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2.
Nat Immunol ; 18(12): 1288-1298, 2017 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-29144501

RESUMO

Progress at the beginning of the 21st century transformed the perception of complement from that of a blood-based antimicrobial system to that of a global regulator of immunity and tissue homeostasis. More recent years have witnessed remarkable advances in structure-function insights and understanding of the mechanisms and locations of complement activation, which have added new layers of complexity to the biology of complement. This complexity is readily reflected by the multifaceted and contextual involvement of complement-driven networks in a wide range of inflammatory and neurodegenerative disorders and cancer. This Review provides an updated view of new and previously unanticipated functions of complement and how these affect immunity and disease pathogenesis.


Assuntos
Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Imunidade Inata/imunologia , Linfócitos T CD4-Positivos/imunologia , Proteínas do Sistema Complemento/metabolismo , Homeostase/imunologia , Humanos , Inflamação/imunologia , Neoplasias/imunologia
4.
J Pharmacol Exp Ther ; 389(1): 87-95, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38448247

RESUMO

The organic anion transporting polypeptide (OATP)2B1 [(gene: solute carrier organic anion transporter family member 2B1 (SLCO2B1)] is an uptake transporter that facilitates cellular accumulation of its substrates. Comparison of SLCO2B1+/+ knockin and rSlco2b1-/- knockout rats showed a higher expression of rCYP3A1 in the humanized animals. We hypothesize that humanization of OATP2B1 not only affects cellular uptake but also metabolic activity. To further investigate this hypothesis, we used SLCO2B1+/+ and rSlco2b1-/ - rats and the OATP2B1 and rCYP3A1 substrate erlotinib, which is metabolized to OSI-420, for in vivo and ex vivo experiments. One hour after administration of a single dose of erlotinib, the knockin rats exhibited significantly lower erlotinib serum levels, but no change was observed in metabolite concentration or the OSI-420/erlotinib ratio. Similar results were obtained for liver tissue levels comparing SLCO2B1+/+ and rSlco2b1-/- rats. Liver microsomes isolated from the erlotinib-treated animals were characterized ex vivo for rCYP3A activity using testosterone, showing higher activity in the knockin rats. The contrary was observed when microsomes isolated from treatment-naïve animals were assessed for the metabolism of erlotinib to OSI-420. The latter is in contrast to the higher rCYP3A1 protein amount observed by western blot analysis in rat liver lysates and liver microsomes isolated from untreated rats. In summary, rats humanized for OATP2B1 showed higher expression of rCYP3A1 in liver and reduced serum levels of erlotinib but no change in the OSI-420/erlotinib ratio despite a lower OSI-420 formation in isolated liver microsomes. Studies with CYP3A-specific substrates are warranted to evaluate whether humanization affects not only rCYP3A1 expression but also metabolic activity in vivo. SIGNIFICANCE STATEMENT: Humanization of rats for the organic anion transporting polypeptide (OATP)2B1 increases rCYP3A1 expression and activity in liver. Using the OATP2B1/CYP3A-substrate erlotinib to assess the resulting phenotype, we observed lower erlotinib serum and liver concentrations but no impact on the liver/serum ratio. Moreover, there was no difference in the OSI-420/erlotinib ratio comparing humanized and knockout rats, suggesting that OSI-420 is not applicable to monitor differences in rCYP3A1 expression as supported by data from ex vivo experiments with rat liver microsomes.


Assuntos
Citocromo P-450 CYP3A , Transportadores de Ânions Orgânicos , Ratos , Animais , Cloridrato de Erlotinib/farmacologia , Citocromo P-450 CYP3A/metabolismo , Quinazolinas/farmacologia , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo
5.
Proc Natl Acad Sci U S A ; 118(26)2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34155115

RESUMO

Complement is an important effector mechanism for antibody-mediated clearance of infections and tumor cells. Upon binding to target cells, the antibody's constant (Fc) domain recruits complement component C1 to initiate a proteolytic cascade that generates lytic pores and stimulates phagocytosis. The C1 complex (C1qr2s2) consists of the large recognition protein C1q and a heterotetramer of proteases C1r and C1s (C1r2s2). While interactions between C1 and IgG-Fc are believed to be mediated by the globular heads of C1q, we here find that C1r2s2 proteases affect the capacity of C1q to form an avid complex with surface-bound IgG molecules (on various 2,4-dinitrophenol [DNP]-coated surfaces and pathogenic Staphylococcus aureus). The extent to which C1r2s2 contributes to C1q-IgG stability strongly differs between human IgG subclasses. Using antibody engineering of monoclonal IgG, we reveal that hexamer-enhancing mutations improve C1q-IgG stability, both in the absence and presence of C1r2s2 In addition, hexamer-enhanced IgGs targeting S. aureus mediate improved complement-dependent phagocytosis by human neutrophils. Altogether, these molecular insights into complement binding to surface-bound IgGs could be important for optimal design of antibody therapies.


Assuntos
Membrana Celular/metabolismo , Complemento C1q/metabolismo , Complemento C1r/metabolismo , Complemento C1s/metabolismo , Imunoglobulina G/metabolismo , Ativação do Complemento , Humanos , Microscopia de Força Atômica , Mutação/genética , Fagocitose , Ligação Proteica , Multimerização Proteica , Estabilidade Proteica , Staphylococcus aureus/imunologia
6.
Am J Hematol ; 98 Suppl 4: S82-S89, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36755352

RESUMO

Within a short few years, the number of complement inhibitors that are either approved for therapeutic application or evaluated in late-stage clinical trials has expanded remarkably. The sudden emergence of this target area in the pipelines of many biotech start-ups and even large pharmaceutical companies appears even more surprising when considering that the involvement of the complement system in various clinical conditions had long been recognized. In many aspects, however, the complement system is far from being a traditional drug target, which may explain the delayed breakthrough of this therapeutic strategy. While complement modulation is now considered an attractive "platform technology" with applications in a wide spectrum of disorders, the broad yet heterogeneous disease involvement of the complement system has long restricted its placement in traditional drug discovery programs. Concerns about the safety of complement-targeted interventions, the large number and high plasma concentrations of target proteins, and the complexity of the complement system's engagement in biological processes are among other factors that kept complement off the drug discovery radar for decades. Alongside technical advances and financial incentives, the innovation and persistence of academic and clinical researchers have been the critical driving force to navigate complement therapeutics out of the shadow into the spotlight. In this commentary, we document this remarkable development using select examples and aim to venture some predictions where this promising field may be headed to.


Assuntos
Ativação do Complemento , Proteínas do Sistema Complemento , Humanos , Descoberta de Drogas , Inativadores do Complemento/farmacologia , Inativadores do Complemento/uso terapêutico
7.
Angew Chem Int Ed Engl ; 62(52): e202314280, 2023 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-37947772

RESUMO

Carbohydrate-binding proteins are generally characterized by poor affinities for their natural glycan ligands, predominantly due to the shallow and solvent-exposed binding sites. To overcome this drawback, nature has exploited multivalency to strengthen the binding by establishing multiple interactions simultaneously. The development of oligovalent structures frequently proved to be successful, not only for proteins with multiple binding sites, but also for proteins that possess a single recognition domain. Herein we present the syntheses of a number of oligovalent ligands for Siglec-8, a monomeric I-type lectin found on eosinophils and mast cells, alongside the thermodynamic characterization of their binding. While the enthalpic contribution of each binding epitope was within a narrow range to that of the monomeric ligand, the entropy penalty increased steadily with growing valency. Additionally, we observed a successful agonistic binding of the tetra- and hexavalent and, to an even larger extent, multivalent ligands to Siglec-8 on immune cells and modulation of immune cell activation. Thus, triggering a biological effect is not restricted to multivalent ligands but could be induced by low oligovalent ligands as well, whereas a monovalent ligand, despite binding with similar affinity, showed an antagonistic effect.


Assuntos
Eosinófilos , Polissacarídeos , Ligantes , Polissacarídeos/química , Eosinófilos/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo
8.
Clin Immunol ; 235: 108785, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34147650

RESUMO

The FDA approval of pegcetacoplan (Empaveli), a PEGylated compstatin-based C3 therapeutic, as a new treatment for paroxysmal nocturnal hemoglobinuria (PNH) marks a milestone in the history of complement drug discovery. Almost 15 years after the approval of the first complement-specific drug for PNH, the anti-C5 antibody eculizumab, a novel class of complement inhibitors with a distinct mechanism of action finally enters the clinic. This landmark decision broadens the spectrum of available complement therapeutics, offering patients with unmet clinical needs or insufficient responses to anti-C5 therapy an alternative treatment option with a broad activity profile. Here we present a brief historical account of this newly approved complement drug, consolidating its approval within the long research record of the compstatin family of peptidic C3 inhibitors.


Assuntos
Complemento C3/antagonistas & inibidores , Hemoglobinúria Paroxística/tratamento farmacológico , Peptídeos Cíclicos/farmacologia , Complemento C3/metabolismo , Aprovação de Drogas , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peptídeos Cíclicos/química
9.
Nat Immunol ; 11(9): 785-97, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20720586

RESUMO

Nearly a century after the significance of the human complement system was recognized, we have come to realize that its functions extend far beyond the elimination of microbes. Complement acts as a rapid and efficient immune surveillance system that has distinct effects on healthy and altered host cells and foreign intruders. By eliminating cellular debris and infectious microbes, orchestrating immune responses and sending 'danger' signals, complement contributes substantially to homeostasis, but it can also take action against healthy cells if not properly controlled. This review describes our updated view of the function, structure and dynamics of the complement network, highlights its interconnection with immunity at large and with other endogenous pathways, and illustrates its multiple roles in homeostasis and disease.


Assuntos
Proteínas do Sistema Complemento/imunologia , Homeostase/imunologia , Vigilância Imunológica/imunologia , Apoptose/imunologia , Doença , Regulação da Expressão Gênica , Humanos , Transdução de Sinais
10.
Nat Immunol ; 10(7): 728-33, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19503104

RESUMO

Factor H (FH) is an abundant regulator of complement activation and protects host cells from self-attack by complement. Here we provide insight into the regulatory activity of FH by solving the crystal structure of the first four domains of FH in complex with its target, complement fragment C3b. FH interacted with multiple domains of C3b, covering a large, extended surface area. The structure indicated that FH destabilizes the C3 convertase by competition and electrostatic repulsion and that FH enables proteolytic degradation of C3b by providing a binding platform for protease factor I while stabilizing the overall domain arrangement of C3b. Our results offer general models for complement regulation and provide structural explanations for disease-related mutations in the genes encoding both FH and C3b.


Assuntos
Complemento C3b/química , Fator H do Complemento/química , Estrutura Terciária de Proteína , Sítios de Ligação , Complemento C3b/genética , Complemento C3b/metabolismo , Fator H do Complemento/genética , Fator H do Complemento/metabolismo , Cristalografia por Raios X , Humanos , Substâncias Macromoleculares/química , Substâncias Macromoleculares/metabolismo , Modelos Moleculares , Mutação , Ligação Proteica
11.
Nat Immunol ; 10(7): 721-7, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19503103

RESUMO

Activation of the complement system generates potent chemoattractants and leads to the opsonization of cells for immune clearance. Short-lived protease complexes cleave complement component C3 into anaphylatoxin C3a and opsonin C3b. Here we report the crystal structure of the C3 convertase formed by C3b and the protease fragment Bb, which was stabilized by the bacterial immune-evasion protein SCIN. The data suggest that the proteolytic specificity and activity depend on the formation of dimers of C3 with C3b of the convertase. SCIN blocked the formation of a productive enzyme-substrate complex. Irreversible dissociation of the complex of C3b and Bb is crucial to complement regulation and was determined by slow binding kinetics of the Mg(2+)-adhesion site in Bb. Understanding the mechanistic basis of the central complement-activation step and microbial immune evasion strategies targeting this step will aid in the development of complement therapeutics.


Assuntos
Proteínas de Bactérias/química , C3 Convertase da Via Alternativa do Complemento/química , Proteínas Inativadoras do Complemento/química , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Catálise , Domínio Catalítico , Complemento C3/química , Complemento C3/metabolismo , C3 Convertase da Via Alternativa do Complemento/metabolismo , Convertases de Complemento C3-C5/química , Convertases de Complemento C3-C5/metabolismo , Complemento C3b/química , Complemento C3b/metabolismo , Proteínas Inativadoras do Complemento/imunologia , Proteínas Inativadoras do Complemento/metabolismo , Via Alternativa do Complemento/imunologia , Cristalografia por Raios X , Humanos , Cinética , Modelos Moleculares , Ligação Proteica , Multimerização Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Staphylococcus aureus/química , Staphylococcus aureus/imunologia , Staphylococcus aureus/metabolismo , Especificidade por Substrato , Ressonância de Plasmônio de Superfície
12.
Chimia (Aarau) ; 75(6): 495-499, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34233811

RESUMO

Among the many molecular entities suitable for therapeutic use, peptides have emerged as a particularly attractive option for academic drug discovery and development. Their modular structure and extendibility, the availability of powerful and affordable screening platforms, and the relative ease-of-synthesis render therapeutic peptides highly approachable for teaching and research alike. With a strong focus on the therapeutic modulation of host defence pathways, including the complement and renin-angiotensin systems, the Molecular Pharmacy group at the University of Basel strongly relies on peptides to introduce students to practical aspects of modern drug design, to discover novel therapeutics for immune and inflammatory diseases, and to expand on options for the preclinical development of a promising drug class. Current projects reach from student-driven iterative design of peptidic angiotensin-converting enzyme inhibitors and the use of phage display technology to discover novel immune modulators to the development of protective peptide coatings for biomaterials and transplants and the structure-activity-relationship-guided optimization of therapeutic peptide drug candidates in late-stage clinical trials. Even at the current stage, peptides allow for a perfect circle between pharmaceutical research and education, and the recent spark of clinical applications for peptide-based drugs may only increase the value and relevance of this versatile drug class.


Assuntos
Desenho de Fármacos , Peptídeos , Descoberta de Drogas , Homeostase , Humanos
13.
Clin Immunol ; 214: 108391, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32229292

RESUMO

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss among the elderly population. Genetic studies in susceptible individuals have linked this ocular disease to deregulated complement activity that culminates in increased C3 turnover, retinal inflammation and photoreceptor loss. Therapeutic targeting of C3 has therefore emerged as a promising strategy for broadly intercepting the detrimental proinflammatory consequences of complement activation in the retinal tissue. In this regard, a PEGylated second-generation derivative of the compstatin family of C3-targeted inhibitors is currently in late-stage clinical development as a treatment option for geographic atrophy, an advanced form of AMD which lacks approved therapy. While efficacy has been strongly suggested in phase 2 clinical trials, crucial aspects still remain to be defined with regard to the ocular bioavailability, tissue distribution and residence, and dosing frequency of such inhibitors in AMD patients. Here we report the intraocular distribution and pharmacokinetic profile of the fourth-generation compstatin analog, Cp40-KKK in cynomolgus monkeys following a single intravitreal injection. Using a sensitive surface plasmon resonance (SPR)-based competition assay and ELISA, we have quantified both the amount of inhibitor and the concentration of C3 retained in the vitreous of Cp40-KKK-injected animals. Cp40-KKK displays prolonged intraocular residence, being detected at C3-saturating levels for over 3 months after a single intravitreal injection. Moreover, we have probed the distribution of Cp40-KKK within the ocular tissue by means of immunohistochemistry and highly specific anti-Cp40-KKK antibodies. Both C3 and Cp40-KKK were detected in the retinal tissue of inhibitor-injected animals, with prominent co-localization in the choroid one-month post intravitreal injection. These results attest to the high retinal tissue penetrance and target-driven distribution of Cp40-KKK. Given its subnanomolar binding affinity and prolonged ocular residence, Cp40-KKK constitutes a promising drug candidate for ocular pathologies underpinned by deregulated C3 activation.


Assuntos
Complemento C3/antagonistas & inibidores , Olho/química , Idoso , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Injeções Intravítreas , Macaca fascicularis , Retina/química , Fatores de Tempo , Distribuição Tecidual
14.
EMBO J ; 35(10): 1133-49, 2016 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-27013439

RESUMO

Regulators of complement activation (RCA) inhibit complement-induced immune responses on healthy host tissues. We present crystal structures of human RCA (MCP, DAF, and CR1) and a smallpox virus homolog (SPICE) bound to complement component C3b. Our structural data reveal that up to four consecutive homologous CCP domains (i-iv), responsible for inhibition, bind in the same orientation and extended arrangement at a shared binding platform on C3b. Large sequence variations in CCP domains explain the diverse C3b-binding patterns, with limited or no contribution of some individual domains, while all regulators show extensive contacts with C3b for the domains at the third site. A variation of ~100° rotation around the longitudinal axis is observed for domains binding at the fourth site on C3b, without affecting the overall binding mode. The data suggest a common evolutionary origin for both inhibitory mechanisms, called decay acceleration and cofactor activity, with variable C3b binding through domains at sites ii, iii, and iv, and provide a framework for understanding RCA disease-related mutations and immune evasion.


Assuntos
Complemento C3b/química , Complemento C3b/metabolismo , Sítios de Ligação , Antígenos CD55/química , Antígenos CD55/metabolismo , Ativação do Complemento , Humanos , Proteína Cofatora de Membrana/química , Proteína Cofatora de Membrana/metabolismo , Domínios Proteicos , Receptores de Complemento 3b/química , Receptores de Complemento 3b/metabolismo , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/metabolismo
15.
Trends Immunol ; 38(6): 383-394, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28416449

RESUMO

Complement dysregulation underlies several inflammatory disorders, and terminal complement inhibition has thus far afforded significant clinical gains. Nonetheless, emerging pathologies, fueled by complement imbalance and therapy-skewing genetic variance, underscore the need for more comprehensive, disease-tailored interventions. Modulation at the level of C3, a multifaceted orchestrator of the complement cascade, opens up prospects for broader therapeutic efficacy by targeting multiple pathogenic pathways modulated by C3-triggered proinflammatory crosstalk. Notably, C3 intervention is emerging as a viable therapeutic strategy for renal disorders with predominantly complement-driven etiology, such as C3 glomerulopathy (C3G). Using C3G as a paradigm, we argue that concerns about the feasibility of long-term C3 intervention need to be placed into perspective and weighed against actual therapeutic outcomes in prospective clinical trials.


Assuntos
Complemento C3/metabolismo , Glomerulonefrite Membranosa/tratamento farmacológico , Doenças do Complexo Imune/tratamento farmacológico , Inflamação/tratamento farmacológico , Animais , Anticorpos Bloqueadores/uso terapêutico , Ensaios Clínicos como Assunto , Ativação do Complemento , Complemento C3/imunologia , Medicina Baseada em Evidências , Glomerulonefrite Membranosa/imunologia , Humanos , Doenças do Complexo Imune/imunologia , Inflamação/imunologia , Modelos Imunológicos , Terapia de Alvo Molecular
16.
Semin Immunol ; 28(3): 208-22, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27321574

RESUMO

The complement system is a powerful effector arm of innate immunity that typically confers protection from microbial intruders and accumulating debris. In many clinical situations, however, the defensive functions of complement can turn against host cells and induce or exacerbate immune, inflammatory, and degenerative conditions. Although the value of inhibiting complement in a therapeutic context has long been recognized, bringing complement-targeted drugs into clinical use has proved challenging. This important milestone was finally reached a decade ago, yet the clinical availability of complement inhibitors has remained limited. Still, the positive long-term experience with complement drugs and their proven effectiveness in various diseases has reinvigorated interest and confidence in this approach. Indeed, a broad variety of clinical candidates that act at almost any level of the complement activation cascade are currently in clinical development, with several of them being evaluated in phase 2 and phase 3 trials. With antibody-related drugs dominating the panel of clinical candidates, the emergence of novel small-molecule, peptide, protein, and oligonucleotide-based inhibitors offers new options for drug targeting and administration. Whereas all the currently approved and many of the proposed indications for complement-targeted inhibitors belong to the rare disease spectrum, these drugs are increasingly being evaluated for more prevalent conditions. Fortunately, the growing experience from preclinical and clinical use of therapeutic complement inhibitors has enabled a more evidence-based assessment of suitable targets and rewarding indications as well as related technical and safety considerations. This review highlights recent concepts and developments in complement-targeted drug discovery, provides an overview of current and emerging treatment options, and discusses the new milestones ahead on the way to the next generation of clinically available complement therapeutics.


Assuntos
Anti-Inflamatórios/uso terapêutico , Ativação do Complemento , Proteínas do Sistema Complemento/imunologia , Doenças do Complexo Imune/terapia , Terapia de Alvo Molecular , Animais , Ensaios Clínicos como Assunto , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Medicina Baseada em Evidências , Humanos , Doenças do Complexo Imune/imunologia , Imunidade Inata
17.
Semin Immunol ; 28(3): 285-91, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27021500

RESUMO

Periodontitis is a dysbiotic inflammatory disease leading to the destruction of the tooth-supporting tissues. Current therapies are not always effective and this prevalent oral disease continues to be a significant health and economic burden. Early clinical studies have associated periodontitis with elevated complement activity. Consistently, subsequent genetic and pharmacological studies in rodents have implicated the central complement component C3 and downstream signaling pathways in periodontal host-microbe interactions that promote dysbiosis and inflammatory bone loss. This review discusses these mechanistic advances and moreover focuses on the compstatin family of C3 inhibitors as a novel approach to treat periodontitis. In this regard, local application of the current lead analog Cp40 was recently shown to block both inducible and naturally occurring periodontitis in non-human primates. These promising results from non-human primate studies and the parallel development of Cp40 for clinical use highlight the feasibility for developing an adjunctive, C3-targeted therapy for human periodontitis.


Assuntos
Inativadores do Complemento/uso terapêutico , Disbiose/terapia , Boca/imunologia , Periodontite/terapia , Piridonas/uso terapêutico , Animais , Complemento C3/metabolismo , Complemento C5/metabolismo , Avaliação Pré-Clínica de Medicamentos , Disbiose/imunologia , Humanos , Boca/microbiologia , Periodontite/imunologia , Primatas , Receptor da Anafilatoxina C5a/metabolismo
18.
Proc Natl Acad Sci U S A ; 114(41): 10948-10953, 2017 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-28973891

RESUMO

C4a is a small protein released from complement component C4 upon activation of the complement system's classical and lectin pathways, which are important constituents of innate immune surveillance. Despite the structural similarity between C4a and well-described anaphylatoxins C3a and C5a, the binding partner and biological function of C4a have remained elusive. Using a cell-based reporter assay, we screened C4a against a panel of both known and orphan G protein-coupled receptors and now provide evidence that C4a is a ligand for protease-activated receptor (PAR)1 and PAR4. Whereas C4a showed no activity toward known anaphylatoxin receptors, it acted as an agonist for both PAR1 and PAR4 with nanomolar activity. In human endothelial cells, ERK activation by C4a was mediated through both PAR1 and PAR4 in a Gαi-independent signaling pathway. Like other PAR1 activators, C4a induced calcium mobilization through the PAR1/Gαq/PLCß signaling axis. Moreover, C4a increased stress fiber formation and enhanced endothelial permeability, both of which were reduced by PAR1 antagonists. In sum, our study identifies C4a as an untethered agonist for PAR1 and PAR4 with effects on cellular activation and endothelial permeability, thereby revealing another instance of cross-talk between the complement system and other host defense pathways.


Assuntos
Cálcio/metabolismo , Ativação do Complemento , Complemento C4a/metabolismo , Endotélio Vascular/metabolismo , Receptor PAR-1/agonistas , Receptores de Trombina/agonistas , Células Cultivadas , Complemento C4a/genética , Endotélio Vascular/citologia , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Receptor PAR-1/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Trombina/metabolismo , Transdução de Sinais
19.
Immunol Rev ; 274(1): 152-171, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27782321

RESUMO

The complement cascade is an ancient immune-surveillance system that not only provides protection from pathogen invasion but has also evolved to participate in physiological processes to maintain tissue homeostasis. The alternative pathway (AP) of complement activation is the evolutionarily oldest part of this innate immune cascade. It is unique in that it is continuously activated at a low level and arbitrarily probes foreign, modified-self, and also unaltered self-structures. This indiscriminate activation necessitates the presence of preformed regulators on autologous surfaces to spare self-cells from the undirected nature of AP activation. Although the other two canonical complement activation routes, the classical and lectin pathways, initiate the cascade more specifically through pattern recognition, their activity still needs to be tightly controlled to avoid excessive reactivity. It is the perpetual duty of complement regulators to protect the self from damage inflicted by inadequate complement activation. Here, we review the role of complement regulators as preformed mediators of defense, explain their common and specialized functions, and discuss selected cases in which alterations in complement regulators lead to disease. Finally, rational engineering approaches using natural complement inhibitors as potential therapeutics are highlighted.


Assuntos
Proteínas do Sistema Complemento/imunologia , Homeostase , Doenças do Sistema Imunitário/imunologia , Imunidade Inata , Imunoterapia/tendências , Animais , Inativadores do Complemento/uso terapêutico , Descoberta de Drogas , Humanos , Doenças do Sistema Imunitário/terapia , Terapia de Alvo Molecular
20.
Immunol Rev ; 274(1): 33-58, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27782325

RESUMO

As a preformed defense system, complement faces a delicate challenge in providing an immediate, forceful response to pathogens even at first encounter, while sparing host cells in the process. For this purpose, it engages a tightly regulated network of plasma proteins, cell surface receptors, and regulators. Complement component C3 plays a particularly versatile role in this process by keeping the cascade alert, acting as a point of convergence of activation pathways, fueling the amplification of the complement response, exerting direct effector functions, and helping to coordinate downstream immune responses. In recent years, it has become evident that nature engages the power of C3 not only to clear pathogens but also for a variety of homeostatic processes ranging from tissue regeneration and synapse pruning to clearing debris and controlling tumor cell progression. At the same time, its central position in immune surveillance makes C3 a target for microbial immune evasion and, if improperly engaged, a trigger point for various clinical conditions. In our review, we look at the versatile roles and evolutionary journey of C3, discuss new insights into the molecular basis for C3 function, provide examples of disease involvement, and summarize the emerging potential of C3 as a therapeutic target.


Assuntos
Ativação do Complemento , Complemento C3/imunologia , Doenças do Sistema Imunitário/imunologia , Imunidade Inata , Imunoterapia/tendências , Animais , Evolução Biológica , Humanos
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