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1
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Chen BB, Yi ZY, Dong XQ, Wang CJ. Access to Chiral Oxindoles via Ir-Catalyzed Asymmetric Pudovik Addition/[1,2]-Phospha-Brook Rearrangement/Allylation Cascade. Org Lett 2025; 27:4974-4979. [PMID: 40314413 DOI: 10.1021/acs.orglett.5c01291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
An asymmetric catalytic Pudovik addition/[1,2]-phospha-Brook rearrangement/allylation reaction of readily available isatins, phosphites, and vinyl ethylene carbonate enabled by a chiral iridium catalyst was developed in a one-pot fashion. A wide range of enantioenriched oxindole derivatives containing two adjacent stereocenters could be obtained in good to high yields with excellent diastereoselectivity and enantioselectivity (65-99% yield, 7:1 to >20:1 dr, and generally 99% ee). This cascade protocol owned the advantages of readily available starting materials, high regio-/diastereo-/enantioselectivity, and good substrate scope generality.
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Affiliation(s)
- Bo-Bin Chen
- Hubei Research Center of Fundamental Science-Chemistry, Engineering Research Center of Organosilicon Compounds & Materials, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, People's Republic of China
| | - Zhi-Yuan Yi
- Hubei Research Center of Fundamental Science-Chemistry, Engineering Research Center of Organosilicon Compounds & Materials, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, People's Republic of China
| | - Xiu-Qin Dong
- Hubei Research Center of Fundamental Science-Chemistry, Engineering Research Center of Organosilicon Compounds & Materials, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, People's Republic of China
| | - Chun-Jiang Wang
- Hubei Research Center of Fundamental Science-Chemistry, Engineering Research Center of Organosilicon Compounds & Materials, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, People's Republic of China
- State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 230021, People's Republic of China
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2
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Zhang T, Liu X, Rossio V, Dawson SL, Gygi SP, Paulo JA. Enhancing Proteome Coverage by Using Strong Anion-Exchange in Tandem with Basic-pH Reversed-Phase Chromatography for Sample Multiplexing-Based Proteomics. J Proteome Res 2024; 23:2870-2881. [PMID: 37962907 PMCID: PMC11090996 DOI: 10.1021/acs.jproteome.3c00492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Sample multiplexing-based proteomic strategies rely on fractionation to improve proteome coverage. Tandem mass tag (TMT) experiments, for example, can currently accommodate up to 18 samples with proteins spanning several orders of magnitude, thus necessitating fractionation to achieve reasonable proteome coverage. Here, we present a simple yet effective peptide fractionation strategy that partitions a pooled TMT sample with a two-step elution using a strong anion-exchange (SAX) spin column prior to gradient-based basic pH reversed-phase (BPRP) fractionation. We highlight our strategy with a TMTpro18-plex experiment using nine diverse human cell lines in biological duplicate. We collected three data sets, one using only BPRP fractionation and two others of each SAX-partition followed by BPRP. The three data sets quantified a similar number of proteins and peptides, and the data highlight noticeable differences in the distribution of peptide charge and isoelectric point between the SAX partitions. The combined SAX partition data set contributed 10% more proteins and 20% more unique peptides that were not quantified by BPRP fractionation alone. In addition to this improved fractionation strategy, we provide an online resource of relative abundance profiles for over 11,000 proteins across the nine human cell lines, as well as two additional experiments using ovarian and pancreatic cancer cell lines.
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Affiliation(s)
- Tian Zhang
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Xinyue Liu
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Valentina Rossio
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Shane L Dawson
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Steven P Gygi
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Joao A Paulo
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
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3
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Xie HG, Jiang LP, Tai T, Ji JZ, Mi QY. The Complement System and C4b-Binding Protein: A Focus on the Promise of C4BPα as a Biomarker to Predict Clopidogrel Resistance. Mol Diagn Ther 2024; 28:189-199. [PMID: 38261250 DOI: 10.1007/s40291-023-00691-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2023] [Indexed: 01/24/2024]
Abstract
The complement system plays a dual role in the body, either as a first-line defense barrier when balanced between activation and inhibition or as a potential driver of complement-associated injury or diseases when unbalanced or over-activated. C4b-binding protein (C4BP) was the first circulating complement regulatory protein identified and it functions as an important complement inhibitor. C4BP can suppress the over-activation of complement components and prevent the complement system from attacking the host cells through the binding of complement cleavage products C4b and C3b, working in concert as a cofactor for factor I in the degradation of C4b and C3b, and consequently preventing or reducing the assembly of C3 convertase and C5 convertase, respectively. C4BP, particularly C4BP α-chain (C4BPα), exerts its unique inhibitory effects on complement activation and opsonization, systemic inflammation, and platelet activation and aggregation. It has long been acknowledged that crosstalk or interplay exists between the complement system and platelets. Our unpublished preliminary data suggest that circulating C4BPα exerts its antiplatelet effects through inhibition of both complement activity levels and complement-induced platelet reactivity. Plasma C4BPα levels appear to be significantly higher in patients sensitive to, rather than resistant to, clopidogrel, and we suggest that a plasma C4BPα measurement could be used to predict clopidogrel resistance in the clinical settings.
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Affiliation(s)
- Hong-Guang Xie
- Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China.
| | - Li-Ping Jiang
- Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China
| | - Ting Tai
- Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China
| | - Jin-Zi Ji
- Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China
| | - Qiong-Yu Mi
- Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, China
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4
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Wu M, Zheng W, Song X, Bao B, Wang Y, Ramanan D, Yang D, Liu R, Macbeth JC, Do EA, Andrade WA, Yang T, Cho HS, Gazzaniga FS, Ilves M, Coronado D, Thompson C, Hang S, Chiu IM, Moffitt JR, Hsiao A, Mekalanos JJ, Benoist C, Kasper DL. Gut complement induced by the microbiota combats pathogens and spares commensals. Cell 2024; 187:897-913.e18. [PMID: 38280374 PMCID: PMC10922926 DOI: 10.1016/j.cell.2023.12.036] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 09/25/2023] [Accepted: 12/30/2023] [Indexed: 01/29/2024]
Abstract
Canonically, the complement system is known for its rapid response to remove microbes in the bloodstream. However, relatively little is known about a functioning complement system on intestinal mucosal surfaces. Herein, we report the local synthesis of complement component 3 (C3) in the gut, primarily by stromal cells. C3 is expressed upon commensal colonization and is regulated by the composition of the microbiota in healthy humans and mice, leading to an individual host's specific luminal C3 levels. The absence of membrane attack complex (MAC) components in the gut ensures that C3 deposition does not result in the lysis of commensals. Pathogen infection triggers the immune system to recruit neutrophils to the infection site for pathogen clearance. Basal C3 levels directly correlate with protection against enteric infection. Our study reveals the gut complement system as an innate immune mechanism acting as a vigilant sentinel that combats pathogens and spares commensals.
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Affiliation(s)
- Meng Wu
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Wen Zheng
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Xinyang Song
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Bin Bao
- Division of Gastroenterology, Boston Children's Hospital, and Harvard Medical School, Boston, MA 02115, USA
| | - Yuanyou Wang
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA
| | - Deepshika Ramanan
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Daping Yang
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Rui Liu
- Department of Microbiology & Plant Pathology, University of California, Riverside, CA 92521, USA
| | - John C Macbeth
- Department of Microbiology & Plant Pathology, University of California, Riverside, CA 92521, USA
| | - Elyza A Do
- Department of Microbiology & Plant Pathology, University of California, Riverside, CA 92521, USA
| | | | - Tiandi Yang
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Hyoung-Soo Cho
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | | | - Marit Ilves
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Daniela Coronado
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | | | - Saiyu Hang
- Genentech LLC, South San Francisco, CA 94080, USA
| | - Isaac M Chiu
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Jeffrey R Moffitt
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA
| | - Ansel Hsiao
- Department of Microbiology & Plant Pathology, University of California, Riverside, CA 92521, USA
| | - John J Mekalanos
- Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA
| | | | - Dennis L Kasper
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
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5
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Hallam TM, Sharp SJ, Andreadi A, Kavanagh D. Complement factor I: Regulatory nexus, driver of immunopathology, and therapeutic. Immunobiology 2023; 228:152410. [PMID: 37478687 DOI: 10.1016/j.imbio.2023.152410] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/23/2023] [Accepted: 06/01/2023] [Indexed: 07/23/2023]
Abstract
Complement factor I (FI) is the nexus for classical, lectin and alternative pathway complement regulation. FI is an 88 kDa plasma protein that circulates in an inactive configuration until it forms a trimolecular complex with its cofactor and substrate whereupon a structural reorganization allows the catalytic triad to cleave its substrates, C3b and C4b. In keeping with its role as the master complement regulatory enzyme, deficiency has been linked to immunopathology. In the setting of complete FI deficiency, a consumptive C3 deficiency results in recurrent infections with encapsulated microorganisms. Aseptic cerebral inflammation and vasculitic presentations are also less commonly observed. Heterozygous mutations in the factor I gene (CFI) have been demonstrated to be enriched in atypical haemolytic uraemic syndrome, albeit with a very low penetrance. Haploinsufficiency of CFI has also been associated with decreased retinal thickness and is a strong risk factor for the development of age-related macular degeneration. Supplementation of FI using plasma purified or recombinant protein has long been postulated, however, technical difficulties prevented progression into clinical trials. It is only using gene therapy that CFI supplementation has reached the clinic with GT005 in phase I/II clinical trials for geographic atrophy.
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Affiliation(s)
- T M Hallam
- Gyroscope Therapeutics Limited, A Novartis Company, Rolling Stock Yard, London N7 9AS, UK; Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK; National Renal Complement Therapeutics Centre, Building 26, Royal Victoria Infirmary, UK
| | - S J Sharp
- Gyroscope Therapeutics Limited, A Novartis Company, Rolling Stock Yard, London N7 9AS, UK
| | - A Andreadi
- Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK; National Renal Complement Therapeutics Centre, Building 26, Royal Victoria Infirmary, UK
| | - D Kavanagh
- Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK; National Renal Complement Therapeutics Centre, Building 26, Royal Victoria Infirmary, UK; NIHR Newcastle Biomedical Research Centre, Biomedical Research Building, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK.
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6
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Wu M, Zheng W, Song X, Bao B, Wang Y, Ramanan D, Yang D, Liu R, Macbeth JC, Do EA, Andrade WA, Yang T, Cho HS, Gazzaniga FS, Ilves M, Coronado D, Thompson C, Hang S, Chiu IM, Moffitt JR, Hsiao A, Mekalanos JJ, Benoist C, Kasper DL. Microbiome induced complement synthesized in the gut protects against enteric infections. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.02.523770. [PMID: 36778396 PMCID: PMC9915568 DOI: 10.1101/2023.02.02.523770] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Canonically, complement is a serum-based host defense system that protects against systemic microbial invasion. Little is known about the production and function of complement components on mucosal surfaces. Here we show gut complement component 3 (C3), central to complement function, is regulated by the composition of the microbiota in healthy humans and mice, leading to host-specific gut C3 levels. Stromal cells in intestinal lymphoid follicles (LFs) are the predominant source of intestinal C3. During enteric infection with Citrobacter rodentium or enterohemorrhagic Escherichia coli, luminal C3 levels increase significantly and are required for protection. C. rodentium is remarkably more invasive to the gut epithelium of C3-deficient mice than of wild-type mice. In the gut, C3-mediated phagocytosis of C. rodentium functions to clear pathogens. Our study reveals that variations in gut microbiota determine individuals’ intestinal mucosal C3 levels, dominantly produced by LF stromal cells, which directly correlate with protection against enteric infection. Highlights Gut complement component 3 (C3) is induced by the microbiome in healthy humans and mice at a microbiota-specific level.Gut stromal cells located in intestinal lymphoid follicles are a major source of luminal C3 During enteric infections with Citrobacter rodentium or enterohemorrhagic Escherichia coli, gut luminal C3 levels increase and are required for protection. C. rodentium is significantly more invasive of the gut epithelium in C3-deficient mice when compared to WT mice. In the gut, C3-mediated opsonophagocytosis of C. rodentium functions to clear pathogens.
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Roumani S, Jeanneau C, Giraud T, Cotten A, Laucournet M, Sohier J, Pithioux M, About I. Osteogenic Potential of a Polyethylene Glycol Hydrogel Functionalized with Poly-Lysine Dendrigrafts (DGL) for Bone Regeneration. MATERIALS (BASEL, SWITZERLAND) 2023; 16:ma16020862. [PMID: 36676600 PMCID: PMC9863473 DOI: 10.3390/ma16020862] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/28/2022] [Accepted: 01/12/2023] [Indexed: 05/27/2023]
Abstract
Resorbable hydrogels are widely used as scaffolds for tissue engineering. These hydrogels can be modified by grafting dendrimer-linked functionalized molecules (dendrigrafts). Our aim was to develop a tunable poly(L-lysine) dendrigrafts (DGL)/PEG-based hydrogel with an inverse porosity and to investigate its osteogenic potential. DGL/PEG hydrogels were emulsified in a surfactant-containing oil solution to form microspheres. The toxicity was evaluated on Human Vascular Endothelial Cells (HUVECs) and Bone Marrow Mesenchymal Stem Cells (hMSCs) with Live/Dead and MTT assays. The effects on HUVECs were investigated through C5 Complement expression by RT-PCR and C5a/TGF-β1 secretion by ELISA. Recruitment of hMSCs was investigated using Boyden chambers and their osteogenic differentiation was studied by measuring Alkaline Phosphatase activity (ALP) and BMP-2 secretion by ELISA. Adjusting the stirring speed during the emulsification allowed to obtain spherical microspheres with tunable diameters (10-1600 µm). The cell viability rate with the hydrogel was 95 and 100% with HUVECs and hMSCs, respectively. Incubating HUVECs with the biomaterial induced a 5-fold increase in TGF-β1 and a 3-fold increase in Complement C5a release. Furthermore, HUVEC supernatants obtained after incubation with the hydrogel induced a 2.5-fold increase in hMSC recruitment. The hydrogel induced a 3-fold increase both in hMSC ALP activity and BMP-2 secretion. Overall, the functionalized hydrogel enhanced the osteogenic potential by interacting with endothelial cells and hMSCs and represents a promising tool for bone tissue engineering.
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Affiliation(s)
- Sandra Roumani
- Aix-Marseille University, CNRS, ISM, 13009 Marseille, France
| | | | - Thomas Giraud
- Aix-Marseille University, CNRS, ISM, 13009 Marseille, France
- APHM, Hôpital Timone, Pôle Odontologie, 13005 Marseille, France
| | - Aurélie Cotten
- Aix-Marseille University, CNRS, ISM, 13009 Marseille, France
| | - Marc Laucournet
- Laboratory for Tissue Biology and Therapeutic Engineering (LBTI), UMR 5305, CNRS, Lyon University, 69367 Lyon, France
| | - Jérôme Sohier
- Laboratory for Tissue Biology and Therapeutic Engineering (LBTI), UMR 5305, CNRS, Lyon University, 69367 Lyon, France
| | - Martine Pithioux
- Aix-Marseille University, CNRS, ISM, 13009 Marseille, France
- Aix-Marseille University, APHM, CNRS, ISM, Sainte-Marguerite Hospital, Institute for Locomotion, Department of Orthopaedics and Traumatology, 13009 Marseille, France
| | - Imad About
- Aix-Marseille University, CNRS, ISM, 13009 Marseille, France
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Novel Complement C5 Small-interfering RNA Lipid Nanoparticle Prolongs Graft Survival in a Hypersensitized Rat Kidney Transplant Model. Transplantation 2022; 106:2338-2347. [PMID: 35749284 DOI: 10.1097/tp.0000000000004207] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Prophylaxis of antibody-mediated rejection (AMR) caused by donor-specific antibodies remains challenging. Given the critical roles of complement activity in antibody-mediated graft injury, we developed a lipid nanoparticle (LNP) formulation of small-interfering RNA against complement C5 (C5 siRNA-LNP) and investigated whether C5 siRNA-LNP could downregulate the complement activity and act as an effective treatment for AMR. METHODS Lewis recipient rats were sensitized by skin grafting from Brown Norway donor rats. Kidney transplantation was performed at 4 wk post-skin grafting.C5 siRNA- or control siRNA-LNP was administered intravenously, and the weekly injections were continued until the study's conclusion. Cyclosporin (CsA) and/or deoxyspergualin (DSG) were used as adjunctive immunosuppressants. Complement activity was evaluated using hemolysis assays. The deposition of C5b9 in the grafts was evaluated using immunohistochemical analysis on day 7 posttransplantation. RESULTS C5 siRNA-LNP completely suppressed C5 expression and complement activity (hemolytic activity ≤ 20%) 7 d postadministration. C5 siRNA-LNP in combination with CsA and DSG (median survival time: 56.0 d) prolonged graft survival compared with control siRNA-LNP in combination with CsA and DSG (median survival time: 21.0 d; P = 0.0012; log-rank test). Immunohistochemical analysis of the grafts revealed that downregulation of C5 expression was associated with a reduction in C5b9-positive area ( P = 0.0141, Steel-Dwass test). CONCLUSIONS C5 siRNA-LNP combined with immunosuppressants CsA and DSG downregulated C5 activity and significantly prolonged graft survival compared with control siRNA-LNP with CsA and DSG. Downregulation of C5 expression using C5 siRNA-LNP may be an effective therapeutic approach for AMR.
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Functional and Expressional Analyses Reveal the Distinct Role of Complement Factor I in Regulating Complement System Activation during GCRV Infection in Ctenopharyngodon idella. Int J Mol Sci 2022; 23:ijms231911369. [PMID: 36232671 PMCID: PMC9569754 DOI: 10.3390/ijms231911369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 09/17/2022] [Accepted: 09/22/2022] [Indexed: 11/23/2022] Open
Abstract
Complement factor I (CFI), a complement inhibitor, is well known for regulating the complement system activation by degrading complement component 3b (C3b) in animal serum, thus becoming involved in innate defense. Nevertheless, the functional mechanisms of CFI in the complement system and in host-pathogen interactions are far from being clarified in teleost fish. In the present study, we cloned and characterized the CFI gene, CiCFI, from grass carp (Ctenopharyngodon idella) and analyzed its function in degrading serum C3b and expression changes after grass carp reovirus (GCRV) infection. The open reading frame of CiCFI was found to be 2121 bp, encoding 706 amino acids with a molecular mass of 79.06 kDa. The pairwise alignments showed that CiCFI shared the highest identity (66.9%) with CFI from Carassius gibelio and the highest similarity (78.7%) with CFI from Danio rerio. The CiCFI protein was characterized by a conserved functional core Tryp_SPc domain with the catalytic triad and substrate binding sites. Phylogenetic analysis indicated that CiCFI and the homologs CFIs from other teleost fish formed a distinct evolutionary branch. Similar with the CFIs reported in mammals, the recombinant CiCFI protein could significantly reduce the C3b content in the serum, demonstrating the conserved function of CiCFI in the complement system in the grass carp. CiCFI mRNA and protein showed the highest expression level in the liver. After GCRV infection, the mRNA expressions of CiCFI were first down-regulated, then up-regulated, and then down-regulated to the initial level, while the protein expression levels maintained an overall downward trend to the late stage of infection in the liver of grass carps. Unexpectedly, the protein levels of CiCFI were also continuously down-regulated in the serum of grass carps during GCRV infection, while the content of serum C3b proteins first increases and then returns to the initial level, suggesting a distinct role of CiCFI in regulating complement activation and fish-virus interaction. Combining our previous results that complement factor D, a complement enhancer, shows continuously up-regulated expression levels in grass carps during GCRV infection, and this study may provide the further essential data for the full picture of complex complement regulation mechanism mediated by Df and CFI of the grass carp during pathogen infection.
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Jin S, Kusters YHAM, Houben AJHM, Plat J, Joris PJ, Mensink RP, Schalkwijk CG, Stehouwer CDA, van Greevenbroek MMJ. A randomized diet-induced weight-loss intervention reduces plasma complement C3: Possible implication for endothelial dysfunction. Obesity (Silver Spring) 2022; 30:1401-1410. [PMID: 35785477 PMCID: PMC9545581 DOI: 10.1002/oby.23467] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 04/07/2022] [Accepted: 04/09/2022] [Indexed: 11/21/2022]
Abstract
OBJECTIVE Complement C3 and other components of the alternative pathway are higher in individuals with obesity. Moreover, C3 has been identified as a risk factor for cardiovascular disease. This study investigated whether, and how, a weight-loss intervention reduced plasma C3, activated C3 (C3a), and factor D and explored potential biological effects of such a reduction. METHODS The study measured plasma C3, C3a, and factor D by ELISA and measured visceral adipose tissue, subcutaneous adipose tissue, and intrahepatic lipid by magnetic resonance imaging in lean men (n = 25) and men with abdominal obesity (n = 52). The men with obesity were randomized to habitual diet or an 8-week dietary weight-loss intervention. RESULTS The intervention significantly reduced C3 (-0.15 g/L [95% CI: -0.23 to -0.07]), but not C3a or factor D. The C3 reduction was mainly explained by reduction in visceral adipose tissue but not subcutaneous adipose tissue or intrahepatic lipid. This reduction in C3 explained a part of the weight-loss-induced improvement of markers of endothelial dysfunction, particularly the reduction in soluble endothelial selectin and soluble intercellular adhesion molecule. CONCLUSIONS Diet-induced weight loss in men with abdominal obesity could be a way to lower plasma C3 and thereby improve endothelial dysfunction. C3 reduction may be part of the mechanism via which diet-induced weight loss could ameliorate the risk of cardiovascular disease in men with abdominal obesity.
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Affiliation(s)
- Shunxin Jin
- Department of Internal Medicine, CARIM School for Cardiovascular DiseasesMaastricht University and Medical CenterMaastrichtThe Netherlands
| | - Yvo H. A. M. Kusters
- Department of Internal Medicine, CARIM School for Cardiovascular DiseasesMaastricht University and Medical CenterMaastrichtThe Netherlands
- Top Institute of Food and NutritionWageningenThe Netherlands
| | - Alfons J. H. M. Houben
- Department of Internal Medicine, CARIM School for Cardiovascular DiseasesMaastricht University and Medical CenterMaastrichtThe Netherlands
| | - Jogchum Plat
- Top Institute of Food and NutritionWageningenThe Netherlands
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht University and Medical CenterMaastrichtThe Netherlands
| | - Peter J. Joris
- Top Institute of Food and NutritionWageningenThe Netherlands
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht University and Medical CenterMaastrichtThe Netherlands
| | - Ronald P. Mensink
- Top Institute of Food and NutritionWageningenThe Netherlands
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht University and Medical CenterMaastrichtThe Netherlands
| | - Casper G. Schalkwijk
- Department of Internal Medicine, CARIM School for Cardiovascular DiseasesMaastricht University and Medical CenterMaastrichtThe Netherlands
- Top Institute of Food and NutritionWageningenThe Netherlands
| | - Coen D. A. Stehouwer
- Department of Internal Medicine, CARIM School for Cardiovascular DiseasesMaastricht University and Medical CenterMaastrichtThe Netherlands
| | - Marleen M. J. van Greevenbroek
- Department of Internal Medicine, CARIM School for Cardiovascular DiseasesMaastricht University and Medical CenterMaastrichtThe Netherlands
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11
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Jones AV, MacGregor S, Han X, Francis J, Harris C, Kavanagh D, Lotery A, Waheed N. Evaluating a Causal Relationship between Complement Factor I Protein Level and Advanced Age-Related Macular Degeneration Using Mendelian Randomization. OPHTHALMOLOGY SCIENCE 2022; 2:100146. [PMID: 35693873 PMCID: PMC9186402 DOI: 10.1016/j.xops.2022.100146] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 03/10/2022] [Accepted: 03/14/2022] [Indexed: 01/05/2023]
Abstract
Importance Risk of advanced age-related macular degeneration (AAMD) is associated with rare genetic variants in the gene encoding Complement factor I (CFI), which is associated with lower circulating CFI protein levels, but the nature of the relationship is unclear. Objective Can genetic factors be used to infer whether low circulating CFI is associated with AAMD risk? Design Two-sample inverse variance weighted Mendelian Randomisation (MR) was used to evaluate evidence for a relationship between CFI levels and AAMD risk, comparing CFI levels from genetically predefined subsets in AAMD and control cohorts. Setting Published genetic and proteomic data was combined with data from cohorts of Geographic Atrophy (GA) patients in a series of MR analyses. Participants We derived genetic instruments for systemic CFI level in 3,301 healthy European participants in the INTERVAL study. To evaluate a genetic causal odds ratio (OR) for the effect of CFI levels on AAMD risk, we used results from a genome-wide association study of 12,711 AAMD cases and 14,590 European controls from the International AMD Genomics Consortium (IAMDGC), and CFI levels from patients entered into the research studies SCOPE and SIGHT. Results We identified one common CFI variant rs7439493 which was strongly associated with low CFI level, explaining 4.8% of phenotypic variance. Using rs7439493 our MR analysis estimated that AAMD odds increased per standard deviation (SD) decrease in CFI level; OR 1.47 (95% confidence interval (CI) 1.30-1.65, P=2.1×10-10). We identified one rare variant (rs141853578 encoding p.Gly119Arg) which was genome-wide significantly associated with CFI levels after imputation; based on this, a 1 SD decrease in CFI leads to increased AAMD odds of 1.79 (95% CI 1.46-2.19, P=1.9×10-8). The rare variant rs141853578 explained a further 1.7% of phenotypic variance. To benchmark the effect of low CFI levels on AAMD odds using a CFI-specific proteomic assay, we estimated the effect using CFI levels from 24 rs141853578 positive GA patients; each 1 SD (3.5μg/mL) reduction in CFI was associated with 1.67 fold increased odds of AAMD (95% CI 1.40-2.00, P=1.85×10-8). Conclusion and relevance Excellent concordance in direction and effect size derived from rare and common variant calculations provide good genetic evidence for a potentially causal role of lower CFI level increasing AAMD risk.
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Affiliation(s)
- Amy V. Jones
- Gyroscope Therapeutics Ltd., London, United Kingdom
| | - Stuart MacGregor
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Xikun Han
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
- School of Medicine, University of Queensland, Brisbane, Australia
| | | | - Claire Harris
- Gyroscope Therapeutics Ltd., London, United Kingdom
- Clinical & Translational Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - David Kavanagh
- Clinical & Translational Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
- National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - Andrew Lotery
- Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
- Southampton Eye Unit, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
| | - Nadia Waheed
- Gyroscope Therapeutics Ltd., London, United Kingdom
- Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts
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12
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Qian X, Yang Z, Gao L, Liu Y, Yan J. The role of complement in the clinical course of hepatocellular carcinoma. Immun Inflamm Dis 2022; 10:e569. [PMID: 34813686 PMCID: PMC8926509 DOI: 10.1002/iid3.569] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/06/2021] [Accepted: 11/10/2021] [Indexed: 01/10/2023] Open
Abstract
Background The complement system, an innate immune system, may either play an antitumor role, or promote tumorigenesis and cancer progression in different kinds of cancer. The function of complement in hepatocellular carcinoma (HCC) is unclear. Methods The gene expressions of the complement system were based on data obtained from TCGA and GEO. We explored gene expressions, mutation, enrichment analysis, clinicopathology, patients' outcome, and immune infiltration via Gepia2, cBioPortal, Metascape, UALCAN, Kaplan–Meier Plotter, and TIMER 2. Results Five complement genes, including C1R, C6, C7, CFP, and CFHR3, were not only found to be significantly downregulated in HCC samples compared with normal liver samples, but also found to be significantly associated with overall survival, disease‐free survival, and progress‐free survival in HCC patients. In addition, lower mRNA expression of C1R, C6, C7, and CFHR3 were found correlated with advanced cancer stages and higher tumor grades in HCC patients. Also, the expression levels of CFP were correlated with many sets of immune markers of tumor immune cells, such as those of CD8+ T cells, CD4+ T cells, B cells, M2 macrophages, neutrophils, DCs, Th1 cells, Th2 cells, and T cell exhaustion in HCC. Based on that, we developed a prognostic model for HCC patients—Riskscore = (−0.0053)*C6+(−0.0498)*C7+(−0.1045)*CFHR3. Conclusion C1R, C6, C7, CFP, and CFHR3 could be prognostic biomarkers for patients with HCC.
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Affiliation(s)
- Xinye Qian
- Center of Hepatobiliary Pancreatic Disease, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Zhoujing Yang
- Department of Anesthesiology, Huashan Hospital, Fudan University, Shanghai, China
| | - Lu Gao
- Center of Hepatobiliary Pancreatic Disease, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Yipiao Liu
- Center of Hepatobiliary Pancreatic Disease, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Jun Yan
- Center of Hepatobiliary Pancreatic Disease, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
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13
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Santiesteban-Lores LE, Carneiro MC, Isaac L, Bavia L. Complement System in Alcohol-Associated Liver Disease. Immunol Lett 2021; 236:37-50. [PMID: 34111475 DOI: 10.1016/j.imlet.2021.05.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/20/2021] [Accepted: 05/25/2021] [Indexed: 12/19/2022]
Abstract
Innate immunity contributes effectively to the development of Alcohol-Associated liver disease (ALD). Particularly, human studies and murine models of ALD have shown that Complement activation plays an important role during the initial and later stages of ALD. The Complement System may contribute to the pathogenesis of this disease since it has been shown that ethanol-derived metabolic products activate the Complement cascade on liver membranes, leading to hepatocellular damage. However, studies evaluating the plasma levels of Complement proteins in ALD patients present contradictory results in some cases, and do not establish a well-marked role for each Complement component. The impairment of leukocyte chemoattractant activity observed in these patients may contribute to the susceptibility to bacterial infections in the latter stages of the disease. On the other hand, murine models of ALD have provided more detailed insights into the mechanisms that link the Complement System to the pathogenesis of the disease. It has been observed that Classical pathway can be activated via C1q binding to apoptotic cells in the liver and contributes to the development of hepatic inflammation. C3 contributes to the accumulation of triglycerides in the liver and in adipose tissue, while C5 seems to be involved with inflammation and liver injury after chronic ethanol consumption. In this review, we present a compendium of studies evaluating the role of Complement in human and murine models of ALD. We also discuss potential therapies to human ALD, highlighting the use of Complement inhibitors.
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Affiliation(s)
| | | | - Lourdes Isaac
- Institute of Biomedical Sciences, University of São Paulo, Brazil
| | - Lorena Bavia
- Institute of Biomedical Sciences, University of São Paulo, Brazil.
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14
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Fan X, McCullough RL, Huang E, Bellar A, Kim A, Poulsen KL, McClain CJ, Mitchell M, McCullough AJ, Radaeva S, Barton B, Szabo G, Dasarathy S, Rotroff DM, Nagy LE. Diagnostic and Prognostic Significance of Complement in Patients With Alcohol-Associated Hepatitis. Hepatology 2021; 73:983-997. [PMID: 32557728 PMCID: PMC8005264 DOI: 10.1002/hep.31419] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/06/2020] [Accepted: 05/26/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Given the lack of effective therapies and high mortality in acute alcohol-associated hepatitis (AH), it is important to develop rationally designed biomarkers for effective disease management. Complement, a critical component of the innate immune system, contributes to uncontrolled inflammatory responses leading to liver injury, but is also involved in hepatic regeneration. Here, we investigated whether a panel of complement proteins and activation products would provide useful biomarkers for severity of AH and aid in predicting 90-day mortality. APPROACH AND RESULTS Plasma samples collected at time of diagnosis from 254 patients with moderate and severe AH recruited from four medical centers and 31 healthy persons were used to quantify complement proteins by enzyme-linked immunosorbent assay and Luminex arrays. Components of the classical and lectin pathways, including complement factors C2, C4b, and C4d, as well as complement factor I (CFI) and C5, were reduced in AH patients compared to healthy persons. In contrast, components of the alternative pathway, including complement factor Ba (CFBa) and factor D (CFD), were increased. Markers of complement activation were also differentially evident, with C5a increased and the soluble terminal complement complex (sC5b9) decreased in AH. Mannose-binding lectin, C4b, CFI, C5, and sC5b9 were negatively correlated with Model for End-Stage Liver Disease score, whereas CFBa and CFD were positively associated with disease severity. Lower CFI and sC5b9 were associated with increased 90-day mortality in AH. CONCLUSIONS Taken together, these data indicate that AH is associated with a profound disruption of complement. Inclusion of complement, especially CFI and sC5b9, along with other laboratory indicators, could improve diagnostic and prognostic indications of disease severity and risk of mortality for AH patients.
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Affiliation(s)
- Xiude Fan
- Department of Inflammation and ImmunityCleveland ClinicClevelandOHUSA
- Department of Infectious DiseasesFirst Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Rebecca L McCullough
- Department of Pharmaceutical SciencesSkaggs School of Pharmacy and Pharmaceutical SciencesUniversity of Colorado Anschutz Medical CampusAuroraCOUSA
| | - Emily Huang
- Department of Inflammation and ImmunityCleveland ClinicClevelandOHUSA
| | - Annette Bellar
- Department of Inflammation and ImmunityCleveland ClinicClevelandOHUSA
| | - Adam Kim
- Department of Inflammation and ImmunityCleveland ClinicClevelandOHUSA
| | - Kyle L Poulsen
- Department of Inflammation and ImmunityCleveland ClinicClevelandOHUSA
| | - Craig J McClain
- Department of MedicineUniversity of LouisvilleLouisvilleKYUSA
| | - Mack Mitchell
- Internal MedicineUniversity of Texas Southwestern Medical CenterDallasTXUSA
| | | | | | - Bruce Barton
- Department of Population and Quantitative Health SciencesUniversity of Massachusetts Medical SchoolWorcesterMAUSA
| | - Gyongyi Szabo
- Department of MedicineBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA
| | - Srinivasan Dasarathy
- Department of Inflammation and ImmunityCleveland ClinicClevelandOHUSA
- Department of Gastroenterology and HepatologyCleveland ClinicClevelandOHUSA
- Department of Molecular MedicineCase Western Reserve UniversityClevelandOHUSA
| | - Daniel M Rotroff
- Department of Quantitative Health SciencesCleveland ClinicClevelandOHUSA
| | - Laura E Nagy
- Department of Inflammation and ImmunityCleveland ClinicClevelandOHUSA
- Department of Gastroenterology and HepatologyCleveland ClinicClevelandOHUSA
- Department of Molecular MedicineCase Western Reserve UniversityClevelandOHUSA
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15
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Malik A, Thanekar U, Amarachintha S, Mourya R, Nalluri S, Bondoc A, Shivakumar P. "Complimenting the Complement": Mechanistic Insights and Opportunities for Therapeutics in Hepatocellular Carcinoma. Front Oncol 2021; 10:627701. [PMID: 33718121 PMCID: PMC7943925 DOI: 10.3389/fonc.2020.627701] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 12/22/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a leading cause of death in the US and worldwide. HCC remains a global health problem and is highly aggressive with unfavorable prognosis. Even with surgical interventions and newer medical treatment regimens, patients with HCC have poor survival rates. These limited therapeutic strategies and mechanistic understandings of HCC immunopathogenesis urgently warrant non-palliative treatment measures. Irrespective of the multitude etiologies, the liver microenvironment in HCC is intricately associated with chronic necroinflammation, progressive fibrosis, and cirrhosis as precedent events along with dysregulated innate and adaptive immune responses. Central to these immunological networks is the complement cascade (CC), a fundamental defense system inherent to the liver which tightly regulates humoral and cellular responses to noxious stimuli. Importantly, the liver is the primary source for biosynthesis of >80% of complement components and expresses a variety of complement receptors. Recent studies implicate the complement system in liver inflammation, abnormal regenerative responses, fibrosis, carcinogenesis, and development of HCC. Although complement activation differentially promotes immunosuppressive, stimulant, and angiogenic microenvironments conducive to HCC development, it remains under-investigated. Here, we review derangement of specific complement proteins in HCC in the context of altered complement regulatory factors, immune-activating components, and their implications in disease pathogenesis. We also summarize how complement molecules regulate cancer stem cells (CSCs), interact with complement-coagulation cascades, and provide therapeutic opportunities for targeted intervention in HCC.
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Affiliation(s)
- Astha Malik
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Unmesha Thanekar
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Surya Amarachintha
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Reena Mourya
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Shreya Nalluri
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Alexander Bondoc
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Pranavkumar Shivakumar
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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16
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Valproic acid influences the expression of genes implicated with hyperglycaemia-induced complement and coagulation pathways. Sci Rep 2021; 11:2163. [PMID: 33495488 PMCID: PMC7835211 DOI: 10.1038/s41598-021-81794-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 01/11/2021] [Indexed: 01/04/2023] Open
Abstract
Because the liver plays a major role in metabolic homeostasis and secretion of clotting factors and inflammatory innate immune proteins, there is interest in understanding the mechanisms of hepatic cell activation under hyperglycaemia and whether this can be attenuated pharmacologically. We have previously shown that hyperglycaemia stimulates major changes in chromatin organization and metabolism in hepatocytes, and that the histone deacetylase inhibitor valproic acid (VPA) is able to reverse some of these metabolic changes. In this study, we have used RNA-sequencing (RNA-seq) to investigate how VPA influences gene expression in hepatocytes. Interesting, we observed that VPA attenuates hyperglycaemia-induced activation of complement and coagulation cascade genes. We also observe that many of the gene activation events coincide with changes to histone acetylation at the promoter of these genes indicating that epigenetic regulation is involved in VPA action.
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17
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Liu X, Gygi SP, Paulo JA. Isobaric Tag-Based Protein Profiling across Eight Human Cell Lines Using High-Field Asymmetric Ion Mobility Spectrometry and Real-Time Database Searching. Proteomics 2020; 21:e2000218. [PMID: 33015980 DOI: 10.1002/pmic.202000218] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/26/2020] [Indexed: 12/11/2022]
Abstract
A vast number of human cell lines are available for cell culture model-based studies, and as such the potential exists for discrepancies in findings due to cell line selection. To investigate this concept, the authors determine the relative protein abundance profiles of a panel of eight diverse, but commonly studied human cell lines. This panel includes HAP1, HEK293T, HeLa, HepG2, Jurkat, Panc1, SH-SY5Y, and SVGp12. A mass spectrometry-based proteomics workflow designed to enhance quantitative accuracy while maintaining analytical depth is used. To this end, this strategy leverages TMTpro16-based sample multiplexing, high-field asymmetric ion mobility spectrometry, and real-time database searching. The data show that the differences in the relative protein abundance profiles reflect cell line diversity. The authors also determine several hundred proteins to be highly enriched for a given cell line, and perform gene ontology and pathway analysis on these cell line-enriched proteins. An R Shiny application is designed to query protein abundance profiles and retrieve proteins with similar patterns. The workflows used herein can be applied to additional cell lines to aid cell line selection for addressing a given scientific inquiry or for improving an experimental design.
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Affiliation(s)
- Xinyue Liu
- Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA
| | - Steven P Gygi
- Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA
| | - Joao A Paulo
- Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA
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18
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Tang YY, Li YT, Zha XH, Zhang DZ, Tang BP, Liu QN, Jiang SH, Dai LS. A complement factor I (CFI) gene mediates innate immune responses in yellow catfish Pelteobagrus fulvidraco. Genomics 2020; 113:1257-1264. [PMID: 32949684 DOI: 10.1016/j.ygeno.2020.09.034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 07/23/2020] [Accepted: 09/14/2020] [Indexed: 11/28/2022]
Abstract
This study isolated CFI gene from Pelteobagrus fulvidraco and named it PfCFI. The cDNA of PfCFI is 2374 bp long, including a 52 bp 5' untranslated sequence, a 222 bp 3' untranslated sequence, and an open reading frame (ORF) of 2100 bp encoding polypeptide consisting of 699 amino acids. Phylogenetic analysis revealed that the PfCFI was closely related to CFI of Ictalurus punctatus. Real-time quantitative reverse transcription-PCR (qRT-PCR) analysis indicate that there is the PfCFI gene which expressed in all the rest of tested tissues in varied levels, and mainly distributed in liver and least in heart. The reseachers induce the expressions level of PfCFI gene in liver, spleen, head kidney and blood at different points in time after challenged with lipopolysaccharide (LPS), and polyriboinosinic polyribocytidylic acid (poly I:C), respectively. Together these results suggested that CFI gene plays an important role in resistance to pathogens in yellow catfish immunity.
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Affiliation(s)
- Ying-Yu Tang
- Jiangsu Key Laboratory for Bioresources of Saline Soils, Jiangsu Synthetic Innovation Center for Coastal Bio-agriculture, Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, School of Wetland, Yancheng Teachers University, Yancheng 224007, People's Republic of China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, People's Republic of China; College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology, Nanjing 210009, People's Republic of China
| | - Yue-Tian Li
- Jiangsu Key Laboratory for Bioresources of Saline Soils, Jiangsu Synthetic Innovation Center for Coastal Bio-agriculture, Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, School of Wetland, Yancheng Teachers University, Yancheng 224007, People's Republic of China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, College of Aquaculture and Life Science, Shanghai Ocean University, Shanghai 201306, People's Republic of China
| | - Xiao-Han Zha
- Jiangsu Key Laboratory for Bioresources of Saline Soils, Jiangsu Synthetic Innovation Center for Coastal Bio-agriculture, Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, School of Wetland, Yancheng Teachers University, Yancheng 224007, People's Republic of China
| | - Dai-Zhen Zhang
- Jiangsu Key Laboratory for Bioresources of Saline Soils, Jiangsu Synthetic Innovation Center for Coastal Bio-agriculture, Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, School of Wetland, Yancheng Teachers University, Yancheng 224007, People's Republic of China
| | - Bo-Ping Tang
- Jiangsu Key Laboratory for Bioresources of Saline Soils, Jiangsu Synthetic Innovation Center for Coastal Bio-agriculture, Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, School of Wetland, Yancheng Teachers University, Yancheng 224007, People's Republic of China
| | - Qiu-Ning Liu
- Jiangsu Key Laboratory for Bioresources of Saline Soils, Jiangsu Synthetic Innovation Center for Coastal Bio-agriculture, Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, School of Wetland, Yancheng Teachers University, Yancheng 224007, People's Republic of China.
| | - Sen-Hao Jiang
- Jiangsu Key Laboratory for Bioresources of Saline Soils, Jiangsu Synthetic Innovation Center for Coastal Bio-agriculture, Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, School of Wetland, Yancheng Teachers University, Yancheng 224007, People's Republic of China.
| | - Li-Shang Dai
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, People's Republic of China.
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Lv W, Ma A, Chi X, Li Q, Pang Y, Su P. A novel complement factor I involving in the complement system immune response from Lampetra morii. FISH & SHELLFISH IMMUNOLOGY 2020; 98:988-994. [PMID: 31712129 DOI: 10.1016/j.fsi.2019.11.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 10/08/2019] [Accepted: 11/06/2019] [Indexed: 06/10/2023]
Abstract
Complement factor I (CFI) is a serine protease which plays a key role in the modulation of complement system and the induced-fit factor responsible for controlling the complement-mediated processes. In this study, a CFI gene was cloned and characterized from Lampetra morii (designated as L-CFI) at molecular and cellular levels. The L-CFI protein included a factor I membrane attack complex domain (FIMAC), a scavenger receptor cysteine-rich domain (SRCR), a trypsin-like serine protease domain (Tryp_SPc) and 2 low-density lipoprotein receptor class A domains (LDLa) which would exhibit functional similarities to CFI superfamily proteins. Tissue expression profile analysis showed that L-CFI mRNA constitutively expressed in all tested tissues except erythrocytes, with the predominant expression in liver. The mRNA expression level of L-CFI increased significantly after Vibrio anguillarum and Staphylocccus aureus stimulation. It is demonstrated that L-CFI interacted with L-C3 protein and affected the deposition of L-C3 on the cell surface. Furthermore, lamprey serum after deplete L-CFI and L-C3 reduced the cytotoxic activity against HeLa cells. These findings suggest that L-CFI plays an important role in lamprey immunity and involved in the lamprey complement system.
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Affiliation(s)
- Wanrong Lv
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116081, China
| | - Anqi Ma
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116081, China
| | - Xiaoyuan Chi
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116081, China
| | - Qingwei Li
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116081, China
| | - Yue Pang
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116081, China.
| | - Peng Su
- College of Life Sciences, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116081, China.
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20
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Holers VM, Borodovsky A, Scheinman RI, Ho N, Ramirez JR, Dobó J, Gál P, Lindenberger J, Hansen AG, Desai D, Pihl R, Thiel S, Banda NK. Key Components of the Complement Lectin Pathway Are Not Only Required for the Development of Inflammatory Arthritis but Also Regulate the Transcription of Factor D. Front Immunol 2020; 11:201. [PMID: 32153567 PMCID: PMC7046807 DOI: 10.3389/fimmu.2020.00201] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 01/27/2020] [Indexed: 12/12/2022] Open
Abstract
The complement system plays an important role in the pathogenesis of rheumatoid arthritis (RA). Besides driving lectin pathway (LP) activation, the mannan-binding lectin (MBL)-associated serine proteases (MASPs) also play a key role in regulating the alternative pathway (AP). We evaluated the effects of N-acetylgalactosamine (GalNAc)-conjugated MASP-1 and MASP-2 duplexes in vitro and in mice with and without arthritis to examine whether knockdown of MASP-1 and MASP-2 expression affects the development of arthritis. GalNAc-siRNAs for MASP-1 and MASP-2 demonstrated robust silencing of MASP-1 or MASP-2 at pM concentrations in vitro. To evaluate the impact of silencing in arthritic mice, we used the collagen antibody-induced arthritis (CAIA) mouse model of RA. Mice were injected a 10 mg/kg dose of GalNAc-siRNAs 3x s.q. prior to the induction of CAIA. Liver gene expression was examined using qRT-PCR, and protein levels were confirmed in the circulation by sandwich immunoassays and Western blot. At day 10, CAIA mice separately treated with MASP-1 and MASP-2 duplexes had a specific reduction in expression of liver MASP-1 (70–95%, p < 0.05) and MASP-2 (90%, p < 0.05) mRNA, respectively. MASP-1-siRNA treatment resulted in a 95% reduction in levels of MASP-1 protein in circulation with no effect on MASP-2 levels and clinical disease activity (CDA). In mice injected with MASP-2 duplex, there was a significant (p < 0.05) 90% decrease in ex vivo C4b deposition on mannan, with nearly complete elimination of MASP-2 in the circulation. MASP-2 silencing initially significantly decreased CDA by 60% but subsequently changed to a 40% decrease vs. control. Unexpectedly, GalNAc-siRNA-mediated knockdown of MASP-1 and MASP-2 revealed a marked effect of these proteins on the transcription of FD under normal physiological conditions, whereas LPS-induced inflammatory conditions reversed this effect on FD levels. LPS is recognized by Toll-like receptor 4 (TLR4), we found MBL not only binds to TLR4 an interaction with a Kd of 907 nM but also upregulated FD expression in differentiated adipocytes. We show that MASP-2 knockdown impairs the development of RA and that the interrelationship between proteins of the LP and the AP may extend to the transcriptional modulation of the FD gene.
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Affiliation(s)
- V Michael Holers
- Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | | | - Robert I Scheinman
- Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Nhu Ho
- Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Joseline Ramos Ramirez
- Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - József Dobó
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Péter Gál
- Research Centre for Natural Sciences, Institute of Enzymology, Budapest, Hungary
| | - Jared Lindenberger
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, United States
| | - Annette G Hansen
- Department of Biomedicine, University of Aarhus, Aarhus, Denmark
| | - Dhruv Desai
- Alnylam Pharmaceutical Inc., Boston, MA, United States
| | - Rasmus Pihl
- Department of Biomedicine, University of Aarhus, Aarhus, Denmark
| | - Steffen Thiel
- Department of Biomedicine, University of Aarhus, Aarhus, Denmark
| | - Nirmal K Banda
- Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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21
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Jia BB, Jin CD, Li MF. The trypsin-like serine protease domain of Paralichthys olivaceus complement factor I regulates complement activation and inhibits bacterial growth. FISH & SHELLFISH IMMUNOLOGY 2020; 97:18-26. [PMID: 31830570 DOI: 10.1016/j.fsi.2019.12.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 12/07/2019] [Accepted: 12/09/2019] [Indexed: 06/10/2023]
Abstract
In mammals, complement factor I (CFI) is a serine protease in serum and plays a pivotal role in the regulation of complement activation. In the presence of cofactor, CFI cleaves C3b to iC3b, and further degrades iC3b to C3c and C3d. In teleost, the function of CFI is poorly understood. In this study, we examined the immunological property of CFI from Japanese flounder (Paralichthys olivaceus) (PoCFI), a teleost species with important economic value. PoCFI is composed of 597 amino acid residues and possesses a trypsin-like serine protease (Tryp) domain. We found that PoCFI expressions occurred in nine different tissues and were upregulated by bacterial challenge. Recombinant PoCFI-Tryp (rPoCFI-Tryp) inhibited complement activation and degraded C3b in serum. rPoCFI-Tryp exhibited apparent binding capacities to a board-spectrum of bacteria and inhibited bacterial growth. These results provide the first evidence to indicate that CFI in teleost negatively regulates complement activation via degradation C3b, and probably plays a role in host immune defense against bacterial infection.
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Affiliation(s)
- Bei-Bei Jia
- CAS Key Laboratory of Experimental Marine Biology, CAS Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; Laboratory for Marine Biology and Biotechnology, Pilot National Laboratory for Marine Science and Technology Qingdao, China; University of Chinese Academy of Sciences, Beijing, China
| | - Cheng-Dong Jin
- CAS Key Laboratory of Experimental Marine Biology, CAS Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; Laboratory for Marine Biology and Biotechnology, Pilot National Laboratory for Marine Science and Technology Qingdao, China; University of Chinese Academy of Sciences, Beijing, China
| | - Mo-Fei Li
- CAS Key Laboratory of Experimental Marine Biology, CAS Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; Laboratory for Marine Biology and Biotechnology, Pilot National Laboratory for Marine Science and Technology Qingdao, China.
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22
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Lung T, Sakem B, Risch L, Würzner R, Colucci G, Cerny A, Nydegger U. The complement system in liver diseases: Evidence-based approach and therapeutic options. J Transl Autoimmun 2019; 2:100017. [PMID: 32743505 PMCID: PMC7388403 DOI: 10.1016/j.jtauto.2019.100017] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 09/05/2019] [Accepted: 09/10/2019] [Indexed: 12/12/2022] Open
Abstract
Complement is usually seen to largely originate from the liver to accomplish its tasks systemically - its return to the production site has long been underestimated. Recent progress in genomics, therapeutic effects on complement, standardised possibilities in medical laboratory tests and involvement of complosome brings the complement system with its three major functions of opsonization, cytolysis and phagocytosis back to liver biology and pathology. The LOINC™ system features 20 entries for the C3 component of complement to anticipate the application of artificial intelligence data banks algorythms of which are fed with patient-specific data connected to standard lab assays for liver function. These advancements now lead to increased vigilance by clinicians. This reassessment article will further elucidate the distribution of synthesis sites to the three germ layer-derived cell systems and the role complement now known to play in embryogenesis, senescence, allotransplantation and autoimmune disease. This establishes the liver as part of the gastro-intestinal system in connection with nosological entities never thought of, such as the microbiota-liver-brain axis. In neurological disease etiology infectious and autoimmune hepatitis play an important role in the context of causative viz reactive complement activation. The mosaic of autoimmunity, i.e. multiple combinations of the many factors producing varying clinical pictures, leads to the manifold facets of liver autoimmunity.
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Affiliation(s)
- Thomas Lung
- Labormedizinisches Zentrum Dr. Risch, Lagerstrasse 30, CH-9470, Buchs, Switzerland
| | - Benjamin Sakem
- Labormedizinisches Zentrum Dr. Risch, Waldeggstrasse 37, CH-3097, Liebefeld bei Bern, Switzerland
| | - Lorenz Risch
- Labormedizinisches Zentrum Dr. Risch, Waldeggstrasse 37, CH-3097, Liebefeld bei Bern, Switzerland
| | - Reinhard Würzner
- Medical University Innsbruck, Division of Hygiene & Medical Microbiology, Department of Hygiene, Microbiology and Public Health, Schöpfstrasse 41, A-6020, Innsbruck, Austria
| | - Giuseppe Colucci
- Clinica Luganese Moncucco, Lugano, Via Moncucco, CH-6900, Lugano, Switzerland
- Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Andreas Cerny
- Epatocentro Ticino, Via Soldino 5, CH-6900, Lugano, Switzerland
| | - Urs Nydegger
- Labormedizinisches Zentrum Dr. Risch, Waldeggstrasse 37, CH-3097, Liebefeld bei Bern, Switzerland
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23
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Jeanneau C, Le Fournis C, About I. Xenogeneic bone filling materials modulate mesenchymal stem cell recruitment: role of the Complement C5a. Clin Oral Investig 2019; 24:2321-2329. [PMID: 31646394 DOI: 10.1007/s00784-019-03087-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 09/22/2019] [Indexed: 11/24/2022]
Abstract
OBJECTIVES When bone filling materials are applied onto the periodontal tissues in vivo, they interact with the injured periodontal ligament (PDL) tissue and modulate its activity. This may lead to mesenchymal stem cells (MSCs) recruitment from bone marrow and initiate bone regeneration. Our hypothesis is that the filling materials affect PDL cells and MSCs functional activities by modulating PDL C5a secretion and subsequent MSCs proliferation and recruitment. MATERIALS AND METHODS Materials' extracts were prepared from 3 bone-grafting materials: Gen-Os® of equine and porcine origins and bovine Bio-Oss®. Expression and secretion of C5a protein by injured PDL cells were investigated by RT-PCR and ELISA. MSCs proliferation was analyzed by MTT assay. C5a binding to MSCs C5aR and its phosphorylation was studied by ELISA. C5a implication in MSCs recruitment toward injured PDL cells was investigated using Boyden chambers. RESULTS MSCs proliferation significantly increased with Gen-Os® materials but significantly decreased with Bio-Oss®. C5a secretion slightly increased with Bio-Oss® while its level doubled with Gen-Os® materials. C5a fixation on MSCs C5aR and its phosphorylation significantly increased with Gen-Os® materials but not with Bio-Oss®. MSCs recruitment toward injured PDL cells increased with the three materials but was significantly higher with Gen-Os® materials than with Bio-Oss®. Adding C5a antagonist inhibited MSCs recruitment demonstrating a C5a-mediated migration. CONCLUSIONS Injured PDL cells secrete C5a leading MSCs proliferation and recruitment to the PDL injured cells. Gen-Os® materials enhanced both C5a secretion by injured PDL cells and MSCs recruitment. Bio-Oss® inhibited MSCs and was less efficient than Gen-Os® materials in inducing MSCs recruitment. CLINICAL RELEVANCE Within the limits of this study in vitro, Gen-Os® filling materials have a higher potential than Bio-Oss® on MSCs proliferation and C5a-dependent recruitment to the PDL injury site and the subsequent bone regeneration.
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Affiliation(s)
| | - Chloé Le Fournis
- Aix Marseille Univ, CNRS, ISM, Inst Movement Sci, Marseille, France
| | - Imad About
- Aix Marseille Univ, CNRS, ISM, Inst Movement Sci, Marseille, France.
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24
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Hu L, Zeng Z, Xia Q, Liu Z, Feng X, Chen J, Huang M, Chen L, Fang Z, Liu Q, Zeng H, Zhou X, Liu J. Metformin attenuates hepatoma cell proliferation by decreasing glycolytic flux through the HIF-1α/PFKFB3/PFK1 pathway. Life Sci 2019; 239:116966. [PMID: 31626790 DOI: 10.1016/j.lfs.2019.116966] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 10/12/2019] [Accepted: 10/13/2019] [Indexed: 12/24/2022]
Abstract
AIMS Enhanced aerobic glycolysis is an essential hallmark of malignant cancer. Blocking the glycolytic pathway has been suggested as a therapeutic strategy to impair the proliferation of tumor cells. Metformin, a widely used anti-diabetes drug, exhibits anti-tumor properties. However, the underlying molecular mechanism of its action linking glucose metabolism with the suppression of proliferation has not been fully clarified. MAIN METHODS Stable isotope tracing technology and gas chromatography-mass spectrometry method were utilized to analyze the effect of metformin on glycolytic flux in HCC cells. Western blot and immunohistochemistry were utilized to analyze the expression of phosphofructokinase-1 (PFK1) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in HCC cells or xenograft tumor tissues. Lactate measurement and glucose uptake assay were used to analyze the level of lactate and glucose in the presence of frucose-2,6-diphosphate (F2,6BP) in HCC cells treated with metformin. KEY FINDINGS We found that metformin significantly impaired hepatoma cell proliferation by inhibiting the glycolytic flux via PFK1 blockade. Interestingly, activation of PFK1 by F2,6BP reverses the inhibitory effect of metformin on hepatoma cell proliferation and glycolysis. Mechanistically, PFKFB3，a potent allosteric activator of PFK1, was markedly suppressed through inhibiting hypoxia-induced factor 1 (HIF-1α) accumulation mediated by metformin. SIGNIFICANCE Taken together these data indicate that HIF-1α/PFKFB3/PFK1 regulatory axis is a vital determinant of glucose metabolic reprogramming in hepatocellular carcinoma, which gives new insights into the action of metformin in combatting liver cancer.
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Affiliation(s)
- La Hu
- Cancer Center, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, China
| | - Zicheng Zeng
- Cancer Center, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, China
| | - Qing Xia
- Department of Oncology, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Cancer Institute, Shanghai, 200127, China
| | - Zhaoyu Liu
- Cancer Center, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, China
| | - Xiao Feng
- Cancer Center, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, China
| | - Jitao Chen
- Cancer Center, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, China
| | - Mengqiu Huang
- Cancer Institute, Southern Medical University, Guangzhou, 510515, China
| | - Liangcai Chen
- Cancer Center, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, China
| | - Zhiyuan Fang
- Cancer Center, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, China
| | - Qiuzhen Liu
- Cancer Institute, Southern Medical University, Guangzhou, 510515, China
| | - Hongbo Zeng
- Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB T6G 1H9, Canada
| | - Xinke Zhou
- Cancer Center, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, China.
| | - Jifang Liu
- Cancer Center, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, China.
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25
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Zhang SY, Jouanguy E, Zhang Q, Abel L, Puel A, Casanova JL. Human inborn errors of immunity to infection affecting cells other than leukocytes: from the immune system to the whole organism. Curr Opin Immunol 2019; 59:88-100. [PMID: 31121434 PMCID: PMC6774828 DOI: 10.1016/j.coi.2019.03.008] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 03/29/2019] [Indexed: 01/19/2023]
Abstract
Studies of vertebrate immunity have traditionally focused on professional cells, including circulating and tissue-resident leukocytes. Evidence that non-professional cells are also intrinsically essential (i.e. not via their effect on leukocytes) for protective immunity in natural conditions of infection has emerged from three lines of research in human genetics. First, studies of Mendelian resistance to infection have revealed an essential role of DARC-expressing erythrocytes in protection against Plasmodium vivax infection, and an essential role of FUT2-expressing intestinal epithelial cells for protection against norovirus and rotavirus infections. Second, studies of inborn errors of non-hematopoietic cell-extrinsic immunity have shown that APOL1 and complement cascade components secreted by hepatocytes are essential for protective immunity to trypanosome and pyogenic bacteria, respectively. Third, studies of inborn errors of non-hematopoietic cell-intrinsic immunity have suggested that keratinocytes, pulmonary epithelial cells, and cortical neurons are essential for tissue-specific protective immunity to human papillomaviruses, influenza virus, and herpes simplex virus, respectively. Various other types of genetic resistance or predisposition to infection in human populations are not readily explained by inborn variants of genes operating in leukocytes and may, therefore, involve defects in other cells. The probing of this unchartered territory by human genetics is reshaping immunology, by scaling immunity to infection up from the immune system to the whole organism.
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Affiliation(s)
- Shen-Ying Zhang
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France
| | - Emmanuelle Jouanguy
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France
| | - Qian Zhang
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
| | - Laurent Abel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France
| | - Anne Puel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France; Howard Hughes Medical Institute, New York, NY 10065, USA.
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26
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Wang Y, Luo YH, Piao XJ, Shen GN, Meng LQ, Zhang Y, Wang JR, Li JQ, Wang H, Xu WT, Liu Y, Zhang Y, Zhang T, Wang SN, Sun HN, Han YH, Jin MH, Zang YQ, Zhang DJ, Jin CH. Novel 1,4‑naphthoquinone derivatives induce reactive oxygen species‑mediated apoptosis in liver cancer cells. Mol Med Rep 2018; 19:1654-1664. [PMID: 30592276 PMCID: PMC6390020 DOI: 10.3892/mmr.2018.9785] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 11/15/2018] [Indexed: 12/13/2022] Open
Abstract
Derivatives of 1,4-naphthoquinone have excellent anti-cancer effects, but their use has been greatly limited due to their serious side effects. To develop compounds with decreased side effects and improved anti-cancer activity, two novel types of 1,4-naphthoquinone derivatives, 2,3-dihydro-2,3-epoxy-2-propylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (EPDMNQ) and 2,3-dihydro-2,3-epoxy-2-nonylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (ENDMNQ) were synthesized and their anti-tumor activities were investigated. The effects of EPDMNQ and ENDMNQ on cell viability, apoptosis and accumulation of reactive oxygen species (ROS) in liver cancer cells were determined by MTT cell viability assay and flow cytometry. The expression levels of mitochondrial, mitogen activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling pathway-associated proteins in Hep3B liver cancer cells were analyzed by western blot analysis. The results demonstrated that EPDMNQ and ENDMNQ inhibited the proliferation of liver cancer Hep3B, HepG2, and Huh7 cell lines but not that of normal liver L-02, normal lung IMR-90 and stomach GES-1 cell lines. The number of apoptotic cells and ROS levels were significantly increased following treatment with EPDMNQ and ENDMNQ, and these effects were blocked by the ROS inhibitor N-acetyl-L-cysteine (NAC) in Hep3B cells. EPDMNQ and ENDMNQ induced apoptosis by upregulating the protein expression of p38 MAPK and c-Jun N-terminal kinase and downregulating extracellular signal-regulated kinase and STAT3; these effects were inhibited by NAC. The results of the present study demonstrated that EPDMNQ and ENDMNQ induced apoptosis through ROS-modulated MAPK and STAT3 signaling pathways in Hep3B cells. Therefore, these novel 1,4-naphthoquinone derivatives may be useful as anticancer agents for the treatment of liver cancer.
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Affiliation(s)
- Yue Wang
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Ying-Hua Luo
- Department of Grass Science, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Xian-Ji Piao
- Department of Gynaecology and Obstetrics, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, Heilongjiang 163316, P.R. China
| | - Gui-Nan Shen
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Ling-Qi Meng
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Yi Zhang
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Jia-Ru Wang
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Jin-Qian Li
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Hao Wang
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Wan-Ting Xu
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Yang Liu
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Yu Zhang
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Tong Zhang
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Shi-Nong Wang
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Hu-Nan Sun
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Ying-Hao Han
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Mei-Hua Jin
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Yan-Qing Zang
- Department of Food Science and Engineering, College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Dong-Jie Zhang
- Department of Food Science and Engineering, College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
| | - Cheng-Hao Jin
- Department of Biochemistry and Molecular Biology, College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, P.R. China
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27
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Banda NK, Desai D, Scheinman RI, Pihl R, Sekine H, Fujita T, Sharma V, Hansen AG, Garred P, Thiel S, Borodovsky A, Holers VM. Targeting of Liver Mannan-Binding Lectin-Associated Serine Protease-3 with RNA Interference Ameliorates Disease in a Mouse Model of Rheumatoid Arthritis. Immunohorizons 2018; 2:274-295. [PMID: 30417171 PMCID: PMC6220895 DOI: 10.4049/immunohorizons.1800053] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Mannan-binding lectin–associated serine protease 3 (MASP-3) regulates the alternative pathway of complement and is predominantly synthesized in the liver. The role of liver-derived MASP-3 in the pathogenesis of rheumatoid arthritis (RA) is unknown. We hypothesized that liver-derived MASP-3 is essential for the development of joint damage and that targeted inhibition of MASP-3 in the liver can attenuate arthritis. We used MASP-3–specific small interfering RNAs (siRNAs) conjugated to N-acetylgalactosamine (GalNAc) to specifically target the liver via asialoglycoprotein receptors. Active GalNAc–MASP3–siRNA conjugates were identified, and in vivo silencing of liver MASP-3 mRNA was demonstrated in healthy mice. The s.c. treatment with GalNAc–MASP-3–siRNAs specifically decreased the expression of MASP-3 in the liver and the level of MASP-3 protein in circulation of mice without affecting the levels of the other spliced products. In mice with collagen Ab–induced arthritis, s.c. administration of GalNAc–MASP-3–siRNA decreased the clinical disease activity score to 50% of controls, with decrease in histopathology scores and MASP-3 deposition. To confirm the ability to perform MASP-3 gene silencing in human cells, we generated a lentivirus expressing a short hairpin RNA specific for human MASP-3 mRNA. This procedure not only eliminated the short-term (at day 15) expression of MASP-3 in HepG2 and T98G cell lines but also diminished the long-term (at day 60) synthesis of MASP-3 protein in T98G cells. Our study demonstrates that isoform-specific silencing of MASP-3 in vivo modifies disease activity in a mouse model of RA and suggests that liver-directed MASP3 silencing may be a therapeutic approach in human RA.
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Affiliation(s)
- Nirmal K Banda
- Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Dhruv Desai
- Alnylam Pharmaceuticals Inc., Boston, MA 02142
| | - Robert I Scheinman
- Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Rasmus Pihl
- Department of Biomedicine, University of Aarhus, DK-8000 Aarhus, Denmark
| | - Hideharu Sekine
- Department of Immunology, Fukushima Medical University, Fukushima 960-1295, Japan
| | - Teizo Fujita
- Department of Immunology, Fukushima Medical University, Fukushima 960-1295, Japan
| | - Vibha Sharma
- Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Annette G Hansen
- Department of Biomedicine, University of Aarhus, DK-8000 Aarhus, Denmark
| | - Peter Garred
- Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, University Hospital of Copenhagen, 2200 Copenhagen, Denmark
| | - Steffen Thiel
- Department of Biomedicine, University of Aarhus, DK-8000 Aarhus, Denmark
| | | | - V Michael Holers
- Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
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28
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Nanthapisal S, Eleftheriou D, Gilmour K, Leone V, Ramnath R, Omoyinmi E, Hong Y, Klein N, Brogan PA. Cutaneous Vasculitis and Recurrent Infection Caused by Deficiency in Complement Factor I. Front Immunol 2018; 9:735. [PMID: 29696024 PMCID: PMC5904195 DOI: 10.3389/fimmu.2018.00735] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 03/26/2018] [Indexed: 11/23/2022] Open
Abstract
Cutaneous leukocytoclastic vasculitis arises from immune complex deposition and dysregulated complement activation in small blood vessels. There are many causes, including dysregulated host response to infection, drug reactions, and various autoimmune conditions. It is increasingly recognised that some monogenic autoinflammatory diseases cause vasculitis, although genetic causes of vasculitis are extremely rare. We describe a child of consanguineous parents who presented with chronic cutaneous leukocytoclastic vasculitis, recurrent upper respiratory tract infection, and hypocomplementaemia. A homozygous p.His380Arg mutation in the complement factor I (CFI) gene CFI was identified as the cause, resulting in complete absence of alternative complement pathway activity, decreased classical complement activity, and low levels of serum factor I, C3, and factor H. C4 and C2 levels were normal. The same homozygous mutation and immunological defects were also identified in an asymptomatic sibling. CFI deficiency is thus now added to the growing list of monogenic causes of vasculitis and should always be considered in vasculitis patients found to have persistently low levels of C3 with normal C4.
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Affiliation(s)
- Sira Nanthapisal
- Infection Inflammation and Rheumatology Section, Great Ormond Street Institute of Child Health, University College London, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom.,Department of Pediatrics, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
| | - Despina Eleftheriou
- Infection Inflammation and Rheumatology Section, Great Ormond Street Institute of Child Health, University College London, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom
| | - Kimberly Gilmour
- Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom
| | - Valentina Leone
- Department of Paediatric Rheumatology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Radhika Ramnath
- Department of Histopathology, St. James University Hospital, Leeds, United Kingdom
| | - Ebun Omoyinmi
- Infection Inflammation and Rheumatology Section, Great Ormond Street Institute of Child Health, University College London, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom
| | - Ying Hong
- Infection Inflammation and Rheumatology Section, Great Ormond Street Institute of Child Health, University College London, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom
| | - Nigel Klein
- Infection Inflammation and Rheumatology Section, Great Ormond Street Institute of Child Health, University College London, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom
| | - Paul A Brogan
- Infection Inflammation and Rheumatology Section, Great Ormond Street Institute of Child Health, University College London, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom
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Reichhardt MP, Meri S. Intracellular complement activation-An alarm raising mechanism? Semin Immunol 2018; 38:54-62. [PMID: 29631809 DOI: 10.1016/j.smim.2018.03.003] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 03/26/2018] [Indexed: 12/20/2022]
Abstract
It has become increasingly apparent that the complement system, being an ancient defense mechanism, is not operative only in the extracellular milieu but also intracellularly. In addition to the known synthetic machinery in the liver and by macrophages, many other cell types, including lymphocytes, adipocytes and epithelial cells produce selected complement components. Activation of e.g. C3 and C5 inside cells may have multiple effects ranging from direct antimicrobial defense to cell differentiation and possible influence on metabolism. Intracellular activation of C3 and C5 in T cells is involved in the maintenance of immunological tolerance and promotes differentiation of T helper cells into Th1-type cells that activate cell-mediated immune responses. Adipocytes are unique in producing many complement sensor proteins (like C1q) and Factor D (adipsin), the key enzyme in promoting alternative pathway amplification. The effects of complement activation products are mediated by intracellular and cell membrane receptors, like C3aR, C5aR1, C5aR2 and the complement regulator MCP/CD46, often jointly with other receptors like the T cell receptor, Toll-like receptors and those of the inflammasomes. These recent observations link complement activation to cellular metabolic processes, intracellular defense reactions and to diverse adaptive immune responses. The complement components may thus be viewed as intracellular alarm molecules involved in the cellular danger response.
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Affiliation(s)
- M P Reichhardt
- Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
| | - S Meri
- Department of Bacteriology and Immunology, Haartman Institute, Immunobiology Research Program, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital Laboratory (HUSLAB), Helsinki, Finland.
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30
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Jin H, Yan C, Xiao T, Yan N, Xu J, Zhou L, Zhou X, Shao Q, Xia S. High fish oil diet promotes liver inflammation and activates the complement system. Mol Med Rep 2018; 17:6852-6858. [PMID: 29512716 DOI: 10.3892/mmr.2018.8687] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 02/28/2018] [Indexed: 11/06/2022] Open
Abstract
Diets rich in n-3 polyunsaturated fatty acid (n-3 PUFA) fish oil (FO) have beneficial effects in obesity‑associated metabolic disease. However, contradictory roles in inflammatory disease intervention have been reported. Our previous work revealed that a high‑FO diet promoted myeloid cell differentiation by modifying the bone marrow microenvironment; however, its effects on liver inflammation and complement system activation remain unknown. By performing ELISA, reverse transcription‑quantitative polymerase chain reaction, flow cytometry and histology on mice fed with high‑FO and low‑fat diets, the present study demonstrated that a 4‑week high‑FO diet promoted liver inflammation in mice without affecting body or liver weight. The livers of high‑FO diet mice exhibited increased infiltration of T cells and CD11b+ Gr‑1+ myeloid cells. Additionally, a higher level of IL‑1β and MCP‑1 mRNA expression was detected, suggesting that the high‑FO diet promoted liver inflammation. Further experiments indicated that the high‑FO diet increased the total hemolytic complement activity (CH50), promoted the production of the membrane attack complex and increased the levels of various complement proteins in vivo, including complement components C3, C4b, C1qb and factor B. Furthermore, higher concentrations of triglyceride were detected in the peripheral blood of high‑FO diet mice, indicating the potential protective roles of n‑3 PUFAs in FO against lipotoxicity in hyperlipidemia. Collectively, the present study demonstrated that high FO intake induced inflammation and activated the complement system in the liver. However, further study is required to determine the exact mechanisms.
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Affiliation(s)
- Huimin Jin
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Cheng Yan
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Tengfei Xiao
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Nannan Yan
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Jie Xu
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Liping Zhou
- Department of Molecular Biology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Xiaoming Zhou
- Department of Pathology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Qixiang Shao
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Sheng Xia
- Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
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The Functional Amyloid Curli Protects Escherichia coli against Complement-Mediated Bactericidal Activity. Biomolecules 2018; 8:biom8010005. [PMID: 29364839 PMCID: PMC5871974 DOI: 10.3390/biom8010005] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 01/08/2018] [Accepted: 01/16/2018] [Indexed: 12/30/2022] Open
Abstract
Escherichia coli strains may be beneficial or pathogenic. Many E. coli strains that cause human disease, especially those responsible for bacteremia and sepsis, express virulence factors that impart resistance to the complement system. The bacterial amyloid curli functions in bacterial adherence and enhances the formation of biofilms. Survival of curli-producing parental and curli-deficient mutant E. coli in the context of a human complement response was evaluated using an in vivo murine model of bacteremia. Results showed that curli production enhanced E. coli survival, which suggests that curli defends against complement-mediated killing. This observation was supported by the results of in vitro assays comparing bacterial survival in human serum. Experiments in which the classical or alternative complement pathways were blocked indicated that the classical pathway is the major contributor to complement activation and that curli inhibits this activity. Our analyses indicate that curli does not appear to play a role in protecting E. coli against alternative pathway complement activation. We found that curli increases binding of E. coli cells to complement component Complement component 1q (C1q) but does not affect Complement component 3b (C3b) binding. We conclude that curli defends E. coli against complement-mediated killing via inhibition of the classical complement pathway.
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Jager NM, Poppelaars F, Daha MR, Seelen MA. Complement in renal transplantation: The road to translation. Mol Immunol 2017; 89:22-35. [PMID: 28558950 DOI: 10.1016/j.molimm.2017.05.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 05/17/2017] [Accepted: 05/19/2017] [Indexed: 02/08/2023]
Abstract
Renal transplantation is the treatment of choice for patients with end-stage renal disease. The vital role of the complement system in renal transplantation is widely recognized. This review discusses the role of complement in the different phases of renal transplantation: in the donor, during preservation, in reperfusion and at the time of rejection. Here we examine the current literature to determine the importance of both local and systemic complement production and how complement activation contributes to the pathogenesis of renal transplant injury. In addition, we dissect the complement pathways involved in the different phases of renal transplantation. We also review the therapeutic strategies that have been tested to inhibit complement during the kidney transplantation. Several clinical trials are currently underway to evaluate the therapeutic potential of complement inhibition for the treatment of brain death-induced renal injury, renal ischemia-reperfusion injury and acute rejection. We conclude that it is expected that in the near future, complement-targeted therapeutics will be used clinically in renal transplantation. This will hopefully result in improved renal graft function and increased graft survival.
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Affiliation(s)
- Neeltina M Jager
- Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
| | - Felix Poppelaars
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Mohamed R Daha
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Nephrology, Leiden University Medical Center, University of Leiden, Leiden, The Netherlands
| | - Marc A Seelen
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Lubbers R, van Essen MF, van Kooten C, Trouw LA. Production of complement components by cells of the immune system. Clin Exp Immunol 2017; 188:183-194. [PMID: 28249350 DOI: 10.1111/cei.12952] [Citation(s) in RCA: 336] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/25/2017] [Indexed: 12/14/2022] Open
Abstract
The complement system is an important part of the innate immune defence. It contributes not only to local inflammation, removal and killing of pathogens, but it also assists in shaping of the adaptive immune response. Besides a role in inflammation, complement is also involved in physiological processes such as waste disposal and developmental programmes. The complement system comprises several soluble and membrane-bound proteins. The bulk of the soluble proteins is produced mainly by the liver. While several complement proteins are produced by a wide variety of cell types, other complement proteins are produced by only a few related cell types. As these data suggest that local production by specific cell types may have specific functions, more detailed studies have been employed recently analysing the local and even intracellular role of these complement proteins. Here we review the current knowledge about extrahepatic production and/or secretion of complement components. More specifically, we address what is known about complement synthesis by cells of the human immune system.
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Affiliation(s)
- R Lubbers
- Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands
| | - M F van Essen
- Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
| | - C van Kooten
- Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
| | - L A Trouw
- Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands
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Nong YX, Huang JL, Huang ZS, Zhou XH. Characteristics and experimental applications of human hepatocellular carcinoma cell lines. Shijie Huaren Xiaohua Zazhi 2017; 25:159-165. [DOI: 10.11569/wcjd.v25.i2.159] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
At present, primary hepatocellular carcinoma (HCC), a malignant tumor with a high incidence rate in China, is associated with a high mortality rate as well as a treatment dilemma. The research on HCC is always a hot topic. However, due to ethical considerations, research on HCC cannot directly be done in humans. The establishment of human HCC cell line model has overcome this obstacle. Derived from the tissue of human HCC, HCC cell lines have a complete set of human genes and relatively stable passages. This paper introduces the origins and characteristics of cell lines commonly used in experiments, such as SMMC7721, Bel-7402, MHCC97, HepG2, Hep3B, Huh-7, and PLC/PRF/5, as well as their roles and applications in HCC research.
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Li MF, Hu YH. C5a of Cynoglossus semilaevis has anaphylatoxin-like properties and promotes antibacterial and antiviral defense. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2016; 60:139-148. [PMID: 26934108 DOI: 10.1016/j.dci.2016.02.028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 02/27/2016] [Accepted: 02/27/2016] [Indexed: 06/05/2023]
Abstract
Activation of the complement system leads to the cleavage of component factor C5 into C5a and C5b. C5a can induce chemotaxis and inflammatory responses in mammals. The function of C5a in fish is poorly understood. In this study, we report the identification and analysis of a C5 homologue, CsC5, from tongue sole (Cynoglossus semilaevis). CsC5 is composed of 1683 amino acid residues that include an anaphylatoxin homologous domain. Expression of CsC5 could be detected in a variety of tissues and was up-regulated by bacterial or viral pathogen infection. Purified recombinant CsC5a (rCsC5a) could bind to peripheral blood leukocytes (PBL) and stimulate PBL chemotaxis, proliferation, respiratory burst, acid phosphatase activity, and phagocytosis. Tongue sole administered rCsC5a exhibited enhanced resistance against bacterial and viral infections. These results indicate that CsC5a is an anaphylatoxin with a role in innate immune defense against bacterial and viral infections.
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Affiliation(s)
- Mo-fei Li
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Yong-hua Hu
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
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36
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Yamanaka K, Kakuta Y, Miyagawa S, Nakazawa S, Kato T, Abe T, Imamura R, Okumi M, Maeda A, Okuyama H, Mizuno M, Nonomura N. Depression of Complement Regulatory Factors in Rat and Human Renal Grafts Is Associated with the Progress of Acute T-Cell Mediated Rejection. PLoS One 2016; 11:e0148881. [PMID: 26928779 PMCID: PMC4771804 DOI: 10.1371/journal.pone.0148881] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 01/25/2016] [Indexed: 01/02/2023] Open
Abstract
Background The association of complement with the progression of acute T cell mediated rejection (ATCMR) is not well understood. We investigated the production of complement components and the expression of complement regulatory proteins (Cregs) in acute T-cell mediated rejection using rat and human renal allografts. Methods We prepared rat allograft and syngeneic graft models of renal transplantation. The expression of Complement components and Cregs was assessed in the rat grafts using quantitative real-time PCR (qRT-PCR) and immunofluorescent staining. We also administered anti-Crry and anti-CD59 antibodies to the rat allograft model. Further, we assessed the relationship between the expression of membrane cofactor protein (MCP) by immunohistochemical staining in human renal grafts and their clinical course. Results qRT-PCR results showed that the expression of Cregs, CD59 and rodent-specific complement regulator complement receptor 1-related gene/protein-y (Crry), was diminished in the rat allograft model especially on day 5 after transplantation in comparison with the syngeneic model. In contrast, the expression of complement components and receptors: C3, C3a receptor, C5a receptor, Factor B, C9, C1q, was increased, but not the expression of C4 and C5, indicating a possible activation of the alternative pathway. When anti-Crry and anti-CD59 mAbs were administered to the allograft, the survival period for each group was shortened. In the human ATCMR cases, the group with higher MCP expression in the grafts showed improved serum creatinine levels after the ATCMR treatment as well as a better 5-year graft survival rate. Conclusions We conclude that the expression of Cregs in allografts is connected with ATCMR. Our results suggest that controlling complement activation in renal grafts can be a new strategy for the treatment of ATCMR.
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Affiliation(s)
- Kazuaki Yamanaka
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yoichi Kakuta
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- * E-mail: (YK); (SM)
| | - Shuji Miyagawa
- Division of Organ Transplantation, Department of Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- * E-mail: (YK); (SM)
| | - Shigeaki Nakazawa
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Taigo Kato
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Toyofumi Abe
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Ryoichi Imamura
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Masayoshi Okumi
- Department of Urology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan
| | - Akira Maeda
- Division of Organ Transplantation, Department of Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Hiroomi Okuyama
- Division of Organ Transplantation, Department of Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Masashi Mizuno
- Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Norio Nonomura
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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Savige J, Amos L, Ierino F, Mack HG, Symons RCA, Hughes P, Nicholls K, Colville D. Retinal disease in the C3 glomerulopathies and the risk of impaired vision. Ophthalmic Genet 2016; 37:369-376. [PMID: 26915021 DOI: 10.3109/13816810.2015.1101777] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Dense deposit disease and atypical hemolytic uremic syndrome are often caused by Complement Factor H (CFH) mutations. This study describes the retinal abnormalities in dense deposit disease and, for the first time, atypical haemolytic uremic syndrome. It also reviews our understanding of drusen pathogenesis and their relevance for glomerular disease. METHODS Six individuals with dense deposit disease and one with atypical haemolytic uremic syndrome were studied from 2 to 40 years after presentation. Five had renal transplants. All four who had genetic testing had CFH mutations. Individuals underwent ophthalmological review and retinal photography, and in some cases, optical coherence tomography, and further tests of retinal function. RESULTS All subjects with dense deposit disease had impaired night vision and retinal drusen or whitish-yellow deposits. Retinal atrophy, pigmentation, and hemorrhage were common. In late disease, peripheral vision was restricted, central vision was distorted, and there were scotoma from sub-retinal choroidal neovascular membranes and atypical serous retinopathy. Drusen were present but less prominent in the young person with atypical uremic syndrome due to a heterozygous CFH mutation. CONCLUSIONS Drusen are common in forms of C3 glomerulopathy caused by compound heterozygous or heterozygous CFH mutations. They are useful diagnostically but also impair vision. Drusen have an identical composition to glomerular deposits. They are also identical to the drusen of age-related macular degeneration, and may respond to the same treatments. Individuals with a C3 glomerulopathy should be assessed ophthalmologically at diagnosis, and monitored regularly for vision-threatening complications.
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Affiliation(s)
- J Savige
- a University of Melbourne Department of Medicine , Melbourne Health and Northern Health, Royal Melbourne Hospital , Parkville , Victoria , Australia.,b Department of Nephrology , Royal Melbourne Hospital , Parkville , Victoria , Australia
| | - L Amos
- a University of Melbourne Department of Medicine , Melbourne Health and Northern Health, Royal Melbourne Hospital , Parkville , Victoria , Australia
| | - Frank Ierino
- c Department of Nephrology , Austin Health , Heidelberg , Victoria , Australia
| | - H G Mack
- d University of Melbourne Department of Ophthalmology , Royal Victorian Eye and Ear Hospital , East Melbourne , Victoria , Australia
| | - R C Andrew Symons
- e Department of Ophthalmology , Royal Melbourne Hospital , Parkville Victoria , Australia.,f University of Melbourne Department of Surgery , Royal Melbourne Hospital , Parkville Victoria , Australia
| | - P Hughes
- b Department of Nephrology , Royal Melbourne Hospital , Parkville , Victoria , Australia
| | - K Nicholls
- b Department of Nephrology , Royal Melbourne Hospital , Parkville , Victoria , Australia
| | - D Colville
- a University of Melbourne Department of Medicine , Melbourne Health and Northern Health, Royal Melbourne Hospital , Parkville , Victoria , Australia
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Zhou Z, Xu MJ, Gao B. Hepatocytes: a key cell type for innate immunity. Cell Mol Immunol 2015; 13:301-15. [PMID: 26685902 PMCID: PMC4856808 DOI: 10.1038/cmi.2015.97] [Citation(s) in RCA: 310] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 10/23/2015] [Accepted: 10/23/2015] [Indexed: 02/07/2023] Open
Abstract
Hepatocytes, the major parenchymal cells in the liver, play pivotal roles in metabolism, detoxification, and protein synthesis. Hepatocytes also activate innate immunity against invading microorganisms by secreting innate immunity proteins. These proteins include bactericidal proteins that directly kill bacteria, opsonins that assist in the phagocytosis of foreign bacteria, iron-sequestering proteins that block iron uptake by bacteria, several soluble factors that regulate lipopolysaccharide signaling, and the coagulation factor fibrinogen that activates innate immunity. In this review, we summarize the wide variety of innate immunity proteins produced by hepatocytes and discuss liver-enriched transcription factors (e.g. hepatocyte nuclear factors and CCAAT/enhancer-binding proteins), pro-inflammatory mediators (e.g. interleukin (IL)-6, IL-22, IL-1β and tumor necrosis factor-α), and downstream signaling pathways (e.g. signal transducer and activator of transcription factor 3 and nuclear factor-κB) that regulate the expression of these innate immunity proteins. We also briefly discuss the dysregulation of these innate immunity proteins in chronic liver disease, which may contribute to an increased susceptibility to bacterial infection in patients with cirrhosis.
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Affiliation(s)
- Zhou Zhou
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism National Institutes of Health, Bethesda, MD, USA
| | - Ming-Jiang Xu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism National Institutes of Health, Bethesda, MD, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism National Institutes of Health, Bethesda, MD, USA
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Xiang J, Li X, Chen Y, Lu Y, Yu M, Chen X, Zhang W, Zeng Y, Sun L, Chen S, Sha Z. Complement factor I from flatfish half-smooth tongue (Cynoglossus semilaevis) exhibited anti-microbial activities. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2015; 53:199-209. [PMID: 26148855 DOI: 10.1016/j.dci.2015.06.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2015] [Revised: 05/30/2015] [Accepted: 06/06/2015] [Indexed: 06/04/2023]
Abstract
Complement factor I (Cfi) is a soluble serine protease which plays a crucial role in the modulation of complement cascades. In the presence of substrate modulating cofactors (such as complement factor H, C4bp, CR1, etc), Cfi cleaves and inactivates C3b and C4b, thereby controlling the complement-mediated processes. In this study, we sequenced and characterized Cfi gene from Cynoglossus Semilaevis (designated as CsCfi) for the first time. The full-length cDNA of CsCfi was 2230 bp in length, including a 98 bp 5'-untranslated region (UTR), a 164 bp 3'-UTR and a 1968 bp open reading frame (ORF). It encoded a polypeptide of 656 amino acids, with a molecular mass of 72.28 kDa and an isoelectric point of 7.71. A signal peptide was defined at N-terminus, resulting in a 626-residue mature protein. Multiple sequence alignment revealed that Cfi proteins were well conserved with the typical modular architecture and identical active sites throughout the vertebrates, which suggested the conserved function of Cfi. Phylogenetic analysis indicated that CsCfi and the homologous Cfi sequences from teleosts clustered into a clade, separating from another clade from the cartilaginous fish and other vertebrates. Tissue expression profile analysis by quantitative real-time PCR (qRT-PCR) showed that CsCfi mRNA constitutively expressed in all tested tissues, with the predominant expression in liver and the lowest in stomach. Temporal expression levels of CsCfi after challenging with Vibrio anguillarum showed different expression patterns in intestine, spleen, skin, blood, head kidney and liver. The recombinant CsCfi (rCsCfi) protein showed broad-spectrum antimicrobial activities against the Gram-positive bacteria Staphylococcus aureus and the Gram-negative bacteria Escherichia coli, Pseudomonas aeruginosa and Shewanella putrefaciens. The research revealed that CsCfi plays an important role in C. Semilaevis immunity.
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Affiliation(s)
- Jinsong Xiang
- Key Laboratory for Sustainable Development of Marine Fisheries, Ministry of Agriculture, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China; Colleage of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306, China; Function Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China
| | - Xihong Li
- Key Laboratory for Sustainable Development of Marine Fisheries, Ministry of Agriculture, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China; Function Laboratory for Marine Fisheries Science and Food Production Processes, National Lab for Ocean Science and Technology, Qingdao 266235, China
| | - Yadong Chen
- Key Laboratory for Sustainable Development of Marine Fisheries, Ministry of Agriculture, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China; Function Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China
| | - Yang Lu
- Key Laboratory for Sustainable Development of Marine Fisheries, Ministry of Agriculture, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China; Function Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China
| | - Mengjun Yu
- Key Laboratory for Sustainable Development of Marine Fisheries, Ministry of Agriculture, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China; Function Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China; Colleage of Fisheries and Life Science, Dalian Ocean University, Dalian 116023, China
| | - Xuejie Chen
- Key Laboratory for Sustainable Development of Marine Fisheries, Ministry of Agriculture, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China; Colleage of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306, China; Function Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China
| | - Wenting Zhang
- Key Laboratory for Sustainable Development of Marine Fisheries, Ministry of Agriculture, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China; Colleage of Fisheries and Life Science, Dalian Ocean University, Dalian 116023, China
| | - Yan Zeng
- Key Laboratory for Sustainable Development of Marine Fisheries, Ministry of Agriculture, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China; Colleage of Fisheries and Life Science, Dalian Ocean University, Dalian 116023, China
| | - Luming Sun
- Key Laboratory for Sustainable Development of Marine Fisheries, Ministry of Agriculture, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China; Colleage of Fisheries and Life Science, Dalian Ocean University, Dalian 116023, China
| | - Songlin Chen
- Key Laboratory for Sustainable Development of Marine Fisheries, Ministry of Agriculture, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China; Function Laboratory for Marine Fisheries Science and Food Production Processes, National Lab for Ocean Science and Technology, Qingdao 266235, China
| | - Zhenxia Sha
- Key Laboratory for Sustainable Development of Marine Fisheries, Ministry of Agriculture, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao 266071, China; Function Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China.
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Fearn A, Sheerin NS. Complement activation in progressive renal disease. World J Nephrol 2015; 4:31-40. [PMID: 25664245 PMCID: PMC4317626 DOI: 10.5527/wjn.v4.i1.31] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Revised: 11/14/2014] [Accepted: 12/10/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic kidney disease (CKD) is common and the cause of significant morbidity and mortality. The replacement of functioning nephrons by fibrosis is characteristic of progressive disease. The pathways that lead to fibrosis are not fully understood, although chronic non-resolving inflammation in the kidney is likely to drive the fibrotic response that occurs. In patients with progressive CKD there is histological evidence of inflammation in the interstitium and strategies that reduce inflammation reduce renal injury in pre-clinical models of CKD. The complement system is an integral part of the innate immune system but also augments adaptive immune responses. Complement activation is known to occur in many diverse renal diseases, including glomerulonephritis, thrombotic microangiopathies and transplant rejection. In this review we discuss current evidence that complement activation contributes to progression of CKD, how complement could cause renal inflammation and whether complement inhibition would slow progression of renal disease.
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Zimmer J, Hobkirk J, Mohamed F, Browning MJ, Stover CM. On the Functional Overlap between Complement and Anti-Microbial Peptides. Front Immunol 2015; 5:689. [PMID: 25646095 PMCID: PMC4298222 DOI: 10.3389/fimmu.2014.00689] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 12/22/2014] [Indexed: 12/19/2022] Open
Abstract
Intriguingly, activated complement and anti-microbial peptides share certain functionalities; lytic, phagocytic, and chemo-attractant activities and each may, in addition, exert cell instructive roles. Each has been shown to have distinct LPS detoxifying activity and may play a role in the development of endotoxin tolerance. In search of the origin of complement, a functional homolog of complement C3 involved in opsonization has been identified in horseshoe crabs. Horseshoe crabs possess anti-microbial peptides able to bind to acyl chains or phosphate groups/saccharides of endotoxin, LPS. Complement activity as a whole is detectable in marine invertebrates. These are also a source of anti-microbial peptides with potential pharmaceutical applicability. Investigating the locality for the production of complement pathway proteins and their role in modulating cellular immune responses are emerging fields. The significance of local synthesis of complement components is becoming clearer from in vivo studies of parenchymatous disease involving specifically generated, complement-deficient mouse lines. Complement C3 is a central component of complement activation. Its provision by cells of the myeloid lineage varies. Their effector functions in turn are increased in the presence of anti-microbial peptides. This may point to a potentiating range of activities, which should serve the maintenance of health but may also cause disease. Because of the therapeutic implications, this review will consider closely studies dealing with complement activation and anti-microbial peptide activity in acute inflammation (e.g., dialysis-related peritonitis, appendicitis, and ischemia).
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Affiliation(s)
- Jana Zimmer
- Department of Infectious Diseases - Medical Microbiology and Hygiene, Ruprecht-Karls-University of Heidelberg , Heidelberg , Germany
| | - James Hobkirk
- Department of Academic Endocrinology, Diabetes and Metabolism, Hull York Medical School, University of Hull , Hull , UK
| | - Fatima Mohamed
- Department of Infection, Immunity and Inflammation, University of Leicester , Leicester , UK
| | - Michael J Browning
- Department of Infection, Immunity and Inflammation, University of Leicester , Leicester , UK ; Department of Immunology, Leicester Royal Infirmary , Leicester , UK
| | - Cordula M Stover
- Department of Infection, Immunity and Inflammation, University of Leicester , Leicester , UK
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42
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Wang Y, Chen B, Ke Y, Wang C, Ye B. Molecular characterization and expression analysis of the complement factor I (CpFI) in the whitespotted bamboo shark (Chiloscyllium plagiosum). FISH & SHELLFISH IMMUNOLOGY 2014; 40:414-423. [PMID: 25108086 DOI: 10.1016/j.fsi.2014.07.031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Revised: 07/11/2014] [Accepted: 07/25/2014] [Indexed: 06/03/2023]
Abstract
Complement factor I (FI) is a plasma serine proteinase that plays an essential role in the modulation of the complement cascade. In the presence of substrate modulating cofactors (Factor H, C4bp, CR1, etc), FI cleaves the activation products of C3 (i.e. C3b) and C4 (i.e. C4b) to limit complement activity. In this study, the full length cDNA of factor I (CpFI) is isolated from the liver of the whitespotted bamboo shark (Chiloscyllium plagiosum). The CpFI cDNA is 2326 bp in length, encoding a protein of 671 amino acids, which shares 72-80% identity with FI molecules of other sharks, higher than the teleosts (37-40%) and mammals (44-47%). The sequence alignment and comparative analysis indicates the FI proteins are well conserved, with the typical modular architecture and identical active sites throughout vertebrate evolution, suggesting the conserved function. However, the additional sequence present between the leader peptide (LP) and the factor I membrane attack complex (FIMAC) domain in other fishes is also found in CpFI, which consists of two kind of tandem repeats. Phylogenetic analysis suggests that CpFI belongs to the elasmobranch clade, in parallel with the higher vertebrates, to form a sister taxa to teleosts. Expression analysis revealed that CpFI is ubiquitously distributed in a variety of tissues, with the constitutive expression in liver, which might reflect the species-specific distribution patterns of FI. Together with earlier reports, the presence of FI in various sharks might suggest the existence of a well-developed complement regulation mechanism in cartilaginous fish.
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Affiliation(s)
- Ying Wang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China
| | - Biao Chen
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China
| | - Yan Ke
- National Center for Traditional Chinese Medicine, Beijing 100027, PR China
| | - Conghui Wang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China
| | - Boping Ye
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
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43
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Kanan Y, Siefert JC, Kinter M, Al-Ubaidi MR. Complement factor H, vitronectin, and opticin are tyrosine-sulfated proteins of the retinal pigment epithelium. PLoS One 2014; 9:e105409. [PMID: 25136834 PMCID: PMC4138151 DOI: 10.1371/journal.pone.0105409] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Accepted: 07/23/2014] [Indexed: 01/09/2023] Open
Abstract
Lack of tyrosine sulfation of ocular proteins results in disorganized photoreceptor structure and drastically reduced visual function, demonstrating the importance of this post-translational modification to vision. To understand the role that tyrosine sulfation plays in the function of ocular proteins, we identified some tyrosine-sulfated proteins in the retinal pigment epithelium using two independent methods, immuno-affinity column purification with an anti-sulfotyrosine specific antibody and computer-based sequence analysis of retinal pigment epithelium secretome by means of the prediction program Sulfinator. Radioactive labeling followed by thin layer electrophoresis revealed that three proteins, vitronectin, opticin, and complement factor H (CFH), were post-translationally modified by tyrosine sulfation. The identification of vitronectin and CFH as tyrosine-sulfated proteins is significant, since both are deposited in drusen in the eyes of patients with age-related macular degeneration (AMD). Furthermore, mutations in CFH have been determined to be a major risk factor in the development of AMD. Future studies that seek to understand the role of CFH in the development of AMD should take into account the role that tyrosine sulfation plays in the interaction of this protein with its partners, and examine whether modulating sulfation provides a potential therapeutic target.
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Affiliation(s)
- Yogita Kanan
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Joseph C. Siefert
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Michael Kinter
- Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
- Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Muayyad R. Al-Ubaidi
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
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López-Lera A, Pernia O, López-Trascasa M, Ibanez de Caceres I. Expression of the SERPING1 gene is not regulated by promoter hypermethylation in peripheral blood mononuclear cells from patients with hereditary angioedema due to C1-inhibitor deficiency. Orphanet J Rare Dis 2014; 9:103. [PMID: 25053016 PMCID: PMC4115163 DOI: 10.1186/s13023-014-0103-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Accepted: 06/27/2014] [Indexed: 11/10/2022] Open
Abstract
SERPING1 mutations causing Hereditary Angioedema type I (HAE-I) due to C1-Inhibitor (C1-INH) deficiency display a dominant-negative effect usually resulting in protein levels far below the expected 50%. To further investigate mechanisms for its reduced expression, we analyzed the promoter DNA methylation status of SERPING1 and its influence on C1-INH expression. Global epigenetic reactivation correlated with C1-INH mRNA synthesis and protein secretion in Huh7 hepatoma cells. However, PBMCs extracted from controls, HAE-I and HAE-II patients presented identical methylation status of the SERPING1 promoter when analyzed by bisulphite sequencing; the proximal CpG island (exon 2) is constitutively unmethylated, while the most distant one (5.7Kb upstream the transcriptional start site) is fully methylated. These results correlate with the methylation profile observed in Huh7 cells and indicate that there is not a direct epigenetic regulation of C1-INH expression in PBMCs specific for each HAE type. Other indirect modes of epigenetic regulation cannot be excluded.
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Fang KP, Zhang JL, Ren YH, Qian YB. Talin-1 Correlates with Reduced Invasion and Migration in Human Hepatocellular Carcinoma Cells. Asian Pac J Cancer Prev 2014; 15:2655-61. [DOI: 10.7314/apjcp.2014.15.6.2655] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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46
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Pio R, Corrales L, Lambris JD. The role of complement in tumor growth. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 772:229-62. [PMID: 24272362 DOI: 10.1007/978-1-4614-5915-6_11] [Citation(s) in RCA: 142] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Complement is a central part of the immune system that has developed as a first defense against non-self cells. Neoplastic transformation is accompanied by an increased capacity of the malignant cells to activate complement. In fact, clinical data demonstrate complement activation in cancer patients. On the basis of the use of protective mechanisms by malignant cells, complement activation has traditionally been considered part of the body's immunosurveillance against cancer. Inhibitory mechanisms of complement activation allow cancer cells to escape from complement-mediated elimination and hamper the clinical efficacy of monoclonal antibody-based cancer immunotherapies. To overcome this limitation, many strategies have been developed with the goal of improving complement-mediated effector mechanisms. However, significant work in recent years has identified new and surprising roles for complement activation within the tumor microenvironment. Recent reports suggest that complement elements can promote tumor growth in the context of chronic inflammation. This chapter reviews the data describing the role of complement activation in cancer immunity, which offers insights that may aid the development of more effective therapeutic approaches to control cancer.
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Affiliation(s)
- Ruben Pio
- Oncology Division (CIMA), and Department of Biochemistry and Genetics (School of Science), University of Navarra, Pamplona, Spain,
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Abstract
Factor I (FI) is a soluble, 88 kDa glycoprotein present in plasma at a concentration of approximately 35 mg/L. FI inhibits all complement pathways as it degrades activated C4b and C3b when these are bound to a cofactor such as C4b-binding protein or factor H. Here, we describe a method for purification of FI from human plasma, which is based on affinity chromatography followed by anion exchange chromatography. We also describe a functional assay, in which activity of FI can be assessed.
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Affiliation(s)
- Sara C Nilsson
- Department of Laboratory Medicine, Section of Medical Protein Chemistry, The Wallenberg Laboratory, Lund University, Skåne University Hospital, Malmö, Sweden
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48
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Veszeli N, Füst G, Csuka D, Trauninger A, Bors L, Rozsa C, Nagy Z, Jobbágy Z, Eizler K, Prohászka Z, Varga L, Illes Z. A systematic analysis of the complement pathways in patients with neuromyelitis optica indicates alteration but no activation during remission. Mol Immunol 2013; 57:200-9. [PMID: 24172223 DOI: 10.1016/j.molimm.2013.09.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Revised: 09/10/2013] [Accepted: 09/28/2013] [Indexed: 10/26/2022]
Abstract
Neuromyelitis optica (NMO) is an autoimmune demyelinating inflammatory disorder, mediated by pathogenic autoantibodies against aquaporin 4 (AQP4), the main water channel of the central nervous system (CNS). NMO is characterized by local IgG deposition and complement activation within the CNS, but the three complement pathways have not been systematically investigated. We evaluated the overall activation of the classical, alternative, and MBL-lectin pathways in the peripheral blood of 25 patients with AQP4-seropositive NMO spectrum during remission and 113 healthy controls by three ways: (1) we measured the concentrations of native complement proteins of the three pathways [C1-inhibitor (C1-inh), C1q, C4, C3, C5, factor I, factor B, properdin]; (2) the concentrations of complement products suggesting in vivo activation (C1rC1sC1-inh, C3a, C3bBbP, and SC5b-9); and (3) the total activity of the three complement pathways. Additionally we measured levels of C1rC1sC1-inh, C3a, C3bBbP in cerebrospinal fluid (CSF) of 6 patients with relapsing NMO and of 18 patients with relapsing multiple sclerosis (MS). The serological studies indicated that total complement activity of the classical [median (interquartile range) 72 (61-82) vs. 65 (56-73) CH50/mL; p=0.0122] and of the lectin pathways [73 (59-111) vs. 49 (3-92)%; p=0.0078)] were elevated compared with the controls, whereas that of the alternative pathway was not significantly different. The levels of C3 [1.1 (0.9-1.3) vs. 1.4 (1.2-1.5)g/L; p<0.0001], factor B [89 (77-115) vs. 103 (93-113)%; p=0.0397] and factor I [85 (69-95) vs. 101 (93-107)%; p=0.0007], as well as of properdin [92 (74-104) vs. 108 (97-122)%; p=0.0028] were significantly lower in the patients than in the controls. The only increase in the patients was ascertained in the relative concentration of C1rC1sC1-inh vs. the C1-inhibitor (42.3 [31.9-65.0] vs. 30.8 [13.5-43.5] AU/mg; p=0.0007). The absolute and relative levels of the other complement activation products were not elevated in the patients. On the contrary, the serum concentrations of C3a, C3bBbP, and SC5b-9 of the patients were lower than those of the controls. The absolute concentration of the complement activation products (C1rC1sC1-inh, C3bBbP, C3a) and the ratio of C3bBbP/C1rC1sC1-inh did not differ in NMO and MS CSF samples. The ratio of C3bBbP/C1rC1sC1-inh was similar in NMO plasma and CSF samples. We found a higher ratio of C3bBbP/C1rC1sC1-inh in the plasma of control subjects compared to those in any pathological samples. Our results do not indicate substantial systemic complement activation if NMO activity is adequately controlled; nevertheless, the complement system is abnormally affected even during remission. The relative ancillarity of the alternative compared to the classical pathway may also suggest that suppression of the alternative pathway by treatment may be important to achieve remission.
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Affiliation(s)
- Nóra Veszeli
- 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
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Wang Q, Wang Y, Li Y, Gao X, Liu S, Cheng J. NS5ATP9 contributes to inhibition of cell proliferation by hepatitis C virus (HCV) nonstructural protein 5A (NS5A) via MEK/extracellular signal regulated kinase (ERK) pathway. Int J Mol Sci 2013; 14:10539-51. [PMID: 23698777 PMCID: PMC3676852 DOI: 10.3390/ijms140510539] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Revised: 04/10/2013] [Accepted: 04/15/2013] [Indexed: 01/04/2023] Open
Abstract
Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is a remarkable protein as it clearly plays multiple roles in mediating viral replication, host-cell interactions and viral pathogenesis. However, on the impact of cell growth, there have been different study results. NS5ATP9, also known as KIAA0101, p15PAF, L5, and OEACT-1, was first identified as a proliferating cell nuclear antigen-binding protein. Earlier studies have shown that NS5ATP9 might play an important role in HCV infection. The aim of this study is to investigate the function of NS5ATP9 on hepatocellular carcinoma (HCC) cell lines proliferation under HCV NS5A expression. The results showed that overexpression of NS5ATP9 inhibited the proliferation of Bel7402 cells, whereas knockdown of NS5ATP9 by interfering RNA promoted the growth of HepG2 cells. Under HCV NS5A expression, RNA interference (RNAi) targeting of NS5ATP9 could reverse the inhibition of HepG2 cell proliferation, suggesting that NS5ATP9 might be an anti-proliferation gene that plays an important role in the suppression of cell growth mediated by HCV NS5A via MEK/ERK signaling pathway. These findings might provide new insights into HCV NS5A and NS5ATP9.
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Affiliation(s)
- Qi Wang
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; E-Mails: (Q.W.); (Y.W.); (X.G.); (S.L.)
- Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China
| | - Yongsheng Wang
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; E-Mails: (Q.W.); (Y.W.); (X.G.); (S.L.)
- Institute of Materia Medica, Chinese Academy of Medical Sciences & Perking Union Medical College, Beijing 100050, China
| | - Yue Li
- Beijing Center for Physical and Chemical Analysis, Beijing 100094, China; E-Mail:
| | - Xuesong Gao
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; E-Mails: (Q.W.); (Y.W.); (X.G.); (S.L.)
- Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China
| | - Shunai Liu
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; E-Mails: (Q.W.); (Y.W.); (X.G.); (S.L.)
- Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China
| | - Jun Cheng
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; E-Mails: (Q.W.); (Y.W.); (X.G.); (S.L.)
- Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +86-10-8432-2006; Fax: +86-10-8432-2059
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Bulla R, Bossi F, Tedesco F. The complement system at the embryo implantation site: friend or foe? Front Immunol 2012; 3:55. [PMID: 22566936 PMCID: PMC3341982 DOI: 10.3389/fimmu.2012.00055] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Accepted: 03/02/2012] [Indexed: 12/19/2022] Open
Abstract
An inflammatory-like process and vascular remodeling represent the main changes that occur in decidua in the early phase of pregnancy. These changes are partly induced by trophoblast cells that colonize the decidua and are also contributed by the complement system, which can easily be activated as a result of tissue remodeling. Local control by several complement regulators including surface-bound and soluble molecules is critical to prevent complement-mediated tissue damage in normal pregnancy. C7 expressed on the endothelial cells (ECs) surface has been recognized as a novel complement regulator involved in the control of the proinflammatory effect of the terminal complement complex. The protective role of placental complement regulators in pregnancy is underscored by the recent finding of an association of preeclampsia with mutations in the genes encoding for some of these proteins. Complement components produced at feto-maternal interface serve an important function in placental development. C1q synthesized by decidual ECs and expressed on the cell surface is particularly important in this regard because it acts as a molecular bridge between endovascular trophoblast and ECs. C1q is also produced by extravillous trophoblast and is used to favor trophoblast migration through the decidua. Defective expression of C1q by trophoblast is associated with impaired trophoblast invasion of decidua and may have important implications in pregnancy disorders such as preeclampsia characterized by reduced vascular remodeling.
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Affiliation(s)
- R Bulla
- Department of Life Sciences, University of Trieste Trieste, Italy
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