Complement C5a/C5a receptor 1 induces renal injury in diabetic kidney disease via mitochondrial metabolic reprogramming
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE118089 | GEO | 2019/07/01
REPOSITORIES: GEO
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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.
2018-12-26 | GSE107036 | GEO
Project description:Hookworms are soil-transmitted parasitic nematodes that penetrate the host skin before migrating to the lungs. With an estimated 500-700 million people infected worldwide, hookworm infections are a neglected tropical disease and a significant cause of morbidity, particularly in children, pregnant women, and immunocompromised individuals. Although there is ample evidence that complement activation is pivotal to elicit a protective host immune response against invasive pathogens, its role in hookworm infection remains insufficiently explored. Here, we investigated the complement anaphylatoxin, C5a, during the early lung stage of infection with Nippostrongylus brasiliensis in C57BL/6J wild type and C5aR1-/- mice. Despite the previously reported ability of lung larvae to evade complement activation, C5a was detectable locally in lung tissue and broncho-alveolar lavages. Surprisingly, C5aR1 presence directly contributed to the pathogenicity of hookworm infection. The burden of viable parasites in the lungs was mitigated in C5aR1-/- mice, compared to C57BL/6J mice 48 hours post-infection. Additionally, C5aR1-/- mice showed significantly reduced lung injury, lower cytokine release, attenuated alveolar hemorrhage, and limited alveolar-capillary barrier disruption. Neutrophils were the most abundant and highest C5aR1-expressing cell type in the alveolar space after infection. Deficiency of C5aR1 reduced the influx of neutrophils, monocytes, and eosinophils to the pulmonary airways. RNA sequencing of alveolar neutrophils revealed C5aR1-dependent regulation of the novel nuclear protein, DEDD2. In conclusion, our findings highlight the impact of C5aR1 signaling in neutrophils during hookworm infection uncovering an unexpected downside of complement activation in parasitic infection.
2024-08-29 | GSE272613 | GEO
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.
2023-01-25 | E-MTAB-12548 | biostudies-arrayexpress
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.
2022-03-05 | GSE197591 | GEO
Project description:Complement C5a/C5a receptor 1 induces renal injury in diabetic kidney disease via mitochondrial metabolic reprogramming
| PRJNA484388 | ENA
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: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
Project description:The Fosb gene encodes subunits of the activator protein-1 transcription factor complex. Two mature mRNAs, Fosb and ΔFosb, encoding full-length FOSB and ΔFOSB proteins respectively, are formed by alternative splicing of Fosb mRNA. Fosb products are expressed in several brain regions. Moreover, Fosb-null mice exhibit depressive-like behaviors and adult-onset spontaneous epilepsy, demonstrating important roles in neurological and psychiatric disorders. Study of Fosb products has focused almost exclusively on neurons; their function in glial cells remains to be explored. In this study, we found that microglia express equivalent levels of Fosb and ΔFosb mRNAs to hippocampal neurons and, using microarray analysis, we identified six microglial genes whose expression is dependent on Fosb products. Of these genes, we focused on C5ar1 and C5ar2, which encode receptors for complement C5a. In isolated Fosb-null microglia, chemotactic responsiveness toward the truncated form of C5a was significantly lower than that in wild-type cells. Fosb-null mice were significantly resistant to kainate-induced seizures compared with wild-type mice. C5ar1 mRNA levels and C5aR1 immunoreactivity were increased in wild-type hippocampus 24 hours after kainate administration; however, such induction was significantly reduced in Fosb-null hippocampus. Furthermore, microglial activation after kainate administration was significantly diminished in Fosb-null hippocampus, as shown by significant reductions in CD68 immunoreactivity, morphological change and reduced levels of Il6 and Tnf mRNAs, although no change in the number of Iba-1-positive cells was observed. These findings demonstrate that, under excitotoxicity, Fosb products contribute to a neuroinflammatory response in the hippocampus through regulation of microglial C5ar1 and C5ar2 expression.
2014-04-18 | GSE40714 | 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.
2020-08-06 | PXD017092 | Pride
Project description:In the K14-HPV16 transgenic mouse model of squamous carcinogenesis, activation of C5a receptor (C5aR1) in early neoplastic tissues fosters protumorigenic properties of C5aR1+ mast cells and macrophages, and in turn, suppression of CD8+ T cell cytotoxicity. Therapeutic inhibition of C5a receptor (C5aR1) with a peptide antagonist improved efficacy to paclitaxel chemotherapy associated with CXCR3-dependent CD8+ T cell activation. To investigate the effects of combination therapy on the T cell repertoire, we performed deep sequencing of the complementarity-determining region (CDR) 3 of the T cell receptor (TCR)b chain in matched tumor lysates and peripheral blood mononuclear cells (PBMCs). Intratumoral TCRβ clonotypes were hyperexpanded and increasingly detected in matched peripherally-expanded T cell populations, thereby implicating antigen-dependent peripheral priming in response to systemic C5aR1 inhibition.
2018-11-28 | GSE112322 | GEO