.3389/fimmu.2022.870811] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 03/08/2022] [Indexed: 12/25/2022] Open
Abstract
The innate immune system is rapidly activated during myocardial infarction and blockade of extracellular complement system reduces infarct size. Intracellular complement, however, appears to be closely linked to metabolic pathways and its role in ischemia-reperfusion injury is unknown and may be different from complement activation in the circulation. The purpose of the present study was to investigate the role of intracellular complement in isolated, retrogradely buffer-perfused hearts and cardiac cells from adult male wild type mice (WT) and from adult male mice with knockout of complement component 3 (C3KO). Main findings: (i) Intracellular C3 protein was expressed in isolated cardiomyocytes and in whole hearts, (ii) after ischemia-reperfusion injury, C3KO hearts had larger infarct size (32 ± 9% in C3KO vs. 22 ± 7% in WT; p=0.008) and impaired post-ischemic relaxation compared to WT hearts, (iii) C3KO cardiomyocytes had lower basal oxidative respiration compared to WT cardiomyocytes, (iv) blocking mTOR decreased Akt phosphorylation in WT, but not in C3KO cardiomyocytes, (v) after ischemia, WT hearts had higher levels of ATP, but lower levels of both reduced and oxidized nicotinamide adenine dinucleotide (NADH and NAD+, respectively) compared to C3KO hearts. Conclusion: intracellular C3 protected the heart against ischemia-reperfusion injury, possibly due to its role in metabolic pathways important for energy production and cell survival.
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Affiliation(s)
- M-K. Torp
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
- *Correspondence: M-K. Torp,
| | - T. Ranheim
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
- Division of Surgery, Inflammatory Diseases and Transplantation, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - C. Schjalm
- Department of Immunology, Institute of Clinical Medicine University of Oslo, Oslo, Norway
| | - M. Hjorth
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - C.M. Heiestad
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - K. T. Dalen
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - P. H. Nilsson
- Department of Immunology, Institute of Clinical Medicine University of Oslo, Oslo, Norway
- Linnaeus Centre for Biomaterials Chemistry, and the Department of Chemistry and Biomedicine, Linnaeus University, Kalmar, Sweden
| | - T. E. Mollnes
- Department of Immunology, Institute of Clinical Medicine University of Oslo, Oslo, Norway
- Stiftelsen Kristian Gerhard Jebsen (K.G. Jebsen) Inflammation Research Center (IRC), University of Oslo, Oslo, Norway
- Research Laboratory, Nordland Hospital, Bodø, and Faculty of Health Sciences, Stiftelsen Kristian Gerhard Jebsen (K.G. Jebsen) Thrombosis Research and Expertise Center (TREC), University of Tromsø, Tromsø, Norway
- Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - S. E. Pischke
- Department of Immunology, Institute of Clinical Medicine University of Oslo, Oslo, Norway
- Department of Research & Development, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway
| | - E. Lien
- Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- Division of Infectious Diseases and Immunology, Program in Innate Immunity, Department of Medicine, UMass Medical School, Worchester, MA, United States
| | - J. Vaage
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
- Department of Research & Development, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - A. Yndestad
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
| | - K-O. Stensløkken
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
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22
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Mogilenko DA, Danko K, Larionova EE, Shavva VS, Kudriavtsev IV, Nekrasova EV, Burnusuz AV, Gorbunov NP, Trofimov AV, Zhakhov AV, Ivanov IA, Orlov SV. Differentiation of human macrophages with anaphylatoxin C3a impairs alternative M2 polarization and decreases lipopolysaccharide‐induced cytokine secretion. Immunol Cell Biol 2022; 100:186-204. [DOI: 10.1111/imcb.12534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 01/06/2022] [Accepted: 02/07/2022] [Indexed: 11/28/2022]
Affiliation(s)
- Denis A Mogilenko
- Department of Biochemistry Institute of Experimental Medicine St. Petersburg Russia
- Department of Embryology St. Petersburg State University St. Petersburg Russia
| | - Katerina Danko
- Department of Biochemistry Institute of Experimental Medicine St. Petersburg Russia
- Department of Cytology and Histology St. Petersburg State University St. Petersburg Russia
| | | | - Vladimir S Shavva
- Department of Biochemistry Institute of Experimental Medicine St. Petersburg Russia
| | - Igor V Kudriavtsev
- Department of Cytology and Histology St. Petersburg State University St. Petersburg Russia
- Department of Immunology Institute of Experimental Medicine St. Petersburg Russia
| | | | - Alexandra V Burnusuz
- Department of Biochemistry Institute of Experimental Medicine St. Petersburg Russia
- Department of Cytology and Histology St. Petersburg State University St. Petersburg Russia
- Department of Immunology Institute of Experimental Medicine St. Petersburg Russia
| | - Nikolay P Gorbunov
- The Research Institute of Highly Pure Biopreparations St. Petersburg Russia
| | | | | | | | - Sergey V Orlov
- Department of Biochemistry Institute of Experimental Medicine St. Petersburg Russia
- Department of Embryology St. Petersburg State University St. Petersburg Russia
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23
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Promotion of the inflammatory response in mid colon of complement component 3 knockout mice. Sci Rep 2022; 12:1700. [PMID: 35105928 PMCID: PMC8807838 DOI: 10.1038/s41598-022-05708-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 01/17/2022] [Indexed: 12/14/2022] Open
Abstract
To determine whether complement component 3 (C3) deficiency affects its receptor downstream-mediated inflammatory response, the current study was undertaken to measure alterations in the inducible nitric oxide synthase (iNOS)‑mediated cyclooxygenase‑2 (COX‑2) induction pathway, inflammasome pathway, nuclear factor-κB (NF-κB) activation, and inflammatory cytokine expressions in the mid colon of C3 knockout (KO) mice. Significant enhancement was observed in expressions of key components of the iNOS‑mediated COX‑2 induction pathway, and in the phosphorylation of mitogen‑activated protein (MAP) kinase members. A similar pattern of increase was also observed in the expression levels of inflammasome proteins in C3 KO mice. Moreover, compared to WT mice, C3 KO mice showed remarkably enhanced phosphorylation of NF-κB and Inhibitor of κB-α (IκB-α), which was reflected in entirety as increased expressions of Tumor necrosis factor (TNF), IL-6 and IL-1α. However, the levels of E-cadherin, tight junction channels and ion channels expressions were lower in the C3 KO mice, although myeloperoxidase (MPO) activity for neutrophils was slightly increased. Taken together, results of the current study indicate that C3 deficiency promotes inflammatory responses in the mid colon of C3 KO mice through activation of the iNOS‑mediated COX‑2 induction pathway, Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)-inflammasome pathway and NF-κB signaling pathway, and the enhancement of inflammatory cytokine expressions.
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24
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Reno TA, Tarnus L, Tracy R, Landay AL, Sereti I, Apetrei C, Pandrea I. The Youngbloods. Get Together. Hypercoagulation, Complement, and NET Formation in HIV/SIV Pathogenesis. FRONTIERS IN VIROLOGY 2022. [DOI: 10.3389/fviro.2021.795373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Chronic, systemic T-cell immune activation and inflammation (IA/INFL) have been reported to be associated with disease progression in persons with HIV (PWH) since the inception of the AIDS pandemic. IA/INFL persist in PWH on antiretroviral therapy (ART), despite complete viral suppression and increases their susceptibility to serious non-AIDS events (SNAEs). Increased IA/INFL also occur during pathogenic SIV infections of macaques, while natural hosts of SIVs that control chronic IA/INFL do not progress to AIDS, despite having persistent high viral replication and severe acute CD4+ T-cell loss. Moreover, natural hosts of SIVs do not present with SNAEs. Multiple mechanisms drive HIV-associated IA/INFL, including the virus itself, persistent gut dysfunction, coinfections (CMV, HCV, HBV), proinflammatory lipids, ART toxicity, comorbidities, and behavioral factors (diet, smoking, and alcohol). Other mechanisms could also significantly contribute to IA/INFL during HIV/SIV infection, notably, a hypercoagulable state, characterized by elevated coagulation biomarkers, including D-dimer and tissue factor, which can accurately identify patients at risk for thromboembolic events and death. Coagulation biomarkers strongly correlate with INFL and predict the risk of SNAE-induced end-organ damage. Meanwhile, the complement system is also involved in the pathogenesis of HIV comorbidities. Despite prolonged viral suppression, PWH on ART have high plasma levels of C3a. HIV/SIV infections also trigger neutrophil extracellular traps (NETs) formation that contribute to the elimination of viral particles and infected CD4+ T-cells. However, as SIV infection progresses, generation of NETs can become excessive, fueling IA/INFL, destruction of multiple immune cells subsets, and microthrombotic events, contributing to further tissue damages and SNAEs. Tackling residual IA/INFL has the potential to improve the clinical course of HIV infection. Therefore, therapeutics targeting new pathways that can fuel IA/INFL such as hypercoagulation, complement activation and excessive formation of NETs might be beneficial for PWH and should be considered and evaluated.
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25
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Cui CS, Kumar V, Gorman DM, Clark RJ, Lee JD, Woodruff TM. In Vivo Pharmacodynamic Method to Assess Complement C5a Receptor Antagonist Efficacy. ACS Pharmacol Transl Sci 2022; 5:41-51. [PMID: 35059568 DOI: 10.1021/acsptsci.1c00227] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Indexed: 12/17/2022]
Abstract
The complement C5a receptor 1 (C5aR1) has been studied as a potential therapeutic target for autoimmune and inflammatory diseases, with several drug candidates identified. Understanding the pharmacokinetics and pharmacodynamics of a drug candidate is a crucial preclinical step that allows for a greater understanding of a compound's in vivo biodistribution and target engagement to assist in clinical dose selection and dosing frequency. However, few in vivo pharmacodynamic methods have been described for C5a inhibitors. In this study, we, therefore, developed a complete in vivo pharmacodynamic assay in mice and applied this method to the peptide-based C5aR1 antagonists PMX53 and JPE-1375. Intravenous administration of recombinant mouse C5a induced rapid neutrophil mobilization and plasma TNF elevation over a 60 min period. By using C5a receptor-deficient mice, we demonstrated that this response was driven primarily through C5aR1. We next identified using this model that both PMX53 and JPE-1375 have similar in vivo working doses that can inhibit C5aR1-mediated neutrophilia and cytokine production in a dose as low as 1 mg/kg following intravenous injection. However, the in vivo active duration for PMX53 lasted for up to 6 h, significantly longer than that for JPE-1375 (<2 h). Pharmacokinetic analysis demonstrated rapid plasma distribution and elimination of both compounds, although PMX53 had a longer half-life, which allowed for the development of an accurate pharmacokinetic/pharmacodynamic model. Overall, our study developed a robust in vivo pharmacodynamic model for C5aR1 inhibitors in mice that may assist in preclinical translational studies of therapeutic drug candidates targeting C5a and its receptors.
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Affiliation(s)
- Cedric S Cui
- School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
| | - Vinod Kumar
- School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
| | - Declan M Gorman
- School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
| | - Richard J Clark
- School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
| | - John D Lee
- School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
| | - Trent M Woodruff
- School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.,Queensland Brain Institute, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
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26
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Muldur S, Vadysirisack DD, Ragunathan S, Tang Y, Ricardo A, Sayegh CE, Irimia D. Human Neutrophils Respond to Complement Activation and Inhibition in Microfluidic Devices. Front Immunol 2021; 12:777932. [PMID: 34899737 PMCID: PMC8653703 DOI: 10.3389/fimmu.2021.777932] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 10/29/2021] [Indexed: 12/30/2022] Open
Abstract
Complement activation is key to anti-microbial defenses by directly acting on microbes and indirectly by triggering cellular immune responses. Complement activation may also contribute to the pathogenesis of numerous inflammatory and immunological diseases. Consequently, intense research focuses on developing therapeutics that block pathology-causing complement activation while preserving anti-microbial complement activities. However, the pace of research is slowed down significantly by the limitations of current tools for evaluating complement-targeting therapeutics. Moreover, the effects of potential therapeutic agents on innate immune cells, like neutrophils, are not fully understood. Here, we employ microfluidic assays and measure chemotaxis, phagocytosis, and swarming changes in human neutrophils ex vivo in response to various complement-targeting agents. We show that whereas complement factor 5 (C5) cleavage inhibitor eculizumab blocks all neutrophil anti-microbial functions, newer compounds like the C5 cleavage inhibitor RA101295 and C5a receptor antagonist avacopan inhibit chemotaxis and swarming while preserving neutrophil phagocytosis. These results highlight the utility of microfluidic neutrophil assays in evaluating potential complement-targeting therapeutics.
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Affiliation(s)
- Sinan Muldur
- BioMEMS Resource Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.,Shriners Burns Hospital, Boston, MA, United States
| | | | | | - Yalan Tang
- Ra Pharmaceuticals, Inc., Cambridge, MA, United States
| | | | | | - Daniel Irimia
- BioMEMS Resource Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.,Shriners Burns Hospital, Boston, MA, United States
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27
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Propson NE, Roy ER, Litvinchuk A, Köhl J, Zheng H. Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging. J Clin Invest 2021; 131:140966. [PMID: 32990682 DOI: 10.1172/jci140966] [Citation(s) in RCA: 147] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 09/23/2020] [Indexed: 12/21/2022] Open
Abstract
Dysfunction of immune and vascular systems has been implicated in aging and Alzheimer disease; however, their interrelatedness remains poorly understood. The complement pathway is a well-established regulator of innate immunity in the brain. Here, we report robust age-dependent increases in vascular inflammation, peripheral lymphocyte infiltration, and blood-brain barrier (BBB) permeability. These phenotypes were subdued by global inactivation and by endothelial cell-specific ablation of C3ar1. Using an in vitro model of the BBB, we identified intracellular Ca2+ as a downstream effector of C3a/C3aR signaling and a functional mediator of vascular endothelial cadherin junction and barrier integrity. Endothelial C3ar1 inactivation also dampened microglia reactivity and improved hippocampal and cortical volumes in the aging brain, demonstrating a crosstalk between brain vasculature dysfunction and immune cell activation and neurodegeneration. Further, prominent C3aR-dependent vascular inflammation was also observed in a tau-transgenic mouse model. Our studies suggest that heightened C3a/C3aR signaling through endothelial cells promotes vascular inflammation and BBB dysfunction and contributes to overall neuroinflammation in aging and neurodegenerative disease.
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Affiliation(s)
- Nicholas E Propson
- Department of Molecular and Cellular Biology, and.,Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA
| | - Ethan R Roy
- Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA
| | | | - Jörg Köhl
- Institute for Systemic Inflammation Research, Center for Infectiology and Inflammation Research Lübeck, University of Lübeck, Lübeck, Germany
| | - Hui Zheng
- Department of Molecular and Cellular Biology, and.,Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA.,Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
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28
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Anaphylatoxin receptor promiscuity for commonly used complement C5a peptide agonists. Int Immunopharmacol 2021; 100:108074. [PMID: 34454293 DOI: 10.1016/j.intimp.2021.108074] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/30/2021] [Accepted: 08/11/2021] [Indexed: 11/22/2022]
Abstract
The complement system is an essential component of innate immunity. Its activation generates the effector cleavage proteins, anaphylatoxins C3a and C5a, that exert activity by interacting with three structurally related seven-transmembrane receptors. C3a activates C3aR, whilst C5a interacts with both C5aR1 and C5aR2 with equal potency. Of the three receptors, C5aR1 in particular is considered the most functionally potent inflammatory driver and has been the major target for pharmacological development. Multiple peptidic C5a agonists have been developed to target C5aR1, with the full agonists EP54 (YSFKPMPLaR) and EP67 (YSFKDMP(MeL)aR), and the partial agonist C028 (C5apep, NMe-FKPdChaChadR) being the most commonly utilised in research. Recent studies have indicated that small complement peptide ligands may lack selectivity amongst the three anaphylatoxin receptors, however this has not been uniformly confirmed for these commonly used C5a agonists. In the present study, we therefore characterised the pharmacological activity of EP54, EP67, and C5apep at human C5aR1, C5aR2 and C3aR, by conducting signalling assays in transfected cell lines, and in human primary macrophages. Our results revealed that none of the compounds tested were selective for human C5aR1. Both EP54 and EP67 were potent, full C3aR agonists, and EP54 and C5apep potently and partially activated human C5aR2. Therefore, we caution against the usage of these ligands, particularly EP54 and EP67, as C5a surrogates in C5a/ C5aR research.
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29
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Shinjyo N, Kagaya W, Pekna M. Interaction Between the Complement System and Infectious Agents - A Potential Mechanistic Link to Neurodegeneration and Dementia. Front Cell Neurosci 2021; 15:710390. [PMID: 34408631 PMCID: PMC8365172 DOI: 10.3389/fncel.2021.710390] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 07/09/2021] [Indexed: 12/24/2022] Open
Abstract
As part of the innate immune system, complement plays a critical role in the elimination of pathogens and mobilization of cellular immune responses. In the central nervous system (CNS), many complement proteins are locally produced and regulate nervous system development and physiological processes such as neural plasticity. However, aberrant complement activation has been implicated in neurodegeneration, including Alzheimer's disease. There is a growing list of pathogens that have been shown to interact with the complement system in the brain but the short- and long-term consequences of infection-induced complement activation for neuronal functioning are largely elusive. Available evidence suggests that the infection-induced complement activation could be protective or harmful, depending on the context. Here we summarize how various infectious agents, including bacteria (e.g., Streptococcus spp.), viruses (e.g., HIV and measles virus), fungi (e.g., Candida spp.), parasites (e.g., Toxoplasma gondii and Plasmodium spp.), and prion proteins activate and manipulate the complement system in the CNS. We also discuss the potential mechanisms by which the interaction between the infectious agents and the complement system can play a role in neurodegeneration and dementia.
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Affiliation(s)
- Noriko Shinjyo
- Laboratory of Immune Homeostasis, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
- School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan
| | - Wataru Kagaya
- Department of Parasitology and Research Center for Infectious Disease Sciences, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Marcela Pekna
- Laboratory of Regenerative Neuroimmunology, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
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30
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Li G, Xu M, Wang H, Qi X, Wang X, Li Y, Sun J, Li Y. MicroRNA-146a overexpression alleviates intestinal ischemia/reperfusion-induced acute lung injury in mice. Exp Ther Med 2021; 22:937. [PMID: 34335886 PMCID: PMC8290461 DOI: 10.3892/etm.2021.10369] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 04/01/2021] [Indexed: 12/31/2022] Open
Abstract
Previous studies have shown that microRNAs (miRs), such as miR-146a play an important role in the pathogenesis of intestinal ischemia/reperfusion (I/R)-induced injury; however, the role of miR-146a in intestinal I/R-induced acute lung injury has not been elucidated. An intestinal I/R-induced injury mouse model was established in the present study by clamping the superior mesenteric artery and expression levels of miR-146a in intestinal and lung tissue samples were evaluated using reverse transcription-quantitative PCR (RT-qPCR). Intestinal and lung histopathological characteristics in mice with intestinal I/R-induced injury were assessed by hematoxylin and eosin staining, and mRNA and protein expression levels in intestinal and lung tissue samples were evaluated using RT-qPCR and western blotting, respectively. miR-146a expression was significantly downregulated in the intestinal and lung tissue samples of mice with intestinal I/R-induced injury. Intestinal I/R injury-induced histopathological changes in the lung and intestines, and pulmonary edema in mice transduced with an adenoviral miR-146a-overexpression vector (the miR-146a overexpression group) were alleviated. mRNA expression levels of TNF-α, IL-1β, IFN-γ and TGF-β1, and protein expression levels of TNF receptor-associated factor 6, phosphorylated-p65 NF-κB, cleaved caspase-3 and cleaved caspase-9 in lung and intestinal tissue samples were downregulated in I/R-miR-146a-overexpressing mice, compared with those from the I/R-negative control group. Thus, the present study identified that pre-treatment with the miR-146a overexpression vector alleviated intestinal I/R-induced acute lung injury in mice.
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Affiliation(s)
- Gehui Li
- Department of Anesthesiology, Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, Guangdong 518028, P.R. China
| | - Min Xu
- Department of Anesthesiology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei 441000, P.R. China
| | - Hao Wang
- Department of Food Safety, Market Supervision Administration of Shenzhen Municipality, Shenzhen, Guangdong 518040, P.R. China
| | - Xiaofei Qi
- Department of Anesthesiology, Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, Guangdong 518028, P.R. China
| | - Xiaoguang Wang
- Department of Anesthesiology, Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, Guangdong 518028, P.R. China
| | - Yong Li
- Department of Anesthesiology, Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, Guangdong 518028, P.R. China
| | - Jing Sun
- Department of Anesthesiology, Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, Guangdong 518028, P.R. China
| | - Yuantao Li
- Department of Anesthesiology, Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, Guangdong 518028, P.R. China
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31
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Götz P, Braumandl A, Kübler M, Kumaraswami K, Ishikawa-Ankerhold H, Lasch M, Deindl E. C3 Deficiency Leads to Increased Angiogenesis and Elevated Pro-Angiogenic Leukocyte Recruitment in Ischemic Muscle Tissue. Int J Mol Sci 2021; 22:5800. [PMID: 34071589 PMCID: PMC8198161 DOI: 10.3390/ijms22115800] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/26/2021] [Accepted: 05/27/2021] [Indexed: 12/24/2022] Open
Abstract
The complement system is a potent inflammatory trigger, activator, and chemoattractant for leukocytes, which play a crucial role in promoting angiogenesis. However, little information is available about the influence of the complement system on angiogenesis in ischemic muscle tissue. To address this topic and analyze the impact of the complement system on angiogenesis, we induced muscle ischemia in complement factor C3 deficient (C3-/-) and wildtype control mice by femoral artery ligation (FAL). At 24 h and 7 days after FAL, we isolated the ischemic gastrocnemius muscles and investigated them by means of (immuno-)histological analyses. C3-/- mice showed elevated ischemic damage 7 days after FAL, as evidenced by H&E staining. In addition, angiogenesis was increased in C3-/- mice, as demonstrated by increased capillary/muscle fiber ratio and increased proliferating endothelial cells (CD31+/BrdU+). Moreover, our results showed that the total number of leukocytes (CD45+) was increased in C3-/- mice, which was based on an increased number of neutrophils (MPO+), neutrophil extracellular trap formation (MPO+/CitH3+), and macrophages (CD68+) displaying a shift toward an anti-inflammatory and pro-angiogenic M2-like polarized phenotype (CD68+/MRC1+). In summary, we show that the deficiency of complement factor C3 increased neutrophil and M2-like polarized macrophage accumulation in ischemic muscle tissue, contributing to angiogenesis.
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Affiliation(s)
- Philipp Götz
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); (A.B.); (M.K.); (K.K.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Anna Braumandl
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); (A.B.); (M.K.); (K.K.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Matthias Kübler
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); (A.B.); (M.K.); (K.K.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Konda Kumaraswami
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); (A.B.); (M.K.); (K.K.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Hellen Ishikawa-Ankerhold
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); (A.B.); (M.K.); (K.K.); (H.I.-A.); (M.L.)
- Department of Internal Medicine I, Faculty of Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
| | - Manuel Lasch
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); (A.B.); (M.K.); (K.K.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
| | - Elisabeth Deindl
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); (A.B.); (M.K.); (K.K.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
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Sullivan C, Soos BL, Millard PJ, Kim CH, King BL. Modeling Virus-Induced Inflammation in Zebrafish: A Balance Between Infection Control and Excessive Inflammation. Front Immunol 2021; 12:636623. [PMID: 34025644 PMCID: PMC8138431 DOI: 10.3389/fimmu.2021.636623] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 04/21/2021] [Indexed: 12/16/2022] Open
Abstract
The inflammatory response to viral infection in humans is a dynamic process with complex cell interactions that are governed by the immune system and influenced by both host and viral factors. Due to this complexity, the relative contributions of the virus and host factors are best studied in vivo using animal models. In this review, we describe how the zebrafish (Danio rerio) has been used as a powerful model to study host-virus interactions and inflammation by combining robust forward and reverse genetic tools with in vivo imaging of transparent embryos and larvae. The innate immune system has an essential role in the initial inflammatory response to viral infection. Focused studies of the innate immune response to viral infection are possible using the zebrafish model as there is a 4-6 week timeframe during development where they have a functional innate immune system dominated by neutrophils and macrophages. During this timeframe, zebrafish lack a functional adaptive immune system, so it is possible to study the innate immune response in isolation. Sequencing of the zebrafish genome has revealed significant genetic conservation with the human genome, and multiple studies have revealed both functional conservation of genes, including those critical to host cell infection and host cell inflammatory response. In addition to studying several fish viruses, zebrafish infection models have been developed for several human viruses, including influenza A, noroviruses, chikungunya, Zika, dengue, herpes simplex virus type 1, Sindbis, and hepatitis C virus. The development of these diverse viral infection models, coupled with the inherent strengths of the zebrafish model, particularly as it relates to our understanding of macrophage and neutrophil biology, offers opportunities for far more intensive studies aimed at understanding conserved host responses to viral infection. In this context, we review aspects relating to the evolution of innate immunity, including the evolution of viral pattern recognition receptors, interferons and interferon receptors, and non-coding RNAs.
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Affiliation(s)
- Con Sullivan
- College of Arts and Sciences, University of Maine at Augusta, Bangor, ME, United States
| | - Brandy-Lee Soos
- Department of Molecular and Biomedical Sciences, University of Maine, Orono, ME, United States
| | - Paul J. Millard
- Department of Environmental and Sustainable Engineering, University at Albany, Albany, NY, United States
| | - Carol H. Kim
- Department of Biomedical Sciences, University at Albany, Albany, NY, United States
- Department of Biological Sciences, University at Albany, Albany, NY, United States
| | - Benjamin L. King
- Department of Molecular and Biomedical Sciences, University of Maine, Orono, ME, United States
- Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME, United States
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Jaffe GJ, Westby K, Csaky KG, Monés J, Pearlman JA, Patel SS, Joondeph BC, Randolph J, Masonson H, Rezaei KA. C5 Inhibitor Avacincaptad Pegol for Geographic Atrophy Due to Age-Related Macular Degeneration: A Randomized Pivotal Phase 2/3 Trial. Ophthalmology 2021; 128:576-586. [PMID: 32882310 DOI: 10.1016/j.ophtha.2020.08.027] [Citation(s) in RCA: 278] [Impact Index Per Article: 69.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 08/05/2020] [Accepted: 08/26/2020] [Indexed: 12/12/2022] Open
Abstract
PURPOSE The complement pathway may play a key role in the pathogenesis of age-related macular degeneration (AMD). The safety and efficacy of avacincaptad pegol (Zimura, IVERIC bio Inc, New York, NY), a C5 inhibitor, were assessed in participants with geographic atrophy (GA) secondary to AMD (GATHER1 Study). DESIGN International, prospective, randomized, double-masked, sham-controlled, pivotal phase 2/3 clinical trial. PARTICIPANTS A total of 286 participants with GA secondary to AMD. MAIN OUTCOME MEASURES The primary efficacy endpoint was the mean rate of change in GA over 12 months measured by fundus autofluorescence (FAF) at 3 timepoints: baseline, month 6, and month 12. RESULTS The reduction in the mean rate of GA growth (square root transformation) over 12 months was 27.4% (P = 0.0072) for the avacincaptad pegol 2 mg cohort and 27.8% (P = 0.0051) for the avacincaptad pegol 4 mg cohort compared with their corresponding sham cohorts. The results for both dose groups were statistically significant. Avacincaptad pegol was generally well tolerated after monthly administration over 12 months. There were no avacincaptad pegol-related adverse events (AEs) or inflammation. Further, there were no ocular serious AEs (SAEs) and no cases of endophthalmitis. The most frequent ocular AEs were related to the injection procedure. CONCLUSIONS Intravitreal administration of avacincaptad pegol 2 mg and 4 mg led to a significant reduction of GA growth in eyes with AMD over a 12-month period. Because C5 inhibition theoretically preserves C3 activity, it may offer additional safety advantages. A second confirmatory pivotal clinical trial is underway to confirm the efficacy and safety of avacincaptad pegol in slowing the GA growth (GATHER2 Study).
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Affiliation(s)
- Glenn J Jaffe
- Department of Ophthalmology, Duke University, Durham, North Carolina
| | | | | | - Jordi Monés
- Institut de la Màcula and Barcelona Macula Foundation, Barcelona, Spain
| | | | | | | | - John Randolph
- Center for Retina and Macular Disease, Winter Haven, Florida
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Vandendriessche S, Cambier S, Proost P, Marques PE. Complement Receptors and Their Role in Leukocyte Recruitment and Phagocytosis. Front Cell Dev Biol 2021; 9:624025. [PMID: 33644062 PMCID: PMC7905230 DOI: 10.3389/fcell.2021.624025] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 01/15/2021] [Indexed: 12/21/2022] Open
Abstract
The complement system is deeply embedded in our physiology and immunity. Complement activation generates a multitude of molecules that converge simultaneously on the opsonization of a target for phagocytosis and activation of the immune system via soluble anaphylatoxins. This response is used to control microorganisms and to remove dead cells, but also plays a major role in stimulating the adaptive immune response and the regeneration of injured tissues. Many of these effects inherently depend on complement receptors expressed on leukocytes and parenchymal cells, which, by recognizing complement-derived molecules, promote leukocyte recruitment, phagocytosis of microorganisms and clearance of immune complexes. Here, the plethora of information on the role of complement receptors will be reviewed, including an analysis of how this functionally and structurally diverse group of molecules acts jointly to exert the full extent of complement regulation of homeostasis.
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Affiliation(s)
- Sofie Vandendriessche
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
| | - Seppe Cambier
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
| | - Paul Proost
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
| | - Pedro E Marques
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
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Zhang Y, Han K, Du C, Li R, Liu J, Zeng H, Zhu L, Li A. Carboxypeptidase B blocks ex vivo activation of the anaphylatoxin-neutrophil extracellular trap axis in neutrophils from COVID-19 patients. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2021; 25:51. [PMID: 33557911 PMCID: PMC7868871 DOI: 10.1186/s13054-021-03482-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 01/26/2021] [Indexed: 02/06/2023]
Abstract
Background Thrombosis and coagulopathy are highly prevalent in critically ill patients with COVID-19 and increase the risk of death. Immunothrombosis has recently been demonstrated to contribute to the thrombotic events in COVID-19 patients with coagulopathy. As the primary components of immunothrombosis, neutrophil extracellular traps (NETs) could be induced by complement cascade components and other proinflammatory mediators. We aimed to explore the clinical roles of NETs and the regulation of complement on the NET formation in COVID-19. Methods We recruited 135 COVID-19 patients and measured plasma levels of C5, C3, cell-free DNA and myeloperoxidase (MPO)-DNA. Besides, the formation of NETs was detected by immunofluorescent staining and the cytotoxicity to vascular endothelial HUVEC cells was evaluated by CCK-8 assay. Results We found that the plasma levels of complements C3 and MPO-DNA were positively related to coagulation indicator fibrin(-ogen) degradation products (C3: r = 0.300, p = 0.005; MPO-DNA: r = 0.316, p = 0.002) in COVID-19 patients. Besides, C3 was positively related to direct bilirubin (r = 0.303, p = 0.004) and total bilirubin (r = 0.304, p = 0.005), MPO-DNA was positively related to lactate dehydrogenase (r = 0.306, p = 0.003) and creatine kinase (r = 0.308, p = 0.004). By using anti-C3a and anti-C5a antibodies, we revealed that the complement component anaphylatoxins in the plasma of COVID-19 patients strongly induced NET formation. The pathological effect of the anaphylatoxin-NET axis on the damage of vascular endothelial cells could be relieved by recombinant carboxypeptidase B (CPB), a stable homolog of enzyme CPB2 which can degrade anaphylatoxins to inactive products. Conclusions Over-activation in anaphylatoxin-NET axis plays a pathological role in COVID-19. Early intervention in anaphylatoxins might help prevent thrombosis and disease progression in COVID-19 patients.
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Affiliation(s)
- Yue Zhang
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Kai Han
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Chunjing Du
- Department of Critical Care Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Rui Li
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Jingyuan Liu
- Department of Critical Care Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
| | - Hui Zeng
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.
| | - Liuluan Zhu
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.
| | - Ang Li
- Department of Critical Care Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.
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Li XX, Kumar V, Clark RJ, Lee JD, Woodruff TM. The "C3aR Antagonist" SB290157 is a Partial C5aR2 Agonist. Front Pharmacol 2021; 11:591398. [PMID: 33551801 PMCID: PMC7859635 DOI: 10.3389/fphar.2020.591398] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 12/02/2020] [Indexed: 12/29/2022] Open
Abstract
Innate immune complement activation generates the C3 and C5 protein cleavage products C3a and C5a, defined classically as anaphylatoxins. C3a activates C3aR, while C5a activates two receptors (C5aR1 and C5aR2) to exert their immunomodulatory activities. The non-peptide compound, SB290157, was originally reported in 2001 as the first C3aR antagonist. In 2005, the first report on the non-selective nature of SB290157 was published, where the compound exerted clear agonistic, not antagonistic, activity in variety of cells. Other studies also documented the non-selective activities of this drug in vivo. These findings severely hamper data interpretation regarding C3aR when using this compound. Unfortunately, given the dearth of C3aR inhibitors, SB290157 still remains widely used to explore C3aR biology (>70 publications to date). Given these issues, in the present study we aimed to further explore SB290157's pharmacological selectivity by screening the drug against three human anaphylatoxin receptors, C3aR, C5aR1 and C5aR2, using cell models. We identified that SB290157 exerts partial agonist activity at C5aR2 by mediating β-arrestin recruitment at higher compound doses. This translated to a functional outcome in both human and mouse primary macrophages, where SB290157 significantly dampened C5a-induced ERK signaling. We also confirmed that SB290157 acts as a potent agonist at human C3aR in transfected cells, but as an antagonist in primary human macrophages. Our results therefore provide even more caution against using SB290157 as a research tool to explore C3aR function. Given the reported immunomodulatory and anti-inflammatory activities of C5aR2 agonism, any function observed with SB290157 could be due to these off-target activities.
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Affiliation(s)
| | | | | | | | - Trent M. Woodruff
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia
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Akhir FNM, Noor MHM, Leong KWK, Nabizadeh JA, Manthey HD, Sonderegger SE, Fung JNT, McGirr CE, Shiels IA, Mills PC, Woodruff TM, Rolfe BE. An Immunoregulatory Role for Complement Receptors in Murine Models of Breast Cancer. Antibodies (Basel) 2021; 10:2. [PMID: 33430104 PMCID: PMC7838807 DOI: 10.3390/antib10010002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/20/2020] [Accepted: 12/07/2020] [Indexed: 12/25/2022] Open
Abstract
The complement system has demonstrated roles in regulating tumor growth, although these may differ between tumor types. The current study used two murine breast cancer models (EMT6 and 4T1) to investigate whether pharmacological targeting of receptors for complement proteins C3a (C3aR) and C5a (C5aR1) is protective in murine breast cancer models. In contrast to prior studies in other tumor models, treatment with the selective C5aR1 antagonist PMX53 had no effect on tumor growth. However, treatment of mice with a dual C3aR/C5aR1 agonist (YSFKPMPLaR) significantly slowed mammary tumor development and progression. Examination of receptor expression by quantitative polymerase chain reaction (qPCR) analysis showed very low levels of mRNA expression for either C3aR or C5aR1 by EMT6 or 4T1 mammary carcinoma cell lines compared with the J774 macrophage line or bone marrow-derived macrophages. Moreover, flow cytometric analysis found no evidence of C3aR or C5aR1 protein expression by either EMT6 or 4T1 cells, leading us to hypothesize that the tumor inhibitory effects of the dual agonist are indirect, possibly via regulation of the anti-tumor immune response. This hypothesis was supported by flow cytometric analysis of tumor infiltrating leukocyte populations, which demonstrated a significant increase in T lymphocytes in mice treated with the C3aR/C5aR1 agonist. These results support an immunoregulatory role for complement receptors in primary murine mammary carcinoma models. They also suggest that complement activation peptides can influence the anti-tumor response in different ways depending on the cancer type, the host immune response to the tumor and levels of endogenous complement activation within the tumor microenvironment.
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Affiliation(s)
- Fazrena Nadia Md Akhir
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia; (F.N.M.A.); (K.W.K.L.); (J.A.N.); (H.D.M.); (S.E.S.); (J.N.T.F.); (C.E.M.)
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia;
| | - Mohd Hezmee Mohd Noor
- School of Veterinary Science, The University of Queensland, Gatton, QLD 4343, Australia; (M.H.M.N.); (I.A.S.); (P.C.M.)
| | - Keith Weng Kit Leong
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia; (F.N.M.A.); (K.W.K.L.); (J.A.N.); (H.D.M.); (S.E.S.); (J.N.T.F.); (C.E.M.)
| | - Jamileh A. Nabizadeh
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia; (F.N.M.A.); (K.W.K.L.); (J.A.N.); (H.D.M.); (S.E.S.); (J.N.T.F.); (C.E.M.)
| | - Helga D. Manthey
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia; (F.N.M.A.); (K.W.K.L.); (J.A.N.); (H.D.M.); (S.E.S.); (J.N.T.F.); (C.E.M.)
| | - Stefan E. Sonderegger
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia; (F.N.M.A.); (K.W.K.L.); (J.A.N.); (H.D.M.); (S.E.S.); (J.N.T.F.); (C.E.M.)
| | - Jenny Nga Ting Fung
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia; (F.N.M.A.); (K.W.K.L.); (J.A.N.); (H.D.M.); (S.E.S.); (J.N.T.F.); (C.E.M.)
| | - Crystal E. McGirr
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia; (F.N.M.A.); (K.W.K.L.); (J.A.N.); (H.D.M.); (S.E.S.); (J.N.T.F.); (C.E.M.)
| | - Ian A. Shiels
- School of Veterinary Science, The University of Queensland, Gatton, QLD 4343, Australia; (M.H.M.N.); (I.A.S.); (P.C.M.)
| | - Paul C. Mills
- School of Veterinary Science, The University of Queensland, Gatton, QLD 4343, Australia; (M.H.M.N.); (I.A.S.); (P.C.M.)
| | - Trent M. Woodruff
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia;
| | - Barbara E. Rolfe
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia; (F.N.M.A.); (K.W.K.L.); (J.A.N.); (H.D.M.); (S.E.S.); (J.N.T.F.); (C.E.M.)
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Fang X, Duan SF, Gong YZ, Wang F, Chen XL. Identification of Key Genes Associated with Changes in the Host Response to Severe Burn Shock: A Bioinformatics Analysis with Data from the Gene Expression Omnibus (GEO) Database. J Inflamm Res 2020; 13:1029-1041. [PMID: 33293847 PMCID: PMC7718973 DOI: 10.2147/jir.s282722] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 11/13/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Patients with severe burns continue to display a high mortality rate during the initial shock period. The precise molecular mechanism underlying the change in host response during severe burn shock remains unknown. This study aimed to identify key genes leading to the change in host response during burn shock. METHODS The GSE77791 dataset, which was utilized in a previous study that compared hydrocortisone administration to placebo (NaCl 0.9%) in the inflammatory reaction of severe burn shock, was downloaded from the Gene Expression Omnibus (GEO) database and analyzed to identify the differentially expressed genes (DEGs). Functional enrichment analyses of Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed. The protein-protein interaction (PPI) network of DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes (STRING) database and then visualized in Cytoscape. In addition, important modules in this network were selected using the Molecular Complex Detection (MCODE) algorithm, and hub genes were identified in cytoHubba, a Cytoscape plugin. RESULTS A total of 1059 DEGs (508 downregulated genes and 551 upregulated genes) were identified from the dataset. The DEGs enriched in GO terms and KEGG pathways were related to immune response. The PPI network contained 439 nodes and 2430 protein pairs. Finally, important modules and hub genes were identified using the different Cytoscape plugins. The key genes in burn shock were identified as arginase 1 (ARG1), cytoskeleton-associated protein (CKAP4), complement C3a receptor (C3AR1), neutrophil elastase (ELANE), gamma-glutamyl hydrolase (GGH), orosomucoid (ORM1), and quiescin sulfhydryl (QSOX1). CONCLUSION The DEGs, functional terms and pathways, and hub genes identified in the present study can help shed light on the molecular mechanism underlying the changes in host response during burn shock and provide potential targets for early detection and treatment of burn shock.
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Affiliation(s)
- Xiao Fang
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China
| | - Shu-Fang Duan
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China
| | - Yu-Zhou Gong
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China
| | - Fei Wang
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China
| | - Xu-Lin Chen
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China
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Huber-Lang MS, Ignatius A, Köhl J, Mannes M, Braun CK. Complement in trauma-Traumatised complement? Br J Pharmacol 2020; 178:2863-2879. [PMID: 32880897 DOI: 10.1111/bph.15245] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/23/2020] [Accepted: 08/17/2020] [Indexed: 12/17/2022] Open
Abstract
Physical trauma represents a major global burden. The trauma-induced response, including activation of the innate immune system, strives for regeneration but can also lead to post-traumatic complications. The complement cascade is rapidly activated by damaged tissue, hypoxia, exogenous proteases and others. Activated complement can sense, mark and clear both damaged tissue and pathogens. However, excessive and insufficient activation of complement can result in a dysfunctional immune and organ response. Similar to acute coagulopathy, complementopathy can develop with enhanced anaphylatoxin generation and an impairment of complement effector functions. Various remote organ effects are induced or modulated by complement activation. Frequently, established trauma treatments are double-edged. On one hand, they help stabilising haemodynamics and oxygen supply as well as injured organs and on the other hand, they also drive complement activation. Immunomodulatory approaches aim to reset trauma-induced disbalance of complement activation and thus may change surgical trauma management procedures to improve outcome. LINKED ARTICLES: This article is part of a themed issue on Canonical and non-canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc.
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Affiliation(s)
- Markus S Huber-Lang
- Institute of Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, Germany
| | - Anita Ignatius
- Institue of Orthopaedic Research and Biomechanics, University Hospital of Ulm, Ulm, Germany
| | - Jörg Köhl
- Institute for Systemic Inflammatory Research, University of Lübeck, Lübeck, Germany.,Division of Immunobiology, Cincinnati Children's Hospital Medical Centre, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Marco Mannes
- Institute of Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, Germany
| | - Christian Karl Braun
- Institute of Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, Germany.,Department of Paediatrics and Adolescent Medicine, University Hospital of Ulm, Ulm, Germany
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Wu MCL, Lee JD, Ruitenberg MJ, Woodruff TM. Absence of the C5a Receptor C5aR2 Worsens Ischemic Tissue Injury by Increasing C5aR1-Mediated Neutrophil Infiltration. THE JOURNAL OF IMMUNOLOGY 2020; 205:2834-2839. [PMID: 33028618 DOI: 10.4049/jimmunol.2000778] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 09/16/2020] [Indexed: 02/06/2023]
Abstract
Neutrophil infiltration to ischemic tissues following reperfusion worsens injury. A key driver of neutrophil recruitment and activation is the complement factor C5a, which signals through two receptors, C5aR1 and C5aR2. In this study, we used a neutrophil-dependent mouse model of intestinal ischemia-reperfusion (IR) injury to investigate the underexplored role of C5aR2 in neutrophil mobilization, recruitment, and disease outcomes. We show that intestinal IR induces rapid neutrophil mobilization along with a concomitant reduction in plasma C5a levels that is driven by both C5aR1 and C5aR2. Intestinal IR in C5aR2-/- mice led to worsened intestinal damage and increased neutrophil infiltration. Inhibition of C5aR1 signaling in C5aR2-/- mice with PMX53 prevented neutrophil accumulation and reduced IR pathology, suggesting a key requirement for enhanced neutrophil C5aR1 activation in the absence of C5aR2 signaling. Interestingly, C5aR2 deficiency also reduced circulating neutrophil numbers after IR, as well as following G-CSF-mediated bone marrow mobilization, which was independent of C5aR1, demonstrating that C5aR2 has unique and distinct functions from C5aR1 in neutrophil egress. Despite enhanced tissue injury in C5aR2-/- IR mice, there were significant reductions in intestinal proinflammatory cytokines, highlighting complicated dual protective/pathogenic roles for C5aR2 in pathophysiology. Collectively, we show that C5aR2 is protective in intestinal IR by inhibiting C5aR1-mediated neutrophil recruitment to the ischemic tissue. This is despite the potentially local pathogenic effects of C5aR2 in increasing intestinal proinflammatory cytokines and enhancing circulating neutrophil numbers in response to mobilizing signals. Our data therefore suggest that this balance between the dual pro- and anti-inflammatory roles of C5aR2 ultimately dictates disease outcomes.
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Affiliation(s)
- Mike C L Wu
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Queensland 4072, Australia
| | - John D Lee
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Queensland 4072, Australia
| | - Marc J Ruitenberg
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Queensland 4072, Australia
| | - Trent M Woodruff
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Queensland 4072, Australia
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Gaashan MM, Al-Mubarak AIA, Hussen J. Leukocyte populations and their cell adhesion molecules expression in newborn dromedary camel calves. Vet World 2020; 13:1863-1869. [PMID: 33132598 PMCID: PMC7566236 DOI: 10.14202/vetworld.2020.1863-1869] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 07/31/2020] [Indexed: 12/25/2022] Open
Abstract
Background and Aim Different properties of the newborn immune system have been characterized in many species. For the newborn camel calf, however, the phenotype and composition of blood leukocytes have so far not been evaluated. The current study aimed to analyze the distribution of leukocyte subpopulations and their expression pattern of cell adhesion molecules in newborn and adult dromedary camels. Materials and Methods Blood samples were collected from 17 newborn camel calves and 32 adult camels. For each sample, total leukocytes were separated and analyzed for their composition and cell adhesion molecules expression by flow cytometry. Results In comparison to adult camels, newborn camel calves had higher leukocyte numbers and higher numbers of neutrophils, monocytes, and lymphocytes but lower numbers of eosinophils in their blood. Among the lymphocyte populations in calves, the fractions of B cells and γδ T cells were elevated when compared to adults, whereas CD4-positive T cells were reduced. The comparison between camel calves and adult camels revealed significantly lower expression of the cell adhesion molecules CD11a, CD11b, and CD18 on granulocytes, monocytes, and lymphocytes in calves. Conclusion Newborn camel calves show a distinct composition and phenotype pattern of blood leukocytes when compared to adult camels. The observed rise in many leukocyte populations in calf blood may be due to reduced migratory activity in calf leukocyte populations.
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Affiliation(s)
- Muaadh M Gaashan
- Department of Microbiology, College of Veterinary Medicine, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Abdullah I A Al-Mubarak
- Department of Microbiology, College of Veterinary Medicine, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Jamal Hussen
- Department of Microbiology, College of Veterinary Medicine, King Faisal University, Al-Ahsa, Saudi Arabia
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Wei LL, Ma N, Wu KY, Wang JX, Diao TY, Zhao SJ, Bai L, Liu E, Li ZF, Zhou W, Chen D, Li K. Protective Role of C3aR (C3a Anaphylatoxin Receptor) Against Atherosclerosis in Atherosclerosis-Prone Mice. Arterioscler Thromb Vasc Biol 2020; 40:2070-2083. [PMID: 32762445 DOI: 10.1161/atvbaha.120.314150] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Emerging evidence suggests that C3aR (C3a anaphylatoxin receptor) signaling has protective roles in various inflammatory-related diseases. However, its role in atherosclerosis has been unknown. The purpose of the study was to investigate the possible protective role of C3aR in aortic atherosclerosis and explore molecular and cellular mechanisms involved in the protection. Approach and Results: C3ar-/-/Apoe-/- mice were generated by cross-breeding of atherosclerosis-prone Apoe-/- mice and C3ar-/- mice. C3ar-/-/Apoe-/- mice and Apoe-/- mice (as a control) underwent high-fat diet for 16 weeks were assessed for (1) atherosclerotic plaque burden, (2) aortic tissue inflammation, (3) recruitment of CD11b+ leukocytes into atherosclerotic lesions, and (4) systemic inflammatory responses. Compared with Apoe-/- mice, C3ar-/-/Apoe-/- mice developed more severe atherosclerosis. In addition, C3ar-/-/Apoe-/- mice have increased local production of proinflammatory mediators (eg, CCL2 [chemokine (C-C motif) ligand 2], TNF [tumor necrosis factor]-α) and infiltration of monocyte/macrophage in aortic tissue, and their lesional macrophages displayed an M1-like phenotype. Local pathological changes were associated with enhanced systemic inflammatory responses (ie, elevated plasma levels of CCL2 and TNF-α, increased circulating inflammatory cells). In vitro analyses using peritoneal macrophages showed that C3a stimulation resulted in upregulation of M2-associated signaling and molecules, but suppression of M1-associated signaling and molecules, supporting the roles of C3a/C3aR axis in mediating anti-inflammatory response and promoting M2 macrophage polarization. CONCLUSIONS Our findings demonstrate a protective role for C3aR in the development of atherosclerosis and suggest that C3aR confers the protection through C3a/C3aR axis-mediated negative regulation of proinflammatory responses and modulation of macrophage toward the anti-inflammatory phenotype.
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Affiliation(s)
- Lin-Lin Wei
- From the Core Research Laboratory (L.-L.W., N.M., K.-Y.W., J.-X.W., T.-Y.D., S.-J.Z., K.L.), Xi'an Jiaotong University, China
| | - Ning Ma
- From the Core Research Laboratory (L.-L.W., N.M., K.-Y.W., J.-X.W., T.-Y.D., S.-J.Z., K.L.), Xi'an Jiaotong University, China
| | - Kun-Yi Wu
- From the Core Research Laboratory (L.-L.W., N.M., K.-Y.W., J.-X.W., T.-Y.D., S.-J.Z., K.L.), Xi'an Jiaotong University, China
| | - Jia-Xing Wang
- From the Core Research Laboratory (L.-L.W., N.M., K.-Y.W., J.-X.W., T.-Y.D., S.-J.Z., K.L.), Xi'an Jiaotong University, China
| | - Teng-Yue Diao
- From the Core Research Laboratory (L.-L.W., N.M., K.-Y.W., J.-X.W., T.-Y.D., S.-J.Z., K.L.), Xi'an Jiaotong University, China
| | - Shu-Juan Zhao
- From the Core Research Laboratory (L.-L.W., N.M., K.-Y.W., J.-X.W., T.-Y.D., S.-J.Z., K.L.), Xi'an Jiaotong University, China
| | - Liang Bai
- The Second Affiliated Hospital and Cardiovascular Research Center, School of Basic Medical Sciences, Health Science Center (L.B., E.L.), Xi'an Jiaotong University, China
| | - Enqi Liu
- The Second Affiliated Hospital and Cardiovascular Research Center, School of Basic Medical Sciences, Health Science Center (L.B., E.L.), Xi'an Jiaotong University, China
| | - Zong-Fang Li
- National Local Joint Engineering Research Centre of Biodiagnostics and Biotherapy (Z.-F.L.), Xi'an Jiaotong University, China
| | - Wuding Zhou
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine (W.Z.), King's College London, United Kingdom
| | - Daxin Chen
- Department of Inflammation Biology, School of Immunology & Microbial Sciences (D.C.), King's College London, United Kingdom
| | - Ke Li
- From the Core Research Laboratory (L.-L.W., N.M., K.-Y.W., J.-X.W., T.-Y.D., S.-J.Z., K.L.), Xi'an Jiaotong University, China
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Autophagy Induction Ameliorates Inflammatory Responses in Intestinal Ischemia-Reperfusion Through Inhibiting NLRP3 Inflammasome Activation. Shock 2020; 52:387-395. [PMID: 30216227 DOI: 10.1097/shk.0000000000001259] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Intestinal ischemia/reperfusion (I/R)-induced systemic inflammation leads to multiple organ dysfunction syndrome. Previous studies have indicated that the NOD-like receptor protein (NLRP)3 inflammasome modulates intestinal inflammation; however, the pathophysiological mechanisms remain unclear. Autophagy is a critical metabolic mechanism that promotes cellular survival following ischemic injury. Recently, basal autophagy has been implicated in the alleviation of extensive inflammation. However, the role of autophagy in NLRP3 inflammasome activation in intestinal I/R-induced inflammatory injury remains undefined. In the present study, we examined whether NLRP3 inflammasome activation is induced in mice subjected to intestinal I/R injury, which is measured as increased apoptosis-associated speck-like protein containing a CARD levels, caspase-1 activity, and interleukin-1β (IL-1β) secretion. Importantly, the in-vitro results showed that NLRP3 knockdown decreases proinflammatory cytokine production and increases resistance to hypoxia/reoxygenation (H/R)-triggered inflammation. Subsequently, we demonstrated a critical role for autophagy in suppressing intestinal I/R-induced NLRP3 inflammasome activation in vivo. Furthermore, we showed that the loss of autophagy activates inflammasome-mediated IL-1β secretion, which aggravates H/R injury, and NLRP3 knockdown reverses these effects. Collectively, these results directly implicated the homeostatic process of autophagy and NLRP3 inflammasome in ischemic bowel disease and identified a novel pathway for therapeutic intervention in intestinal I/R.
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Mellors J, Tipton T, Longet S, Carroll M. Viral Evasion of the Complement System and Its Importance for Vaccines and Therapeutics. Front Immunol 2020; 11:1450. [PMID: 32733480 PMCID: PMC7363932 DOI: 10.3389/fimmu.2020.01450] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 06/04/2020] [Indexed: 12/17/2022] Open
Abstract
The complement system is a key component of innate immunity which readily responds to invading microorganisms. Activation of the complement system typically occurs via three main pathways and can induce various antimicrobial effects, including: neutralization of pathogens, regulation of inflammatory responses, promotion of chemotaxis, and enhancement of the adaptive immune response. These can be vital host responses to protect against acute, chronic, and recurrent viral infections. Consequently, many viruses (including dengue virus, West Nile virus and Nipah virus) have evolved mechanisms for evasion or dysregulation of the complement system to enhance viral infectivity and even exacerbate disease symptoms. The complement system has multifaceted roles in both innate and adaptive immunity, with both intracellular and extracellular functions, that can be relevant to all stages of viral infection. A better understanding of this virus-host interplay and its contribution to pathogenesis has previously led to: the identification of genetic factors which influence viral infection and disease outcome, the development of novel antivirals, and the production of safer, more effective vaccines. This review will discuss the antiviral effects of the complement system against numerous viruses, the mechanisms employed by these viruses to then evade or manipulate this system, and how these interactions have informed vaccine/therapeutic development. Where relevant, conflicting findings and current research gaps are highlighted to aid future developments in virology and immunology, with potential applications to the current COVID-19 pandemic.
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Affiliation(s)
- Jack Mellors
- Public Health England, National Infection Service, Salisbury, United Kingdom.,Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
| | - Tom Tipton
- Public Health England, National Infection Service, Salisbury, United Kingdom
| | - Stephanie Longet
- Public Health England, National Infection Service, Salisbury, United Kingdom
| | - Miles Carroll
- Public Health England, National Infection Service, Salisbury, United Kingdom
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Schofield ZV, Wu MCL, Hansbro PM, Cooper MA, Woodruff TM. Acetate protects against intestinal ischemia‐reperfusion injury independent of its cognate free fatty acid 2 receptor. FASEB J 2020; 34:10418-10430. [DOI: 10.1096/fj.202000960r] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/19/2020] [Accepted: 05/22/2020] [Indexed: 12/16/2022]
Affiliation(s)
- Zoe V. Schofield
- School of Biomedical Sciences The University of Queensland Brisbane QLD Australia
- The Institute for Molecular Bioscience The University of Queensland Brisbane QLD Australia
| | - Mike C. L. Wu
- School of Biomedical Sciences The University of Queensland Brisbane QLD Australia
| | - Philip M. Hansbro
- Centre for Inflammation Centenary Institute Sydney NSW Australia
- Faculty of Science University of Technology Sydney Ultimo NSW Australia
| | - Matthew A. Cooper
- The Institute for Molecular Bioscience The University of Queensland Brisbane QLD Australia
| | - Trent M. Woodruff
- School of Biomedical Sciences The University of Queensland Brisbane QLD Australia
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46
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Lo MW, Woodruff TM. Complement: Bridging the innate and adaptive immune systems in sterile inflammation. J Leukoc Biol 2020; 108:339-351. [PMID: 32182389 DOI: 10.1002/jlb.3mir0220-270r] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 02/07/2020] [Accepted: 02/19/2020] [Indexed: 12/24/2022] Open
Abstract
The complement system is a collection of soluble and membrane-bound proteins that together act as a powerful amplifier of the innate and adaptive immune systems. Although its role in infection is well established, complement is becoming increasingly recognized as a key contributor to sterile inflammation, a chronic inflammatory process often associated with noncommunicable diseases. In this context, damaged tissues release danger signals and trigger complement, which acts on a range of leukocytes to augment and bridge the innate and adaptive immune systems. Given the detrimental effect of chronic inflammation, the complement system is therefore well placed as an anti-inflammatory drug target. In this review, we provide a general outline of the sterile activators, effectors, and targets of the complement system and a series of examples (i.e., hypertension, cancer, allograft transplant rejection, and neuroinflammation) that highlight complement's ability to bridge the 2 arms of the immune system.
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Affiliation(s)
- Martin W Lo
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, Queensland, Australia
| | - Trent M Woodruff
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, Queensland, Australia
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Abstract
The recognition of microbial or danger-associated molecular patterns by complement proteins initiates a cascade of events that culminates in the activation of surface complement receptors on immune cells. Such signalling pathways converge with those activated downstream of pattern recognition receptors to determine the type and magnitude of the immune response. Intensive investigation in the field has uncovered novel pathways that link complement-mediated signalling with homeostatic and pathological T cell responses. More recently, the observation that complement proteins also act in the intracellular space to shape T cell fates has added a new layer of complexity. Here, we consider fundamental mechanisms and novel concepts at the interface of complement biology and immunity and discuss how these affect the maintenance of homeostasis and the development of human pathology.
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48
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Kumar V, Lee JD, Clark RJ, Noakes PG, Taylor SM, Woodruff TM. Preclinical Pharmacokinetics of Complement C5a Receptor Antagonists PMX53 and PMX205 in Mice. ACS OMEGA 2020; 5:2345-2354. [PMID: 32064396 PMCID: PMC7017397 DOI: 10.1021/acsomega.9b03735] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 01/21/2020] [Indexed: 05/16/2023]
Abstract
The cyclic hexapeptides PMX53 and PMX205 are potent noncompetitive inhibitors of complement C5a receptor 1 (C5aR1). They are widely utilized to study the role of C5aR1 in mouse models, including central nervous system (CNS) disease, and are dosed through a variety of routes of administration. However, a comprehensive pharmacokinetics analysis of these drugs has not been reported. In this study, the blood and CNS pharmacokinetics of PMX53 and PMX205 were performed in mice following intravenous, intraperitoneal, subcutaneous, and oral administration at identical doses. The absorption and distribution of both drugs were rapid and followed a two-compartment model with elimination half-lives of ∼20 min for both compounds. Urinary excretion was the major route of elimination following intravenous dosing with ∼50% of the drug excreted unchanged within the first 12 h. Oral bioavailability of PMX205 was higher than that of PMX53 (23% versus 9%), and PMX205 was also more efficient than PMX53 at entering the intact CNS. In comparison to other routes, subcutaneous administration of PMX205 resulted in high bioavailability (above 90%), as well as prolonged plasma and CNS exposure. Finally, repeated daily oral or subcutaneous administration of PMX205 demonstrated no accumulation of drug in blood, the brain, or the spinal cord, promoting its safety for chronic dosing. These results will be helpful in correlating the desired therapeutic effects of these C5aR1 antagonists with their pharmacokinetic profile. It also suggests that subcutaneous dosing of PMX205 may be an appropriate route of administration for future clinical testing in neurological disease.
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Affiliation(s)
- Vinod Kumar
- School
of Biomedical Sciences, The University of
Queensland, St Lucia, Brisbane, QLD 4072, Australia
| | - John D. Lee
- School
of Biomedical Sciences, The University of
Queensland, St Lucia, Brisbane, QLD 4072, Australia
- University
of Queensland Centre for Clinical Research, the University of Queensland, Brisbane, QLD 4029, Australia
| | - Richard J. Clark
- School
of Biomedical Sciences, The University of
Queensland, St Lucia, Brisbane, QLD 4072, Australia
| | - Peter G. Noakes
- School
of Biomedical Sciences, The University of
Queensland, St Lucia, Brisbane, QLD 4072, Australia
- Queensland
Brain Institute, the University of Queensland,
St Lucia, Brisbane, QLD 4072, Australia
| | - Stephen M. Taylor
- School
of Biomedical Sciences, The University of
Queensland, St Lucia, Brisbane, QLD 4072, Australia
| | - Trent M. Woodruff
- School
of Biomedical Sciences, The University of
Queensland, St Lucia, Brisbane, QLD 4072, Australia
- Wesley
Medical Research, The Wesley Hospital, Auchenflower, Brisbane, QLD 4066, Australia
- . Phone: +61-7-336 52924. Fax: +61-7-336-51766
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C3a elicits unique migratory responses in immature low-density neutrophils. Oncogene 2020; 39:2612-2623. [PMID: 32020055 DOI: 10.1038/s41388-020-1169-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 12/14/2019] [Accepted: 01/20/2020] [Indexed: 12/31/2022]
Abstract
Neutrophils represent the immune system's first line of defense and are rapidly recruited into inflamed tissue. In cancer associated inflammation, phenotypic heterogeneity has been ascribed to this cell type, whereby neutrophils can manifest anti- or pro-metastatic functions depending on the cellular/micro-environmental context. Here, we demonstrate that pro-metastatic immature low-density neutrophils (iLDNs) more efficiently accumulate in the livers of mice bearing metastatic lesions compared with anti-metastatic mature high-density neutrophils (HDNs). Transcriptomic analyses reveal enrichment of a migration signature in iLDNs relative to HDNs. We find that conditioned media derived from liver-metastatic breast cancer cells, but not lung-metastatic variants, specifically induces chemotaxis of iLDNs and not HDNs. Chemotactic responses are due to increased surface expression of C3aR in iLDNs relative to HDNs. In addition, we detect elevated secretion of cancer-cell derived C3a from liver-metastatic versus lung-metastatic breast cancer cells. Perturbation of C3a/C3aR signaling axis with either a small molecule inhibitor, SB290157, or reducing the levels of secreted C3a from liver-metastatic breast cancer cells by short hairpin RNAs, can abrogate the chemotactic response of iLDNs both in vitro and in vivo, respectively. Together, these data reveal novel mechanisms through which iLDNs prefentially accumulate in liver tissue harboring metastases in response to tumor-derived C3a secreted from the liver-aggressive 4T1 breast cancer cells.
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Affiliation(s)
- Xiang-Na Guo
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xin Ma
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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