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1.
Biochemistry (Mosc) ; 84(5): 529-539, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31234767

RESUMO

Hypoxia plays a critical role in progression of atherosclerosis. Local oxygen deficiency in a plaque creates a specific microenvironment that alters the transcriptome of resident cells, particularly of macrophages. Reverse cholesterol transport from plaque to liver is considered a main mechanism for regression of atherosclerosis. Ubiquitously expressed ATP-binding cassette transporter A1 (ABCA1) and liver- and small intestine-derived apolipoprotein A-1 (ApoA-1) are two main actors in this process. We recently reported endogenous apoA-1 expression in human macrophages. While ABCA1 and ApoA-1 have antiatherogenic properties, the role of complement factor C3 is controversial. Plasma C3 level positively correlates with the risk of cardiovascular diseases. On the other hand, C3 gene knockout in a murine atherosclerosis model increases both plaque size and triglycerides level in blood. In the present study, we show for the first time that a hypoxia-mimicking agent, CoCl2, induces the upregulation of the apoA-1 and C3 genes and the accumulation of intracellular and membrane protein ApoA-1 in THP-1 macrophages. The MEK1/2-Erk1/2 and MKK4/7-JNK1/2/3 cascades are involved in upregulation of ABCA1 and C3 via activation of transcription factor NF-κB, which interacts with the HIF-1α subunit of hypoxia-inducible factor 1 (HIF-1). The three major MAP-kinase cascades (Erk1/2, JNK1/2/3, and p38) and the NF-κB transcription factor are involved in the hypoxia-induced expression of the apoA-1 gene in THP-1 macrophages.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Apolipoproteína A-I/metabolismo , Hipóxia Celular , Complemento C3/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Apolipoproteína A-I/genética , Linhagem Celular Tumoral , Cobalto/farmacologia , Complemento C3/análise , Complemento C3/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Regulação para Cima/efeitos dos fármacos
2.
Fish Shellfish Immunol ; 91: 376-387, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31125666

RESUMO

As a core component of the complement system, complement component 3 (C3) plays a central role in the opsonization of pathogens, immune defense and immune regulation in the mammalian for its activation is required to trigger classical as well as alternative complement pathways. However, the molecular mechanism underlying C3 activation in invertebrates remains unknown. Several C3 genes have been characterized in invertebrates but very few in crustacean. To understand the molecular characterization and immunological functions of shrimp C3, we characterized a novel complement C3 like gene (designated Lv-C3L) with full-length cDNA sequence identified from pacific white shrimp Litopenaeus vannamei in the present study. The full length cDNA of Lv-C3L sequence was 4769 bp (GenBank accession number: MH638255) containing a 4077 bp open reading frame (ORF), which encodes 1358 amino acids contained a putative signal peptide of 17 amino acids. Six model motifs of C3 were found in Lv-C3L including typical A2M domain, a highly conserved thioester region (GCGEQ) and proteolytic cleavage site of ANATO. In addition to typical conservative domains, Lv-C3L also contains a particular GLN-rich region which might be involved in the protein interaction and transcriptional activation. The transcripts of Lv-C3L were mainly detected in hemocytes and gill which might be involved in defense response. At 36 h post V.parahaemolyticus and B.thuringensis infection, the expression level of Lv-C3L gene in hemocytes were significantly upregulated. At 48 h and 72 h post WSSV infection, the expression level of Lv-C3L gene in hemocytes and gill were significantly upregulated. These results indicated that Lv-C3L gene play a pivotal role in innate immune responses to the WSSV and G+/G- bacterial infection. The obvious immune function of Lv-C3L was described as an effective membrane rupture in bacteriolytic and hemolytic activities on V.parahaemolyticus, V.anguillarum and rabbit erythrocytes. Combining with WSSV copy number, WSSV-VP28 gene expression profile and shrimp cumulative mortality analysis, RNAi knockdown of Lv-C3L gene could obviously promote the in vivo propagation of WSSV in shrimp. This is the first report in crustaceans that Lv-C3L, as a key complement like components, is involved in shrimp antiviral immune response. It is speculated that complicated complement response cascade may exist in shrimp. These results collectively indicated that the complement pathway in shrimp might play an important protective role against pathogenic infection and activation of complement pathway including C3 could restrict the propagation of WSSV.


Assuntos
Complemento C3/genética , Complemento C3/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Penaeidae/genética , Penaeidae/imunologia , Sequência de Aminoácidos , Animais , Proteínas de Artrópodes/química , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/imunologia , Sequência de Bases , Complemento C3/química , Perfilação da Expressão Gênica , Filogenia , Alinhamento de Sequência , Vírus da Síndrome da Mancha Branca 1/fisiologia
3.
Fish Shellfish Immunol ; 88: 189-197, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30826411

RESUMO

Complement is traditionally recognized as part of the innate immune system, defending the host against the invasion of foreign pathogens. In complement system, C3 (complement component 3) is a central component. Therefore, research into C3 can help us better understand the functions of fish complement system. In this study, we detected the grass carp C3 (gcC3) mRNA expression in all sample tissues from healthy grass carp, which was highest in the liver, followed by the heart and the spleen, and lowest in the muscle, head kidney, trunk kidney, blood and intestine. After infection with Aeromonas hydrophila, gcC3 mRNA expression levels were significantly upregulated in the gill, liver, spleen, intestine, trunk kidney and head kidney. Interestingly, C3 protein levels were downregulated and subsequently upregulated in the liver and serum. Histologically, C3 protein at 24 h pi was over expressed in necrotic liver sites, and the liver index (LI) at this point was significantly higher than that of the control. These findings are indicated that C3 plays an important role in the immune response of grass carp after A. hydrophila infection, and C3 protein may play an assistant role in repairing liver tissues from A. hydrophila injury.


Assuntos
Aeromonas hydrophila , Carpas/imunologia , Complemento C3/genética , Doenças dos Peixes/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Animais , Carpas/microbiologia , Complemento C3/metabolismo , Doenças dos Peixes/microbiologia , Expressão Gênica , Infecções por Bactérias Gram-Negativas/imunologia , Imunidade Inata , Fígado/microbiologia , Fígado/patologia
4.
Fish Physiol Biochem ; 45(3): 965-976, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30656452

RESUMO

Lipopolysaccharides (LPS) and salinity are important variables in aquatic environments. High concentration of LPS and large changes in salinity seriously threat the survival of a variety of organisms, including fish. To reveal the effects of salinity and LPS on a fish immune response, we measured the immune-related parameters (total leukocyte count, total serum protein, albumin and globulin concentrations, complement C3 concentration, and lysozyme activity) and genes (the expressions of TNF-α, IL-1ß, and SOCS1-3 at the mRNA and protein levels) of juvenile Takifugu fasciatus exposed to phosphate buffered saline (PBS) or LPS (25 µg mL-1) under different salinities (0, 15, and 30 ppt) for 24 h. Changes in key immunological indicators suggested that the LPS challenge induced considerable damage to T. fasciatus, whereas an increase in salinity mitigated the harmful effects. Moreover, although the immune responses in blood and other selected tissues (gill and kidney) were suppressed with an increase in salinity, the increased response in liver in saltwater enabled T. fasciatus to conquer large salinity variation during migration. The appropriate addition of salts appeared to be a sensible strategy to mitigate LPS-induced toxicity in the aquaculture of T. fasciatus.


Assuntos
Salinidade , Tolerância ao Sal , Takifugu/imunologia , Envelhecimento , Albuminas/metabolismo , Animais , Proteínas Sanguíneas/metabolismo , Complemento C3/genética , Complemento C3/metabolismo , Citocinas/genética , Citocinas/metabolismo , Exposição Ambiental/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Brânquias/fisiologia , Globulinas/metabolismo , Muramidase , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Água/química
5.
Lipids Health Dis ; 18(1): 5, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30611277

RESUMO

OBJECTIVE: Coronary artery disease (CAD) is a multi-factor disease. Complement component 3 (C3) plays an important role in the development of CAD. The present study investigated the association between DNA methylation status of C3 gene promoter and the risk of CAD. METHODS: One hundred CAD patients and 1 hundred age-and gender- matched controls were recruited in current study. Methylation levels in CpG island in C3 promoter were determined by the method of bisulfite amplicon sequencing. RESULTS: Methylation levels of four CpG sites in C3 promoter were measured. There were no significant difference in methylation level of each CpG site between CAD patients and controls. Average methylation rate was also calculated. No significant difference in average methylation rate was observed between CAD and control groups. Stratified analyses based on EH, DM and smoking status were carried out, no significant association between C3 promoter methylation levels and the susceptibility of CAD was observed. Furthermore, seven haplotypes were established and no significant difference in haplotypes was observed between CAD and control groups. However, our study showed that C3 DNA methylation levels were positively associated with LDL-C levels. CONCLUSION: The present study showed no association between methylation levels of C3 promoter and the risk of CAD. However, the methylation levels might be related to LDL-C levels.


Assuntos
Complemento C3/genética , Doença da Artéria Coronariana/genética , Metilação de DNA , Epigênese Genética , Regiões Promotoras Genéticas , Idoso , Estudos de Casos e Controles , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Complemento C3/imunologia , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/imunologia , Doença da Artéria Coronariana/patologia , Ilhas de CpG , Diabetes Mellitus/sangue , Diabetes Mellitus/imunologia , Diabetes Mellitus/fisiopatologia , Feminino , Expressão Gênica , Haplótipos , Humanos , Hipertensão/sangue , Hipertensão/imunologia , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fumar/sangue , Fumar/imunologia , Fumar/fisiopatologia , Triglicerídeos/sangue
6.
Fish Shellfish Immunol ; 86: 196-203, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30458310

RESUMO

Complement C3 is a pivotal component of three cascades of complement activation. C3 in circulation is mainly provided by the hepatic cecum. The expression and secretion of C3 by hepatocytes is increased during acute inflammation. The detailed information on the regulationary mechanism underlying C3 transcriptional activation is limited. Here, we characterized the 5'-flanking region of the amphioxus C3 gene. To functionally analyze the upstream regulatory region of the C3 gene, a series of luciferase reporter gene constructs containing deleted or mutant regulatory elements were prepared. Using luciferase assay, we revealed that a potential C-JUN-1 binding sites within the proximal promoter region were necessary for full activation of the C3 promoter, whereas NF-κB, AP-1, C-JUN-2 and NFAT transcription factor binding sites played roles in governing the promoter activity at a homeostatic level. Our data also indicated that sp600125, a c-Jun N-terminal kinase (JNK) inhibitor, decreased lipopolysaccharide (LPS)-stimulated C3 promoter activity, mRNA expression and protein secretion using western blotting and quantitative real-time PCR analysis. These findings demonstrated that JNK signaling pathway is involved in the regulation of C3 gene transcription by targeting C-JUN transcription factor binding sites in the 5'-flanking promoter region, leading to LPS-induced C3 activation and therefore providing a potential target for regulating C3 expression.


Assuntos
Complemento C3/metabolismo , Anfioxos/metabolismo , Ativação Transcricional/efeitos dos fármacos , Animais , Sítios de Ligação , Complemento C3/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Anfioxos/genética , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases , Regiões Promotoras Genéticas/efeitos dos fármacos , Transdução de Sinais
7.
J Clin Invest ; 129(1): 422-436, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30382946

RESUMO

The negatively charged sugar sialic acid (Sia) occupies the outermost position in the bulk of cell surface glycans. Lack of sialylated glycans due to genetic ablation of the Sia-activating enzyme CMP-sialic acid synthase (CMAS) resulted in embryonic lethality around day 9.5 post coitum (E9.5) in mice. Developmental failure was caused by complement activation on trophoblasts in Cmas-/- implants and was accompanied by infiltration of maternal neutrophils at the fetal-maternal interface, intrauterine growth restriction, impaired placental development, and a thickened Reichert's membrane. This phenotype, which shared features with complement receptor 1-related protein Y (Crry) depletion, was rescued in E8.5 Cmas-/- mice upon injection of cobra venom factor, resulting in exhaustion of the maternal complement component C3. Here we show that Sia is dispensable for early development of the embryo proper but pivotal for fetal-maternal immune homeostasis during pregnancy, i.e., for protecting the allograft implant against attack by the maternal innate immune system. Finally, embryos devoid of cell surface sialylation suffered from malnutrition due to inadequate placentation as a secondary effect.


Assuntos
Ativação do Complemento/imunologia , Complemento C3/imunologia , Feto/imunologia , Troca Materno-Fetal/imunologia , Ácido N-Acetilneuramínico/imunologia , Trofoblastos/imunologia , Animais , Ativação do Complemento/genética , Complemento C3/genética , Feminino , Troca Materno-Fetal/genética , Camundongos , Camundongos Knockout , Ácido N-Acetilneuramínico/genética , Gravidez , Receptores de Complemento/genética , Receptores de Complemento/imunologia
8.
Fish Shellfish Immunol ; 84: 865-875, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30389643

RESUMO

The complement system plays an important role in protecting fish against attack by pathogens early in life. Complement component C3 is a central component in the complement system. The present work aimed to clone the full length C3 cDNA sequence of southern catfish (Silurus meridionalis), detect the tissue expression patterns of C3, investigate the ontogeny of C3 in embryo and larva, and assess the expression of C3 in response to pathogen infection. The full length C3 cDNA sequence of 5157 bp with an open reading frame (ORF) of 4938 bp was cloned from southern catfish. The deduced amino acid sequence showed similarity with other teleost fish. The mRNA expression of C3 was detected in liver, spleen, stomach, intestine, and head kidney with RT-PCR and in situ hybridization. Whole mount in situ hybridization results revealed that C3 was first expressed in the yolk syncytial layer at 34 h post fertilization (hpf), followed by the liver at 36 h post hatching (hph). When challenged with Aeromonas hydrophila, the transcripts of C3 showed a significant up-regulation in liver and spleen at 24 h. The results suggested that complement C3 played a key role in defense against invading pathogens in the early development stages of southern catfish. Therefore, these results provide important information to understand the functions of C3 during fish early development in Siluriformes.


Assuntos
Peixes-Gato/genética , Peixes-Gato/imunologia , Complemento C3/genética , Complemento C3/imunologia , Doenças dos Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Imunidade Adaptativa/genética , Aeromonas hydrophila/fisiologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Complemento C3/química , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Filogenia , Alinhamento de Sequência/veterinária
9.
Immunology ; 156(1): 69-73, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30179254

RESUMO

Vaccines can serve as essential tools to prevent bacterial diseases via the induction of long-lasting IgG responses. The efficacy of such vaccines depends on the effector mechanisms triggered by IgG. The complement system and Fc-gamma receptors (FcγRs) can potentially play a crucial role in IgG-mediated immunity against bacterial diseases. However, their relative importance in vivo is unclear, and has been the object of controversy and debate. In this brief study, we have used gene-targeted mice lacking either FcγRI, II, II and IV or the C3 complement component as well as a novel mouse strain lacking both C3 and FcγRs to conclusively show the essential role of complement in antibody-mediated host resistance to Salmonella enterica systemic infection. By comparing the effect of IgG2a antibodies against Salmonella O-antigen in gene-targeted mice, we demonstrate that the complement system is essential for the IgG-mediated reduction of bacterial numbers in the tissues.


Assuntos
Complemento C3/metabolismo , Antígenos O/imunologia , Receptores de IgG/metabolismo , Infecções por Salmonella/imunologia , Vacinas contra Salmonella/imunologia , Salmonella enterica/fisiologia , Animais , Carga Bacteriana , Ativação do Complemento , Complemento C3/genética , Humanos , Imunidade Humoral , Imunoglobulina G/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de IgG/genética
10.
Nephrology (Carlton) ; 24(3): 357-364, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29292855

RESUMO

AIM: The aim of the present study was to characterize the molecular basis of complement factor I deficiency in Tunisian atypical haemolytic and uremic syndrome patients with low factor I levels. METHODS: Six adults and seven children were enrolled in this study. Complement factor I levels were assessed by a homemade sandwich ELISA and ranged between 12.5% and 60%. Genomic DNA was amplified by way of a polymerase chain reaction using intronic primers flanking the 13 coding exons. Sequencing of amplified products was carried out by the dye terminator sequencing method. Molecular study was performed on parental samples for three dead paediatric patients. The control group consisted of 100 healthy Tunisian donors. RESULTS: We identified a total of 13 substitutions and one insertion: seven in introns, four in exons and three in UTR. The new mutations were c.-132G > C, c.71 + 181 T > A in 5'UTR and intron 1, respectively. Three intronic polymorphisms were predicted to have impact on splicing events: c.482 + 6C > T, c.884-42_884-41insTTAAA (rs34422850) and c.1429 + 33 A > G (rs9998151). They were three missense mutations leading to a p.Ile 357Met, p.Ile416Leu and p.GLu548Gln. p.Ile 357Met was found in two patients and one relative. Half of the patients had associated mutation and/or polymorphisms. CONCLUSION: This is the first genetic study in Tunisian and Maghrebin atypical haemolytic and uraemic syndrome patients. The high occurrence of Ile357Met mutation may reflect a founding effect. Functional impact of the two new mutations c.-132G > C and c.71 + 181A > T have to be studied. Association of simultaneous genetic abnormalities may explain the variability of atypical haemolytic and uraemic syndrome, penetrance and disease phenotype.


Assuntos
Síndrome Hemolítico-Urêmica Atípica , Complemento C3/deficiência , Fator I do Complemento , Doenças Genéticas Inatas , Adulto , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/epidemiologia , Síndrome Hemolítico-Urêmica Atípica/genética , Criança , Pré-Escolar , Estudos de Coortes , Complemento C3/genética , Fator I do Complemento/análise , Fator I do Complemento/genética , Feminino , Doenças Genéticas Inatas/sangue , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Humanos , Lactente , Masculino , Mutação , Polimorfismo Genético , Tunísia/epidemiologia
11.
Curr Diabetes Rev ; 15(1): 44-48, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29663892

RESUMO

INTRODUCTION: Increased systemic inflammation plays a significant role in the development of adult cardiometabolic diseases such as insulin resistance, dyslipidemia, atherosclerosis, and hypertension. The complement system is a part of the innate immune system and plays a key role in the regulation of inflammation. Of particular importance is the activation of complement components C3 and C4. C3 is produced primarily by the liver but is also produced in adipocytes, macrophages and endothelial cells, all of which are present in adipose tissues. Dietary fat and chylomicrons stimulate C3 production. Adipocytes in addition to producing C3 also have receptors for activated C3 and other complement components and thus also respond to as well as produce a target for complement. C3adesArg, also known as acylation stimulation factor, increases adipocyte triglyceride synthesis and release. These physiological effects play a significant role in the development of metabolic syndrome. Epidemiologically, obese adults and non-obese adults with cardiometabolic disease who are not obese have been shown to have increased complement levels. C4 levels also correlate with body mass index. Genetically, specific C3 polymorphisms have been shown to predict future cardiovascular events and. D decreased C4 long gene copy number is associated with increased longevity. CONCLUSION: Future research is clearly needed to clarify the role of complement in the development of cardiovascular disease and mechanisms for its action. The complement system may provide a new area for intervention in the prevention of cardiometabolic diseases.


Assuntos
Complemento C3/fisiologia , Complemento C4/fisiologia , Síndrome Metabólica/imunologia , Adulto , Complemento C3/genética , Complemento C4/genética , Via Clássica do Complemento/genética , Humanos , Resistência à Insulina/fisiologia , Síndrome Metabólica/etiologia , Síndrome Metabólica/genética , Obesidade/complicações , Obesidade/genética , Obesidade/imunologia , Obesidade/metabolismo
12.
Nephrology (Carlton) ; 24(2): 263-271, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29280536

RESUMO

AIM: The aim of the present study was to screen and verify downstream genes involved in the epithelial mesenchymal transition (EMT) induced by paired box 2 (PAX2) in NRK-52E cells. METHODS: NRK-52E cells were transfected with lentivirus carrying PAX2 gene or no-load virus respectively. Total RNA was isolated 72 h after transfection from PAX2-overexpressing cells and control cells. Isolated RNA was then hybridized with the Rat OneArray Plus expression profile chip. The chips were examined by Agilent 0.1 XDR to screen for differentially expressed genes, which were further analyzed to investigate complement-related genes as genes of interest. RESULTS: In NRK-52E cells, PAX2 overexpression promoted EMT followed by upregulation of 298 genes and downregulation of 293 genes. KEGG analysis indicated the differential expression of genes related to cytokines and their receptors, extracellular matrix (ECM), MAPKs, local adhesion, cancer, the complement cascade, and coagulation. Gene oncology analysis screened out genes related to molecular functions (e.g., hydrolase activity, phospholipase activity, components of the ECM) and biological processes (e.g., cell development, signal transduction, phylogeny), and cell components (e.g., cytoplasm, cell membrane, and ECM). Analysis of the complement system revealed upregulation of C3 and downregulation of CD55 and complement regulator factor H (CFH). CONCLUSION: PAX2 overexpression upregulates EMT in vitro and may regulate C3, CD55, and CFH.


Assuntos
Proteínas do Sistema Complemento/metabolismo , Transição Epitelial-Mesenquimal , Túbulos Renais/metabolismo , Fator de Transcrição PAX2/metabolismo , Animais , Western Blotting , Antígenos CD55/genética , Antígenos CD55/metabolismo , Linhagem Celular , Complemento C3/genética , Complemento C3/metabolismo , Fator H do Complemento/genética , Fator H do Complemento/metabolismo , Proteínas do Sistema Complemento/genética , Transição Epitelial-Mesenquimal/genética , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Túbulos Renais/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Fator de Transcrição PAX2/genética , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais
13.
Front Immunol ; 9: 2524, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30443255

RESUMO

It is now increasingly recognized that some monogenic autoinflammatory diseases and immunodeficiencies cause vasculitis, although genetic causes of vasculitis are extremely rare. We describe a child of non-consanguineous parents who presented with cutaneous vasculitis, digital ischaemia and hypocomplementaemia. A heterozygous p.R1042G gain-of-function mutation (GOF) in the complement component C3 gene was identified as the cause, resulting in secondary C3 consumption and complete absence of alternative complement pathway activity, decreased classical complement activity, and low levels of serum C3 with normal C4 levels. The same heterozygous mutation and immunological defects were also identified in another symptomatic sibling and his father. C3 deficiency due GOF C3 mutations 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.


Assuntos
Complemento C3/genética , Mutação com Ganho de Função/genética , Isquemia/genética , Dermatopatias/genética , Vasculite/genética , Criança , Complemento C4/genética , Feminino , Heterozigoto , Humanos , Masculino
14.
J. physiol. biochem ; 74(4): 559-568, nov. 2018. tab, graf
Artigo em Inglês | IBECS | ID: ibc-179034

RESUMO

Obesity is usually associated with low-grade inflammation, which determines the appearance of comorbidities like atherosclerosis and insulin resistance. Infiltrated macrophages in adipose tissue are partly responsible of this inflammatory condition. Numerous studies point to the existence of close intercommunication between macrophages and adipocytes and pay particular attention to the proinflammatory cytokines released by both cell types. However, it has been recently described that in both, circulation and tissue level, there are extracellular vesicles (including microvesicles and exosomes) containing miRNAs, mRNAs, and proteins that can influence the inflammatory response. The objective of the present research is to investigate the effect of exosomes released by lipopolysaccharide (LPS)-activated macrophages on gene expression and cell metabolism of adipocytes, focusing on the differential exosomal miRNA pattern between LPS- and non-activated macrophages. The results show that the exosomes secreted by the macrophages do not influence the preadipocyte-to-adipocyte differentiation process, fat storage, and insulin-mediated glucose uptake in adipocytes. However, exosomes induce changes in adipocyte gene expression depending on their origin (LPS- or non-activated macrophages), including genes such as CXCL5, SOD, TNFAIP3, C3, and CD34. Some of the pathways or metabolic processes upregulated by exosomes from LPS-activated macrophages are related to inflammation (complement activation, regulation of reactive oxygen species, migration and activation of leukocyte, and monocyte chemotaxis), carbohydrate catabolism, and cell activation. miR-530, chr9_22532, and chr16_34840 are more abundant in exosomes from LPS-activated macrophages, whereas miR-127, miR-143, and miR-486 are more abundant in those secreted by non-activated macrophages


No disponible


Assuntos
Humanos , Adipócitos Brancos/fisiologia , Adipogenia , Regulação da Expressão Gênica , Resistência à Insulina , Ativação de Macrófagos , Macrófagos/fisiologia , Absorção Fisiológica , Adipócitos Brancos/citologia , Adipócitos Brancos/imunologia , Antígenos CD34/metabolismo , Comunicação Celular , Quimiocina CXCL5/genética , Quimiocina CXCL5/metabolismo , Técnicas de Cocultura , Complemento C3/genética , Complemento C3/metabolismo
15.
MBio ; 9(5)2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30301856

RESUMO

Acute respiratory distress syndrome (ARDS) is immune-driven pathologies that are observed in severe cases of severe acute respiratory syndrome coronavirus (SARS-CoV) infection. SARS-CoV emerged in 2002 to 2003 and led to a global outbreak of SARS. As with the outcome of human infection, intranasal infection of C57BL/6J mice with mouse-adapted SARS-CoV results in high-titer virus replication within the lung, induction of inflammatory cytokines and chemokines, and immune cell infiltration within the lung. Using this model, we investigated the role of the complement system during SARS-CoV infection. We observed activation of the complement cascade in the lung as early as day 1 following SARS-CoV infection. To test whether this activation contributed to protective or pathologic outcomes, we utilized mice deficient in C3 (C3-/-), the central component of the complement system. Relative to C57BL/6J control mice, SARS-CoV-infected C3 -/- mice exhibited significantly less weight loss and less respiratory dysfunction despite equivalent viral loads in the lung. Significantly fewer neutrophils and inflammatory monocytes were present in the lungs of C3 -/- mice than in C56BL/6J controls, and subsequent studies revealed reduced lung pathology and lower cytokine and chemokine levels in both the lungs and the sera of C3 -/- mice than in controls. These studies identify the complement system as an important host mediator of SARS-CoV-induced disease and suggest that complement activation regulates a systemic proinflammatory response to SARS-CoV infection. Furthermore, these data suggest that SARS-CoV-mediated disease is largely immune driven and that inhibiting complement signaling after SARS-CoV infection might function as an effective immune therapeutic.IMPORTANCE The complement system is a critical part of host defense to many bacterial, viral, and fungal infections. It works alongside pattern recognition receptors to stimulate host defense systems in advance of activation of the adaptive immune response. In this study, we directly test the role of complement in SARS-CoV pathogenesis using a mouse model and show that respiratory disease is significantly reduced in the absence of complement even though viral load is unchanged. Complement-deficient mice have reduced neutrophilia in their lungs and reduced systemic inflammation, consistent with the observation that SARS-CoV pathogenesis is an immune-driven disease. These data suggest that inhibition of complement signaling might be an effective treatment option following coronavirus infection.


Assuntos
Ativação do Complemento , Interações Hospedeiro-Patógeno/imunologia , Pulmão/imunologia , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/imunologia , Animais , Quimiocinas/sangue , Complemento C3/deficiência , Complemento C3/genética , Citocinas/sangue , Modelos Animais de Doenças , Feminino , Imunidade Inata , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos C57BL , Vírus da SARS/imunologia , Síndrome Respiratória Aguda Grave/virologia , Carga Viral , Replicação Viral
16.
Kidney Int ; 94(6): 1141-1150, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30322716

RESUMO

Properdin is the only known positive regulator of complement activation by stabilizing the alternative pathway convertase through C3 binding, thus prolonging its half-life. Recent in vitro studies suggest that properdin may act as a specific pattern recognition molecule. To better understand the role of properdin in vivo, we used an experimental model of acute anti-glomerular basement membrane disease with wild-type, C3- and properdin knockout mice. The model exhibited severe proteinuria, acute neutrophil infiltration and activation, classical and alternative pathway activation, and progressive glomerular deposition of properdin, C3 and C9. Although the acute renal injury was likely due to acute neutrophil activation, we found properdin deposition in C3-knockout mice that was not associated with IgG. Thus, properdin may deposit in injured tissues in vivo independent of its main ligand C3.


Assuntos
Doença Antimembrana Basal Glomerular/imunologia , Ativação do Complemento/imunologia , Complemento C3/imunologia , Properdina/imunologia , Animais , Doença Antimembrana Basal Glomerular/patologia , Complemento C3/genética , Complemento C3/metabolismo , Modelos Animais de Doenças , Feminino , Membrana Basal Glomerular/citologia , Membrana Basal Glomerular/imunologia , Membrana Basal Glomerular/patologia , Humanos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Properdina/genética , Properdina/metabolismo , Ligação Proteica/imunologia
17.
BMC Ophthalmol ; 18(1): 274, 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30352574

RESUMO

BACKGROUND: The purpose of this study is to discuss whether genetic variants (rs2230199, rs1047286, rs2230205, and rs2250656) in the C3 gene account for a significant risk of advanced AMD. METHODS: We performed a meta-analysis using electronic databases to search relevant articles. A total of 40 case-control studies from 38 available articles (20,673 cases and 20,025 controls) were included in our study. RESULTS: In our meta-analysis, the pooled results showed that the carriage of G allele for rs2230199 and the T allele for rs1047286 had a tendency to the risk of advanced AMD (OR = 1.49, 95% CI = 1.39-1.59, P < 0.001; OR = 1.45, 95% CI = 1.37-1.54, P < 0.001). Moreover, in the subgroup analysis based on ethnicity, rs2230199 and rs1047286 polymorphisms were more likely to be a predictor of response for Caucasian region (OR = 1.48, 95% CI = 1.38-1.59, P < 0.001; OR = 1.45, 95% CI = 1.37-1.54, P < 0.001). Besides, pooled results suggested that the G allele of rs2230199 could confer susceptibility to advanced AMD in Middle East (OR = 1.62, 95% CI = 1.33-1.97, P < 0.001). CONCLUSION: In our meta-analysis, C3 genetic polymorphisms unveiled a positive effect on the risk of advanced AMD, especially in Caucasians. Furthermore, numerous well-designed studies with large sample-size are required to validate this conclusion.


Assuntos
Complemento C3/genética , Predisposição Genética para Doença , Degeneração Macular/genética , Alelos , Frequência do Gene , Estudos de Associação Genética , Variação Genética , Humanos , Polimorfismo de Nucleotídeo Único
18.
Am J Physiol Renal Physiol ; 315(6): F1747-F1758, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30256128

RESUMO

We previously showed that complement 3 (C3) is highly expressed in mesenchymal tissues in spontaneously hypertensive rats (SHR). We targeted C3 gene by zinc-finger nuclease (ZFN) gene-editing technology and investigated blood pressure and phenotype in SHR. Blood pressure was measured by tail-cuff and telemetry methods. Histology and expression of liver X receptor α (LXRα), renin, Krüppel-like factor 5 (KLF5), and E-cadherin were evaluated in kidneys. Mesangial cells (MCs) were removed from glomeruli from three strains, and we evaluated the phenotype in vitro. SHR showed the salt-sensitive hypertension that was abolished in C3 knockout (KO) SHR. Proliferation of MCs from SHR was higher than that from Wistar-Kyoto (WKY) rats and showed a synthetic phenotype. Renal injury scores were higher in SHR than in WKY rats and C3 KO SHR. Expression of E-cadherin was lower, and expression of renin was higher in the nephrotubulus from SHR than WKY rats and C3 KO SHR. Expression of C3 α-chain protein and α-smooth muscle actin protein was significantly higher in renal medulla from SHR than from WKY rats. Expression of angiotensinogen, LXRα, renin, and KLF5 mRNA was increased in kidney from SHR compared with C3 KO SHR. Intrarenal angiotensin II levels were significantly higher in kidney from SHR than WKY rats and C3 KO SHR. Urinary epinephrine and norepinephrine excretions were significantly higher in SHR than in WKY rats and C3 KO SHR. These findings showed that increased C3 induces salt-sensitive hypertension with increases in urinary catecholamine excretion and intrarenal activation of the renin-angiotensin system by the dedifferentiation of mesenchymal tissues in kidney from SHR.


Assuntos
Pressão Sanguínea , Complemento C3/metabolismo , Hipertensão/metabolismo , Rim/metabolismo , Sistema Renina-Angiotensina , Cloreto de Sódio na Dieta , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Animais , Pressão Sanguínea/genética , Caderinas/genética , Caderinas/metabolismo , Desdiferenciação Celular , Proliferação de Células , Células Cultivadas , Complemento C3/genética , Modelos Animais de Doenças , Predisposição Genética para Doença , Hipertensão/genética , Hipertensão/patologia , Hipertensão/fisiopatologia , Rim/patologia , Rim/fisiopatologia , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Masculino , Fenótipo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Transgênicos , Renina/genética , Renina/metabolismo , Sistema Renina-Angiotensina/genética , Transdução de Sinais
19.
J Cell Mol Med ; 22(12): 6087-6098, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30246940

RESUMO

Diabetes is considered as a risk for cognitive decline, which is characterized by neurodegenerative alteration and innate immunity activation. Recently, complement 3 (C3), the critical central component of complement system, has been reported to play a key role in neurodegenerative alterations under pathological condition. Receptor for advanced glycation end products (RAGE) activation is confirmed to mediate several inflammatory cytokines production. However, whether C3 activation participates in the diabetic neuropathology and whether this process is regulated by RAGE activation remains unknown. The present study aimed to investigate the role of C3 in streptozotocin-induced diabetic mice and high glucose-induced primary astrocytes and the underlying modulatory mechanisms. The decreased synaptophysin density and increased C3 deposition at synapses were observed in the diabetic brain compared to the control brain. Furthermore, the elevated C3 was co-localized with GFAP-positive astrocytes in the diabetic brain slice in vivo and high glucose-induced astrocytes culture in vitro. Diabetes/high glucose-induced up-regulation of C3 expression at gene, protein and secretion levels, which were attenuated by pre-treatment with RAGE, p38MAPK and NF-κB inhibitors separately. These results demonstrate that high glucose induces C3 up-regulation via RAGE- p38MAPK-NF-κB signalling in vivo and in vitro, which might be associated with synaptic protein loss.


Assuntos
Complemento C3/genética , Diabetes Mellitus Experimental/genética , Diabetes Mellitus/genética , Receptor para Produtos Finais de Glicação Avançada/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Células Cultivadas , Ativação do Complemento/efeitos dos fármacos , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Diabetes Mellitus Experimental/patologia , Glucose/administração & dosagem , Produtos Finais de Glicação Avançada/genética , Humanos , Sistema de Sinalização das MAP Quinases/genética , Camundongos , NF-kappa B/genética , Sinapses/genética , Sinapses/metabolismo , Fator de Transcrição RelA/genética
20.
Am J Med Sci ; 356(2): 114-120, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30219152

RESUMO

BACKGROUND: In immunoglobulin A nephropathy (IgAN), complement activation occurs in both the systemic circulation and in situ (glomerular). A recent IgAN-genome-wide association study (GWAS) identified 1q32 as an IgAN susceptible locus that contained the complement regulatory protein coding gene complement factor H (CFH). Here, we explored the combined genetic effects of coding and noncoding variants in CFH, rs6677604 and rs800292 on complement activation in IgAN. METHODS: In total, 1,194 IgAN patients and 900 healthy controls who were the same as the Beijing Discovery Cohort in our recent IgAN-GWAS were recruited. The genotyping information of rs800292 and rs6677604 were extracted from GWAS data, while the information regarding plasma C3 levels and mesangial C3 deposits were collected from medical records. RESULTS: We found both rs800292-GG and rs6677604-GG were risk genotypes for complement activation in IgAN patients, as represented by lower plasma C3 levels in IgAN patients with rs800292-GG and a higher intensity of glomerular C3 deposits in those with rs6677604-GG, respectively. Additionally, IgAN patients with 2 risk genotypes (rs800292-GG and rs6677604-GG) showed a higher degree of complement activation compared to those with no risk genotypes (rs800292-AA/AG and rs6677604-AA/AG), as represented by both lower plasma C3 levels and a higher intensity of glomerular C3 deposits. Moreover, when compared to rs800292 or rs6677604 alone, the combined genetic effects of rs800292 and rs6677604 showed a stronger association with IgAN susceptibility. CONCLUSIONS: Our findings suggested that both coding and noncoding variants in CFH acted synergistically to regulate the degree of complement activation and thereby contributed to IgAN susceptibility.


Assuntos
Cromossomos Humanos Par 1/genética , Loci Gênicos , Genótipo , Glomerulonefrite por IGA/genética , Polimorfismo Genético , Adulto , Cromossomos Humanos Par 1/metabolismo , Ativação do Complemento/genética , Complemento C3/genética , Complemento C3/metabolismo , Fator H do Complemento/genética , Fator H do Complemento/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Glomerulonefrite por IGA/metabolismo , Glomerulonefrite por IGA/patologia , Humanos , Masculino
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