Expression data from primary human neutrophils incubated with complement anaphylatoxin C5a
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PROVIDER: PRJNA634018 | ENA |
REPOSITORIES: ENA
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Project description:Influence of complement anaphylatoxin C5a on neutrophil gene expression Trauma causes an early activation of the complement system, which leads to excessive generation of the anaphylatoxin C5a. Furthermoren, alterations in neutrophil function are often associated with infectious complication after trauma. Studies have shown that C5a is a main contributor to neutrophil dysfunction. However, the pathophysiological mechanisms still remain elusive. Aim of the study was to evaluate whether C5a can induce changes in expression profiles. We identified distinct classes of up-regulated genes during this process.
2020-09-23 | GSE150902 | GEO
Project description:Critical illness is characterised by organ failure, dysregulated immune activation and frequent secondary infections. Unbridled complement activation in these patients exposes immune cells to high levels of the anaphylotoxin, C5a. C5a suppresses antimicrobial functions of key immune cells, in particular the neutrophil, and this suppression is associated with poorer outcomes amongst critically ill adults. The intracellular signalling pathways which mediate C5a-induced neutrophil dysfunction are incompletely understood. Healthy donor peripheral blood neutrophils exposed to purified C5a demonstrated a prolonged defect in phagocytosis of the common nosocomial pathogen Staphylococcus aureus which persisted for 7 hours after exposure. Phosphoproteomic profiling of 2712 unique phosphoproteins identified persistent C5a signalling at 1 hour, and selective impairment of phagosomal protein phosphorylation on exposure to S. aureus. Notable proteins included early endosomal marker ZFYVE16 and V-ATPase proton channel component ATPV1G1. A multi-function assay of bacterial ingestion and phagosomal acidification demonstrated C5a-induced impairment of phagosomal acidification in a whole blood model of Staphylococcal bacteraemia which was recapitulated in neutrophils from critically ill patients. Examination of the C5a-impaired protein phosphorylation indicated a role for the phosphatidylinositol 3-kinase VPS34 in phagosomal maturation. Inhibition of VPS34 impaired neutrophil phagosomal acidification, late bacterial ingestion and killing of S. aureus in whole blood. This study provides a deep phosphoproteomic assessment of human neutrophil signalling in response to S. aureus, and demonstrates how some of these pathways are disrupted by exposure to C5a, identifying a defect in phagosomal maturation and providing new information on mechanisms of immune failure in critical illness.
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Project description:The anaphylatoxin C5a is a potent mediator of innate immunity and promotes inflammation via its receptor C5aR1 upon complement system activation danger-associated molecular patterns. Both C5a and C5aR1 are thought to be contributing factors in inflammatory and infectious conditions of the bone. Bone fracture healing, for example, was significantly improved when applying a C5aR1-antagonist in a rodent model of severe systemic inflammation and osteoblasts were found to be target cells for C5a in this setting. Interestingly, osteoblasts up-regulate C5aR1 during osteogenic differentiation and after bone injury. Further, C5a induces inflammatory cytokines, such as IL-6, and the osteoclastogenic mediator RANKL in osteoblasts. However, the molecular mechanisms underlying C5a-C5aR1 signaling axis in osteoblasts remain unclear, and further targets of C5a are still elusive. Using microarray analysis, we analyzed intracellular events following C5aR1 activation in osteoblasts and defined up- or down-regulated genes and their belonging biological pathways.
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Project description:In this project, we aimed to examine gene expression changes in intestinal organoids treated with the complement C5a receptor 1 (C5aR1) antagonist PMX205 either with or without irradiation. Intestinal organoids from wild-type C57BL/6 mice were cultured and plated. The following day, the media was supplemented with 5 μg/ml of PMX205 or a vehicle control, and after one hour, organoids were subjected to either 0 Gy or 9 Gy of radiation. Samples were collected after 24 and 48 hours, and RNA was extracted and processed for RNA sequencing.
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Project description:Complement C5a/C5a receptor 1 induces renal injury in diabetic kidney disease via mitochondrial metabolic reprogramming
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Project description:The complement system is part of the innate immune system that works to clear pathogens and cellular debris. In the central nervous system (CNS) complement activation can promote synaptic pruning clearance of neuronal blebs recruitment of phagocytes and protection from pathogens. However in a neuropathologic environment complement activation may contribute to inflammatory pathways neuronal dysfunction and in the Alzheimer’s disease (AD) brain cognitive decline. If complement activation proceeds to the cleavage of C5 and thus generation of C5a engagement of C5a with the receptor C5aR1 can instigate a feed-forward loop of inflammation injury and neuronal death thus making this molecule a potential target for modulation in AD therapeutics. The Arctic (Arc) AD mouse model known to rapidly accumulate fibrillar amyloid plaques was crossed to a model that lacks the receptor for C5a (ArcC5aR1KO) or to a transgenic mouse that generates C5a under the GFAP promoter (ArcC5a+). ArcticC5a+ mice showed accelerated loss of spatial memory compared to Arc mice. While eliminating C5aR1 did not alter amyloid plaque accumulation in this AD model C5aR1KO delayed or prevented the expression of important AD-associated genes in the hippocampus indicating a separation between those genes induced by amyloid plaques and those influenced by C5a-C5aR1 signaling. C5ar1 deletion also reduced/delayed the expression of select pan-reactive and A1 reactive astrocyte genes. ArcC5aR1KO showed delayed expression of genes enriched for biological processes that are significant in the AD context such as regulation of inflammatory signaling microglial cell activation astrocyte migration and lysosome pathway. Interestingly overexpression of C5a also delayed the increase of some AD- complement and astrocyte-associated genes perhaps mediated by C5aR2 and emphasizing the importance of selectively suppressing C5aR1. Immunohistochemical investigation further confirmed that modulation of C5a-C5aR1 either delayed or reduced some reactive microglial markers in the Arc hippocampus including CD11b and CD11c. These results suggest that C5a-C5aR1 signaling in the context of AD largely exerts its effects by suppressing those microglial activation pathways that accelerate disease enhancing pathways. Given the highly focused modulation of a common driver of neurotoxicity pharmacological inhibition of this C5aR1 signaling pathway is a promising therapeutic strategy to treat AD.
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Project description:Systemic candidiasis is a common, high-mortality, nosocomial fungal infection. Unexpectedly, it has emerged as a complication of anti-complement C5-targeted monoclonal antibody treatment, indicating a critical niche for C5 in antifungal immunity. We identified transcription of complement system genes as the top biological pathway induced in candidemic patients and as predictive of candidemia. Mechanistically, C5a-C5aR1 promoted fungal clearance and host survival in a mouse model of systemic candidiasis by stimulating phagocyte effector function and ERK- and AKT-dependent survival in infected tissues. C5ar1 ablation rewired macrophage metabolism downstream of mTOR, promoting their apoptosis and enhancing mortality through kidney injury. Besides hepatocyte-derived C5, local C5 produced intrinsically by phagocytes provided a key substrate for antifungal protection. Lower serum C5a concentrations or a C5 polymorphism that decreases leukocyte C5 expression correlated independently with poor patient outcomes. Thus, local, phagocyte-derived C5 production licenses phagocyte antimicrobial function and confers innate protection during systemic fungal infection.
2023-05-30 | GSE206205 | GEO