1,721,031 research outputs found
Beyond the Norm: The emerging interplay of complement system and extracellular matrix in the tumor microenvironment
Full text linkGround-breaking awareness has been reached about the intricate and dynamic connection between developing tumors and the host immune system. Being a powerful arm of innate immunity and a functional bridge with adaptive immunity, the complement system (C) has also emerged as a pivotal player in the tumor microenvironment (TME). Its “double-edged sword” role in cancer can find an explanation in the controversial relationship between C capability to mediate tumor cell cytolysis or, conversely, to sustain chronic inflammation and tumor progression by enhancing cell invasion, angiogenesis, and metastasis to distant organs. However, comprehensive knowledge about the actual role of C in cancer progression is impaired by several limitations of the currently available studies. In the current review, we aim to bring a fresh eye to the controversial role of C in cancer by analyzing the interplay between C and extracellular matrix (ECM) components as potential orchestrators of the TME. The interaction of C components with specific ECM components can determine C activation or inhibition and promote specific non-canonical functions, which can, in the tumor context, favor or limit progression based on the cancer setting. An in-depth and tumor-specific characterization of TME composition in terms of C components and ECM proteins could be essential to determine their potential interactions and become a key element for improving drug development, prognosis, and therapy response prediction in solid tumors
Emerging Roles of the Complement System at Foeto-maternal Interface
No full textThe complement system is one of the major components of humoral innate immunity, acting as one of the first lines of defence against microbes, but new roles in inflammatory and immunological processes are emerging. The placenta undergoes
an intense process of tissue remodelling which leads to the activation of the complement (C) system resulting in the release of potentially destructive activation products that need to be neutralized. The protection of the foetus against maternal C activation products is achieved by the surface expression of regulators. The liver is the main source of the plasma C components although extra-hepatic synthesis in several tissues and organs has been documented. The data collected recently indicate that trophoblast cells are able to secrete C3 and C4 and the recognition molecule C1q, contributing to the local synthesis at the placental level. Besides trophoblast cells, decidual endothelial cells acquire the ability to synthesize and express C1q on the cell surface. All these observations support the role of C1q in the placental development and its importance in trophoblast endovascular and interstitial invasion. In conclusion it is increasingly evident that a new role of complement and in particular C1q in the processes of tissue homeostasis as well as is in inflammation and infection is now emerging
Analysis of the cAMP-PCT-CGRP axis in normal and pathological pregnancy
No full textThe pro-hormone Procalcitonin (PCT) is one of the best diagnostic and prognostic markers in clinical practice, which exerts an immunomodulatory role during inflammation. We previously showed that PCT has turned out to be a powerful tool to study the ability of pregnant serum to regulate mononuclear phagocytes function. The modulation of PCT may help us to understand the mechanisms responsible for the imbalance in the immune-endocrine crosstalk in pregnancy and encourage further research to identify effective therapeutic strategies in pre-eclampsia (PE). Our recent findings show that PCT levels are higher in PE sera compared to those of healthy pregnant women. We demonstrated the local synthesis of PCT in normal and PE placenta due to macrophages and trophoblast cells. PE sera have the ability to upregulate the PCT production in trophoblasts cells and MΦ. TNFα, IL-1β and IL-6 are more concentrated in PE serum, their expression is upregulated in M1 MΦ, and seem to drive together the regulation of the synthesis of PCT and CGRP. We show that TNFα alone is not able to increase the PCT expression in human MΦ. A mAb to TNFα completely abrogated the ability of PE sera to upregulate PCT production in these cells. These data emphasize that additional factors in the gravid serum play a role in the PCT synthesis, indicating that its regulation might have an impact on the use of this laboratory marker for the analysis of the inflammatory status in healthy and pathological pregnancy
The role of the recognition molecules of the complement system: from local host defence to promotion of embryo implantation
No full text16:50-17:10: The potential interplay between the innate immune system and the microbiota in uterine related pathology
No full textUterine mucosa is an important tissue barrier whose main function is to offer protection against pathogens and other toxic factors, while maintaining a symbiotic relationship with commensal microbes. Compared to other districts the uterine mucosa is unique since it changes cyclically during the menstrual cycle as well as pregnancy. The immune system, besides its role in the defense process, plays crucial roles in reproduction as it ensures local immune tolerance to fetal/paternal antigens, trophoblast invasion, and vascular remodeling. The human endometrium contains a high number of immune cells phenotypically distinct from the cells present in the peripheral blood. The number and the phenotype of these cells change during the menstrual cycle. Furthermore, in the endometrium it is possible to identify few lymphoid aggregates comprising B cell and CD8+ T cells. The microbiota can influence the cell phenotype and function of the local immune system. Immune cells can sense the presence of microbes through their pattern recognition receptors, setting up host-microbe interaction. The microbiota exerts an appropriately controlled defense mechan- ism by competing for nutrients and mucosal space with pathogens. Alteration in the uterine microbiota is likely to play a role in diseases such as endometriosis. There has been an increasing interest in the understanding of the potential relationship between the microbiota and the immune system present in the uterine environment for its potential impact on fertility and pregnancy
A non-redundant role of complement protein C1q in normal and adverse pregnancy
Full text linkAvailability of data and materials: Not applicable.Copyright © The Author(s) 2022. Complement component 1q (C1q) is the recognition molecule of the classical pathway of the complement system that can bind to an array of closely spaced antigen-bound immunoglobulin G (IgG) and IgM antibodies. In addition to its involvement in defence against a range of pathogens and clearance of apoptotic and necrotic cells, C1q has also been implicated in immune and non-immune homeostasis. C1q is locally produced by immune cells such as monocytes, macrophages, and dendritic cells. C1q is also synthesized by decidual endothelial cells, thus acting as a link between decidual cells and trophoblasts, as well as contributing to the remodelling of spiral arteries. Furthermore, C1q is produced by the extravillous trophoblasts (EVTs) invading the decidua. As a pro-angiogenic molecule, C1q is also important for normal placentation processes as it favors the active angiogenesis in the developing decidua. These observations have been validated by C1q gene knock-out mice which showed pre-eclampsia (PE)-like symptoms, characterized by hypertension, proteinuria, glomerular endotheliosis, and increased soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio, and increased oxidative stress. The role of C1q in normal and adverse human pregnancy is being studied extensively due to its absence or low level as a likely precipitating factor for the development of PE.Funding: Not applicable
Alternative functions of the complement protein C1q at embryo implantation site
No full textComplement component C1q is one of the recognition molecules of the complement system which can serve several functions unrelated to complement activation. This molecule is produced at foeto-maternal interface by macrophages as wells as by decidual endothelial cells and invading trophoblast. Foetal trophoblast cells migrating through the decidua in the early stages of pregnancy synthesize and express C1q on their surface, which is actively involved in promoting trophoblast endovascular and interstitial invasion of the decidua. These functions are mediated by two cell surface receptors, gC1qR and α4β1 integrin, which promote trophoblast adhesion and migration through the activation of ERK1/2 MAPKs. C1q(-/-) mice manifest increased frequency of foetal resorption, reduced foetal weight, and smaller litter size when compared to their wild-type counterparts, suggesting that defective local production of C1q may be involved in pregnancy disorders, such as pre-eclampsia. C1q acts also as a strong angiogenic factor and promotes neovascularization. These studies suggest novel and unexpected roles of this complement component in physiological and pathological pregnancies
C1q is responsible of the anti-inflammatory behavior of decidual endothelial cells
No full textPROBLEM: Endothelial cells (ECs), although similar in function and morphology, represent an heterogeneous population of cells in terms of secretion of inflammatory mediators, modulation of adhesion molecules, leakiness and pro-coagulant activity and play a fundamental role in the control of the inflammatory response. Excessive inflammation at foetal-maternal interface is thought to be a key contributor in a compromised pregnancy. Intrauterine infections have been associated with pregnancy complications such as preterm labor, intrauterine growth restriction and preeclampsia.
We demonstrated that decidual endothelial cells (DECs) compared to ECs isolated from adult skin (ADMECs) are ipo-responsive to the pro-inflammatory stimulus LPS for the expression of adhesion molecules and cytokines secretion. We showed also that DECs express lower level of TLR4, MD2 and MyD88 compared to ADMECs and this may be important for the control of the inflammatory response at foeto-maternal interface.
We have previously shown that DECs acquired the ability to synthesize C1q during pregnancy which is to a large extent localized on the cell surface. Since it has been demonstrated that C1q suppressed LPS-induced IL-12p40 production in bone marrow-derived DC (BMDC) we hypothesised that C1q can play a role in the control of DECs response to LPS.
METHODS: We investigated the expression of TLR4, MD-2, and MyD88 in ADMECs previously incubated for two hours with C1q in cells stimulated or not with LPS by Real Time PCR, Western blotting and cytofluorimetric analysis.
RESULTS: Our results showed that C1q affects mRNA expression of TLR4, MD-2, and MyD88 both in resting and in stimulated cells,
CONCLUSION: The presence of C1q at foeto maternal interface may be responsible of the control of inflammation during pregnancy
Systematic review of the complement components as potential biomarkers of pre-eclampsia: pitfalls and opportunities
Full text linkUnlabelled: The complement system (C) is a crucial component of the innate immune system. An increasing body of research has progressively shed light on the pivotal role of C in immunological tolerance at the feto-maternal interface. Excessive C activation or impaired C regulation may determine the onset of pregnancy-related pathological conditions, including pre-eclampsia (PE). Thus, several studies have investigated the presence of C components or split products in blood matrixes (i.e., plasma, serum), urine, and amniotic fluid in PE. In the current study, we systematically reviewed the currently available scientific literature reporting measurements of C components as circulating biomarkers in PE, based on a literature search using Pubmed, Scopus, and Embase databases. A total of 41 out of 456 studies were selected after full-text analysis. Fourteen studies (34.1%) were identified as measuring the blood concentrations of the classical pathway, 5 (12.1%) for the lectin pathway, 28 (68.3%) for the alternative pathway, 17 (41.5%) for the terminal pathway components, and 16 (39%) for C regulators. Retrieved results consistently reported C4, C3, and factor H reduction, and increased circulating levels of C4d, Bb, factor D, C3a, C5a, and C5b-9 in PE compared to normal pregnancies, depicting an overall scenario of excessive C activation and aberrant C regulation. With evidence of C activation and dysregulation, C-targeted therapy is an intriguing perspective in PE management. Moreover, we also discussed emerging pitfalls in C analysis, mainly due to a lack of experimental uniformity and biased cohort selection among different studies and laboratories, aiming to raise a more comprehensive awareness for future standardization. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024503070
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