RESUMO
The complement cascade is an important arm of the immune system that plays a key role in protecting the central nervous system (CNS) from infection. Recently, it has also become clear that complement proteins have fundamental roles in the developing and aging CNS that are distinct from their roles in immunity. During neurodevelopment, complement signalling is involved in diverse processes including neural tube closure, neural progenitor proliferation and differentiation, neuronal migration, and synaptic pruning. In acute neurotrauma and ischamic brain injury, complement drives inflammation and neuronal death, but also neuroprotection and regeneration. In diseases of the aging CNS including dementias and motor neuron disease, chronic complement activation is associated with glial activation, and synapse and neuron loss. Proper regulation of complement is thus essential to allow for an appropriately developed CNS and prevention of excessive damage following neurotrauma or during neurodegeneration. This review provides a comprehensive overview of the evidence for functional roles of complement in brain formation, and its dysregulation during acute and chronic disease. We also provide working models for how complement can lead to neurodevelopmental disorders such as schizophrenia and autism, and either protect, or propagate neurodegenerative diseases including Alzheimer's disease and amyotrophic lateral sclerosis.
Assuntos
Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Proteínas do Sistema Complemento/imunologia , Suscetibilidade a Doenças , Neurogênese , Animais , Proteínas do Sistema Complemento/metabolismo , Humanos , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurogênese/genética , Neurogênese/imunologiaRESUMO
From its discovery in the late nineteenth century, as a 'complement' to the cellular immune response, the complement system has been widely affirmed as a powerful controller of innate and adaptive immune responses. In recent decades however, new roles for complement have been discovered, with multiple complement proteins now known to function in a broad array of non-immune systems. This includes during development, where complement exerts control over stem cell populations from fertilization and implantation throughout embryogenesis and beyond post-natal development. It is involved in processes as diverse as cell localisation, tissue morphogenesis, and the growth and refinement of the brain. Such physiological actions of complement have also been described in adult stem cell populations, with roles in proliferation, differentiation, survival, and regeneration. With such a broad range of complement functions now described, it is likely that current research only describes a fraction of the full reach of complement proteins. Here, we review how complement control of physiological cell processes has been harnessed in stem cell populations throughout both development and in adult physiology.
Assuntos
Ativação do Complemento , Proteínas do Sistema Complemento/metabolismo , Células-Tronco/fisiologia , Animais , Diferenciação Celular , Desenvolvimento Embrionário , Humanos , Imunidade Celular , Neurogênese , OrganogêneseRESUMO
BACKGROUND: Vagus nerve stimulation (VNS) therapy was first approved in the mid-1990s in the USA, Europe and Australia, with demonstrable efficacy in paediatric populations. Benefit in seizure frequency reduction can be observed up to 2 years post-intervention; however, few studies assess outcomes beyond this period. Furthermore, paediatric cohort sizes are small, limiting generalisability of outcome assessments. We evaluate VNS insertion outcomes and complications or side-effects in a large paediatric cohort, over a 20-year period from Queensland's first VNS insertion. METHODS: A retrospective review was conducted of all paediatric VNS insertions at the Queensland Children's Hospital (QCH) and the Mater Children's Hospital/Mater Children's Private Hospital (MCH/MCPH) Brisbane. A minimum of 1-year follow-up from 1999 to 2020 was required for inclusion. Patients were assessed on demographics, epilepsy details, seizure outcomes and complications or side-effects. RESULTS: In this extended follow-up cohort (76 patients, 7.2 ± 5.3 years), 51.3% of patients had ≥ 50% seizure frequency reduction, while 73.7% experienced an Engel III outcome (worthwhile benefit) or better. Eleven patients (14.9%) were seizure-free at follow-up, and 81.6% retained long-term therapy. Stimulation-related side-effects are common (17.1%) but rarely result in stimulation cessation (3.9%). Cessation occurred in 14 patients (18.4%) and most commonly related to minimal benefit (13.2%). Demographics, aetiology, seizure nature and surgical factors did not influence outcomes. CONCLUSION: Over extended treatment periods, a large proportion of patients will benefit significantly from VNS therapy. Approximately 4 of 5 patients will retain VNS therapy, and in cases of cessation, this is most commonly related to minimal benefit. Underlying demographics, aetiology or seizure nature do not influence outcomes. This 20-year Queensland assessment of VNS therapy outcomes informs long-term expectation of VNS therapy.
Assuntos
Epilepsia , Estimulação do Nervo Vago , Austrália , Criança , Epilepsia/terapia , Humanos , Estudos Retrospectivos , Resultado do Tratamento , Nervo Vago , Estimulação do Nervo Vago/efeitos adversosRESUMO
OBJECTIVE: We have previously reported inferior post-operative clinical outcomes in younger children with Chiari type-I malformation (CIM). We sought to quantify the CSF volumetric changes pre- and post-decompression, in a paediatric cohort, to determine whether cisternal volume change is associated with clinical outcomes. METHODS: In this retrospective clinical study, the CSF spaces of the posterior fossa (supracerebellar/quadrigeminal, prepontine, fourth ventricle, cisterna magna) were measured on magnetic resonance images pre- and post-operatively using a semi-automated method. Additionally, we describe a novel CSF space of the upper cervical canal incorporating the subarachnoid space from the foramen magnum to the inferior cortex of the C2 body, FM-C2 cistern. Morphometric measurements included the pB-C2 distance, clivoaxial angle, clival length, clival angle and Boogard's angle. Volumetric and morphometric data were correlated with clinical outcomes at 4-12 months post-operatively as measured by the Chicago Chiari Outcome Scale (CCOS). RESULTS: Of 59 adequate clinical cases, 57 and 36 patients had acceptable imaging for morphometric and volumetric analysis respectively. All CSF spaces measured had a significant increase in volume post-operatively (p < 0.05). There was no correlation between the change in volume or post-operative CSF volumes and CCOS. The pre-operative volume of the FM-C2 was positively correlated with total CCOS (Wald [Formula: see text], [Formula: see text]) and was significantly smaller in the 0-6-year age group (2.38 ± 1.27 ml vs. 3.67 ± 1.56 ml, p = 0.014). No morphometric measurement changed significantly after surgery or demonstrated a relationship with CCOS. CONCLUSIONS: Volumetric changes in the CSF cisterns of the posterior cranial fossa and upper cervical canal do not correlate with the age-related differences in clinical outcomes in paediatric CIM. The pre-operative volume of the FM-C2 cistern may have a role in predicting the likelihood of a beneficial post-operative outcome in paediatric CIM.
Assuntos
Malformação de Arnold-Chiari , Malformação de Arnold-Chiari/diagnóstico por imagem , Malformação de Arnold-Chiari/cirurgia , Criança , Fossa Craniana Posterior/diagnóstico por imagem , Fossa Craniana Posterior/cirurgia , Descompressão Cirúrgica , Humanos , Imageamento por Ressonância Magnética , Estudos Retrospectivos , Resultado do TratamentoRESUMO
INTRODUCTION: Intramedullary thoracic dermoid cysts are rare lesions that are associated with dermal sinus tracts (DSTs). Current recommendations advocate for imaging-based screening of suspected DSTs shortly after birth to exclude associated inclusion lesions. CASE PRESENTATION: A 6-year-old male child presented with a 2-week history of progressive ataxia, lower limb weakness, and hyperreflexia. He was suspected to have a thoracic DST at birth, though initial screening ultrasound was negative for an inclusion lesion or intradural tract. On representation, MRI demonstrated a 3.9-cm intramedullary thoracic dermoid cyst causing significant spinal cord compression. Intraoperatively, a DST extending intradurally was found. The associated dermoid cyst was removed via intracapsular resection. CONCLUSIONS: Whilst dermoid cysts are presumed to progressively develop from DSTs, to our knowledge, this is the first case in English literature documenting a thoracic spinal cord intramedullary dermoid cyst following a negative screening ultrasound for a suspected DST. We use this case to highlight the false-negative rates associated with postnatal screening and advocate for early neurosurgical referral of suspected DSTs, regardless of imaging findings.
Assuntos
Cisto Dermoide , Espinha Bífida Oculta , Neoplasias da Medula Espinal , Criança , Cisto Dermoide/diagnóstico por imagem , Cisto Dermoide/cirurgia , Humanos , Recém-Nascido , Masculino , Espinha Bífida Oculta/diagnóstico por imagem , Espinha Bífida Oculta/cirurgia , Neoplasias da Medula Espinal/diagnóstico por imagem , Neoplasias da Medula Espinal/cirurgia , UltrassonografiaRESUMO
The complement system, typically associated with innate immunity, is emerging as a key controller of nonimmune systems including in development, with recent studies linking complement mutations with neurodevelopmental disease. A key effector of the complement response is the activation fragment C5a, which, through its receptor C5aR1, is a potent driver of inflammation. Surprisingly, C5aR1 is also expressed during early mammalian embryogenesis; however, no clearly defined function is ascribed to C5aR1 in development. Here we demonstrate polarized expression of C5aR1 on the apical surface of mouse embryonic neural progenitor cells in vivo and on human embryonic stem cell-derived neural progenitors. We also show that signaling of endogenous C5a during mouse embryogenesis drives proliferation of neural progenitor cells within the ventricular zone and is required for normal brain histogenesis. C5aR1 signaling in neural progenitors was dependent on atypical protein kinase C ζ, a mediator of stem cell polarity, with C5aR1 inhibition reducing proliferation and symmetric division of apical neural progenitors in human and mouse models. C5aR1 signaling was shown to promote the maintenance of cell polarity, with exogenous C5a increasing the retention of polarized rosette architecture in human neural progenitors after physical or chemical disruption. Transient inhibition of C5aR1 during neurogenesis in developing mice led to behavioral abnormalities in both sexes and MRI-detected brain microstructural alterations, in studied males, demonstrating a requirement of C5aR1 signaling for appropriate brain development. This study thus identifies a functional role for C5a-C5aR1 signaling in mammalian neurogenesis and provides mechanistic insight into recently identified complement gene mutations and brain disorders.SIGNIFICANCE STATEMENT The complement system, traditionally known as a controller of innate immunity, now stands as a multifaceted signaling family with a broad range of physiological actions. These include roles in the brain, where complement activation is associated with diseases, including epilepsy and schizophrenia. This study has explored complement regulation of neurogenesis, identifying a novel relationship between the complement activation peptide C5a and the neural progenitor proliferation underpinning formation of the mammalian brain. C5a was identified as a regulator of cell polarity, with inhibition of C5a receptors during embryogenesis leading to abnormal brain development and behavioral deficits. This work demonstrates mechanisms through which dysregulation of complement causes developmental disease and highlights the potential risk of complement inhibition for therapeutic purposes in pregnancy.
Assuntos
Células-Tronco Embrionárias/fisiologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Proteína Quinase C/metabolismo , Receptor da Anafilatoxina C5a/metabolismo , Animais , Polaridade Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Ativação do Complemento/fisiologia , Células-Tronco Embrionárias/citologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The complement activation product C3a is often described as a proinflammatory mediator, alongside its downstream cousin, C5a. However, emerging studies show that C3a has several anti-inflammatory facets in vivo. For example, in the acute inflammatory response, C3a acts in direct opposition to C5a, through preventing the accumulation of neutrophils in inflamed tissues by independently regulating their mobilization. This acute, protective, and opposing activity of C3a to C5a is also illustrated in models of septicemia. In this article, we reinvestigate the discovery and original classification of C3a as a proinflammatory mediator and highlight the emerging studies demonstrating anti-inflammatory effects for C3a in the immune response. It is our hope that this review illuminates these apparently contradictory roles for C3a and challenges the general dogma surrounding C3a, which, historically, has ubiquitously been described as a proinflammatory mediator. In light of this, we urge investigators to use "inflammatory modulator" as the descriptor for C3a.
Assuntos
Complemento C3/imunologia , Complemento C3a/imunologia , Mediadores da Inflamação/imunologia , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Animais , Complemento C3/genética , Complemento C3a/genética , Complemento C5a/genética , Complemento C5a/imunologia , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Infiltração de Neutrófilos/genética , Neutrófilos/patologiaRESUMO
The complement activation product, C5a, is a pivotal member of the innate immune response; however, a diverse number of nonimmune functions are now being ascribed to C5a signaling, including roles during embryonic development. Here, we identify the expression of the C5a precursor protein, C5, as well as the C5a receptors, C5aR and C5L2, in both human embryonic stem cells and human-induced pluripotent stem cells. We show that administration of a physiologically relevant dose of purified human C5a (1 nM) stimulates activation of ERK1/2 and AKT signaling pathways, and is able to promote maintenance of the pluripotent state in the absence of FGF2. C5a also reduced cell loss following dissociation of human pluripotent stem cells. Our results reveal that complement C5a signaling supports human stem cell pluripotency and survival, and thus may play a key role in shaping early human embryonic development.
Assuntos
Complemento C5a/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Células-Tronco Embrionárias Humanas/citologia , Células-Tronco Pluripotentes/citologia , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Células-Tronco Pluripotentes/metabolismo , Receptor da Anafilatoxina C5a/metabolismo , Transdução de Sinais/imunologiaRESUMO
The complement system is involved in a range of diverse developmental processes, including cell survival, growth, differentiation, and regeneration. However, little is known about the role of complement in embryogenesis. In this study, we demonstrate a novel role for the canonical complement 5a receptor (C5aR) in the development of the mammalian neural tube under conditions of maternal dietary folic acid deficiency. Specifically, we found C5aR and C5 to be expressed throughout the period of neurulation in wild-type mice and localized the expression to the cephalic regions of the developing neural tube. C5aR was also found to be expressed in the neuroepithelium of early human embryos. Ablation of the C5ar1 gene or the administration of a specific C5aR peptide antagonist to folic acid-deficient pregnant mice resulted in a high prevalence of severe anterior neural tube defect-associated congenital malformations. These findings provide a new and compelling insight into the role of the complement system during mammalian embryonic development.
Assuntos
Deficiência de Ácido Fólico/complicações , Defeitos do Tubo Neural/etiologia , Defeitos do Tubo Neural/prevenção & controle , Receptor da Anafilatoxina C5a/metabolismo , Transdução de Sinais , Animais , Complemento C5/genética , Complemento C5/metabolismo , Modelos Animais de Doenças , Embrião de Mamíferos/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Morfogênese/genética , Tubo Neural/embriologia , Tubo Neural/metabolismo , Defeitos do Tubo Neural/patologia , Neurulação/genética , Gravidez , Transporte Proteico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor da Anafilatoxina C5a/genéticaRESUMO
C5a is the paramount proinflammatory mediator of the complement cascade, and has been previously thought to act only through a single, G-protein-coupled, C5a receptor (C5aR; also termed CD88). In 2000, a second C5a receptor, C5L2 (previously known as GPR77), was discovered; yet, despite 12 yr of intensive research, its biological, or pathophysiological, function is both enigmatic and controversial. Unlike C5aR, this receptor does not couple to G proteins, and early studies promoted the hypothesis that C5L2 functions as a decoy receptor. However, recent data have provided other evidence for more complicated and conflicting interactions between C5L2 and other inflammatory mediators. C5L2 has been recently demonstrated to physically interact with both C5aR and ß-arrestin to negatively regulate C5aR signaling toward an anti-inflammatory manner, and to reduce pathology, in several disease models in vivo. In direct contrast, other groups have demonstrated that C5L2 stimulation caused release of HMGB1 both in vitro and in vivo, and enhanced pathology in sepsis models, suggesting a clear proinflammatory signaling role. These astoundingly contradictory data challenge our precepts and complicate the foundational bases for the possible targeting of C5L2 as a therapeutic option in inflammatory disease. C5L2 may be the great masquerader in complement biology; its function dependent on the cell type, species, and disease context. Because of these unusual and unforeseen complexities, we present the current state of knowledge on C5L2 structure, expression and, most controversially, its putative functions.-Li, R., Coulthard, L.G., Wu, M. C. L., Taylor, S. M., Woodruff, T. M. C5L2: a controversial receptor of complement anaphylatoxin, C5a.
Assuntos
Complemento C5a/metabolismo , Receptores de Quimiocinas/metabolismo , Receptores de Complemento/metabolismo , Sepse/metabolismo , Transdução de Sinais , Animais , Arrestinas/genética , Arrestinas/imunologia , Arrestinas/metabolismo , Complemento C5a/genética , Complemento C5a/imunologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Humanos , Estrutura Terciária de Proteína , Receptor da Anafilatoxina C5a , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/imunologia , Receptores de Complemento/genética , Receptores de Complemento/imunologia , Sepse/genética , Sepse/imunologia , Sepse/patologia , Sepse/terapia , beta-ArrestinasRESUMO
OBJECTIVE: Sinogenic intracranial infections in children, such as subdural empyema or intracranial abscess, are a rare disease process with significant associated morbidity. Recent literature has suggested that there may have been an increase in frequency of these infections following the COVID-19 pandemic, but the literature has been conflicting, perhaps related to the heterogenous management of COVID-19 lockdowns in various states and differences in data capture between methods. The collection of statewide Australian data overcomes these limitations by capturing a comprehensive sample though the public healthcare system of patients who were subject to a homogeneous statewide approach to public health policy during the COVID-19 pandemic (population 5.6 million, including 1.3 million children). The objective of this study was to present population-level data to address the question of whether the incidence of intracranial infections changed in pediatric patients before and after the COVID-19 pandemic. METHODS: The authors present a retrospective 10-year statewide description of sinogenic intracranial infections in Queensland, Australia. A comparison was made between the incidence and microbiological profile before and after the onset of COVID-19 lockdowns on March 22, 2020. RESULTS: Forty-four pediatric intracranial infections undergoing neurosurgical intervention were identified within the review period. After exclusion of postsurgical and cardioembolic causes, 33 sinogenic intracranial infections were included (16 before and 17 after 2020, with a mean annualized incidence of 0.25 vs 0.37 cases per 100,000 children, respectively; p > 0.05). The most frequent organisms identified were Streptococcus milleri (n = 19), polymicrobial (n = 4), and S. aureus (n = 3). No significant differences in antimicrobial profile, susceptibility, parenchymal involvement, or clinical outcome were identified between the pre- and post-COVID-19 groups. CONCLUSIONS: No statistically significant differences in the epidemiology of pediatric intracranial infection have occurred in the state of Queensland, Australia, before and after March 22, 2020, and the COVID-19 pandemic.
RESUMO
Complement activation products have long been associated with roles in the innate immune system, linking the humoral and cellular responses. However, among their recently described non-inflammatory roles, complement proteins also have multiple emerging novel functions in brain development. Within this context, separate proteins and pathways of complement have carved out physiological niches in the formation, development, and refinement of neurons. They demonstrate actions that are both reminiscent of peripheral immune actions and removed from them. We review here three key roles for complement proteins in the developing brain: progenitor proliferation, neuronal migration, and synaptic pruning.
Assuntos
Encéfalo , Proteínas do Sistema Complemento/metabolismo , Transdução de Sinais/fisiologia , Animais , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Movimento Celular , Proliferação de Células , Humanos , Imunidade Inata , Plasticidade Neuronal/fisiologiaRESUMO
The complement system of innate immunity is emerging as a novel player in neurodevelopmental processes. The receptor for C3a, C3aR, shares a close evolutionary and functional relationship with C5a receptors. Whilst the C5a receptor, C5aR1, has been demonstrated to promote embryonic neural stem cell proliferation, little is known about the role of C3aR in this process. Here we show that C3aR is expressed in a similar manner to C5aR1 in mice, at the apical pole of the embryonic ventricular zone, though it has an opposing function. Using in utero delivery of C3aR agonist and antagonist compounds to the embryonic ventricle, we demonstrate that C3aR functions to decrease proliferation of apical neural progenitor cells (NPC). Intriguingly, C3aR-/- animals also have altered NPC proliferation, but demonstrate an opposing phenotype to animals subjected to pharmacological blockade of C3aR. Finally, despite a grossly normal development of C3aR-/- animals, cognitive behavioural testing of adult mice showed subtle deficits in recall memory. These data demonstrate that in addition to C5a, C3a also has a critical role in the normal development of the mammalian brain.
Assuntos
Cognição , Embrião de Mamíferos/citologia , Células-Tronco Neurais/metabolismo , Receptores de Complemento/metabolismo , Animais , Comportamento Animal , Proliferação de Células , Células Cultivadas , Memória Imunológica , Masculino , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/citologia , Receptores de Complemento/deficiência , Transdução de SinaisRESUMO
Once regarded solely as an activator of innate immunity, it is now clear that the complement system acts in an assortment of cells and tissues, with immunity only one facet of a diverse array of functions under the influence of the complement proteins. Throughout development, complement activity has now been demonstrated from early sperm-egg interactions in fertilisation, to regulation of epiboly and organogenesis, and later in refinement of cerebral synapses. Complement has also been shown to regulate homeostasis of adult tissues, controlling cell processes such as migration, survival, repair, and regeneration. Given the continuing emergence of such novel actions of complement, the existing research likely represents only a fraction of the myriad of functions of this complex family of proteins. This review is focussed on outlining the current knowledge of complement family members in the regulation of cell processes in non-immune systems. It is hoped this will spur research directed towards revealing more about the role of complement in these fundamental cell processes.
Assuntos
Proteínas do Sistema Complemento/imunologia , Animais , Adesão Celular/fisiologia , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , HumanosRESUMO
The complement system is a pivotal driver of innate immunity, coordinating the host response to protect against pathogens. At the heart of the complement response lie the active fragments, C3a and C5a, acting through their specific receptors, C3aR, C5aR1, and C5aR2, to direct the cellular response to inflammation. Their potent function however, places them at risk of damaging the host, with aberrant C3a and C5a signaling activity linked to a wide range of disorders of inflammatory, autoimmune, and neurodegenerative etiologies. As such, the therapeutic control of these receptors represents an attractive drug target, though, the realization of this clinical potential remains limited. With the success of eculizumab, and the progression of a number of novel C5a-C5aR1 targeted drugs to phase II and III clinical trials, there is great promise for complement therapeutics in future clinical practice. In contrast, the toolbox of drugs available to modulate C3aR and C5aR2 signaling remains limited, however, the emergence of new selective ligands and molecular tools, and an increased understanding of the function of these receptors in disease, has highlighted their unique potential for clinical applications. This review provides an update on the growing arsenal of drugs now available to target C5, and C5a and C3a receptor signaling, and discusses their utility in both clinical and pre-clinical development.
Assuntos
Ativação do Complemento/imunologia , Complemento C3a/imunologia , Complemento C5a/imunologia , Receptor da Anafilatoxina C5a/imunologia , Receptores de Quimiocinas/imunologia , Receptores de Complemento/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Ativação do Complemento/efeitos dos fármacos , Inativadores do Complemento/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologiaRESUMO
The innate immune system is the first line of defence against pathogens and infection. Recently, it has become apparent that many innate immune factors have roles outside of immunity and there is growing evidence that these factors play important functional roles during the development of a range of model organisms. Several studies have documented developmental expression of individual factors of the toll-like receptor and complement systems, and we recently demonstrated a key role for complement C5a receptor (C5aR1) signalling in neural tube closure in mice. Despite these emerging studies, a comprehensive expression analysis of these molecules in embryonic development is lacking. In the current study, we therefore, examined the expression of key innate immune factors in the early development period of neurulation (7.5-10.5dpc) in mice. We found that complement factor genes were differentially expressed during this period of murine development. Interestingly, the expression patterns we identified preclude activation of the classical and alternative pathways and formation of the membrane attack complex. Additionally, several other classes of innate immune molecules were expressed during the period of neurulation, including toll-like receptors (TLR-2, -3, -4 and -9), receptor for advanced glycation end-products (RAGE), and their signalling adapters (TRAF-4, TRAF-6, TAK-1 and MyD88). Taken together, this study highlights a number of innate immune factors as potential novel players in early embryonic development.
Assuntos
Via Alternativa do Complemento/genética , Via Clássica do Complemento/genética , Lectina de Ligação a Manose da Via do Complemento/genética , Proteínas do Sistema Complemento/genética , Imunidade Inata , Neurulação/imunologia , Animais , Proteínas do Sistema Complemento/imunologia , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento , Hibridização In Situ , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Neurulação/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/imunologia , Transdução de Sinais , Fator 4 Associado a Receptor de TNF/genética , Fator 4 Associado a Receptor de TNF/imunologia , Receptores Toll-Like/genética , Receptores Toll-Like/imunologiaRESUMO
PROBLEM: Complement factor 5a (C5a), a potent pro-inflammatory mediator of the complement system, has been implicated in fetal rejection throughout gestation, from miscarriage to preterm birth. This study aimed to investigate the role of the principal C5a receptor, C5aR1 (CD88), in both miscarriage and preterm birth, in a bacterial endotoxin (lipopolysaccharide; LPS) murine model. METHOD OF STUDY: Wild-type and C5ar1 knockout mice were administered LPS at 9.5 or 15.5 days post-conception to induce miscarriage or preterm birth, respectively. RESULTS: C5ar1 knockout mice were protected against miscarriage in response to administration of LPS in early gestation. However, the absence of C5aR1 had no effect on the rates of preterm birth when LPS was administered in late gestation. CONCLUSION: There may be a gestational window in which excessive activation of C5a can exert deleterious effects in pregnancy. Future strategies targeting the C5a-C5aR1 signaling axis should be considered to ameliorate miscarriages in patients with recurrent pregnancy loss.
Assuntos
Aborto Animal/imunologia , Lipopolissacarídeos/farmacologia , Receptor da Anafilatoxina C5a/imunologia , Animais , Feminino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Gravidez , Transdução de SinaisRESUMO
Preeclampsia is a leading cause of morbidity and mortality worldwide, encompassing significant short- and long-term health sequelae. Recently, there has been accumulating evidence for a role of the complement system in the pathogenesis of numerous complications of pregnancy, including preeclampsia. The present cross-sectional study compared the plasma concentrations of complement factors C3a and C5a between normotensive pregnancies and pregnancies complicated with either preeclampsia or gestational hypertension alone. We found that maternal plasma C5a concentration was significantly higher in preeclamptic pregnancy than in pregnancy affected by gestational hypertension alone or normotensive pregnancy. Umbilical cord plasma C5a concentrations were also higher in pregnancies complicated by preeclampsia compared to gestational hypertension or normotensive pregnancy. Maternal and cord plasma C5a concentrations were significantly correlated, suggesting that C5a can freely diffuse between maternal and fetal circulation. There were no significant differences in C3a concentrations in maternal or cord plasma between any groups. These results support the hypothesis that C5a may play a role in preeclampsia, but not in gestational hypertension.