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MRNA profiles of tumor infiltrating macrophage and monocyte derived from C3 wild-type and knock-out mice, subjected to sarcoma transplantable model

ABSTRACT: Complement has emerged as a component of tumor promoting inflammation. We conducted a systematic assessment of the role of complement activation and effector pathways in sarcomas. C3-/-, MBL1/2-/- and C4-/- mice showed reduced susceptibility to 3-methylcholanthrene sarcomagenesis and transplanted sarcomas, whereas C1q and factor B deficiency had marginal effects. Complement 3a receptor (C3aR), but not C5aR1 and C5aR2, deficiency mirrored the phenotype of C3-/- mice. C3 and C3aR deficiency were associated with reduced accumulation and functional skewing of tumor-associated macrophages, increased T cell activation and response to anti-PD-1 therapy. Transcriptional profiling of sarcoma infiltrating macrophages and monocytes revealed the enrichment of MHC II-dependent antigen presentation pathway in C3-deficient cells. In patients, C3aR expression correlated with a macrophage population signature and C3 deficiency-associated signatures predicted better clinical outcome. These results suggest that the lectin pathway and C3a/C3aR axis are key components of complement and macrophage-mediated sarcoma promotion and immunosuppression.

ORGANISM(S): Mus musculus

PROVIDER: GSE141692 | GEO | 2020/11/24

REPOSITORIES: GEO

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Lung epithelial cell-derived C3 protects against pneumonia-induced lung injury

Project description:The complement component C3 is a fundamental plasma protein for host defense, produced largely by the liver. However, recent work has demonstrated the critical importance of tissue-specific C3 expression in cell survival. Here we analyzed the effects of local versus peripheral sources of C3 expression in a model of bacterial pneumonia. While mice with global C3 deficiency had severe pneumonia-induced lung injury, those deficient in liver-deficient C3 remain protected, comparable to wildtype mice. Human lung transcriptome analysis showed that secretory epithelial cells, such as club cells, are a major source of C3. Mice with a tamoxifen-induced C3 gene ablation from club cells in the lung had worse pulmonary injury compared to similarly treated controls, despite maintaining normal circulating C3 levels. Finally, in human cellular and mouse pneumonia models, we show that C3 reduces epithelial cell death mediated through the alternative pathway component Factor B, rather than the C3aR. Thus, our findings suggest that a locally-derived C3-Factor B pathway protects the lung mucosal barrier.

2023-02-03 | GSE218554 | GEO

Development of Specific Therapy Against Right Ventricular Failure

Project description:Right ventricular (RV) failure plays a critical role in any type of heart failure. However, there is no specific therapy developed for RV failure. To understand RV failure, we focused on the RV specific genes. Global gene expression analysis showed that alternative complement pathway-related genes including C3 and Cfd were significantly upregulated in right ventricle in murine heart. We generated the RV failure by right ventricle-specific pressure overload model mice, pulmonary artery constriction (PAC), which induces RV failure around 14 days. In C3 knockout (C3KO) mice, PAC-induced RV dysfunction and fibrosis were significantly attenuated. C3a is produced from C3 by C3 convertase complex including Cfd. Cfd knockout mice also attenuated PAC-induced RV failure. Moreover, C3a receptor (C3aR) antagonist dramatically improved PAC-induced RV dysfunction in wild type mice. Here we revealed the crucial role of C3-Cfd-C3a-C3aR axis in RV failure and highlight the potential therapeutic target for RV failure with no pharmacologic option.

2021-09-07 | GSE183504 | GEO

C5aR2 regulates STING-mediated interferon beta production in human macrophages

Project description:The complement system mediates diverse regulatory effects across the immune system. C5aR2, an enigmatic receptor for anaphylatoxin C5a, has been shown to modulate PRR-dependent pro-inflammatory cytokine secretion in human macrophages. However, the specific downstream targets and underlying molecular mechanisms are less defined. In this study, CRISPR-Cas9 was used to generate macrophage models lacking C5aR2, which were used to probe the role of C5aR2 in the context of PRR stimulation. cGAS and STING-induced IFN-β secretion was significantly increased in C5aR2 KO THP-1 cells and C5aR2-edited primary human monocyte-derived macrophages, and expression of STING and IRF3 was increased in C5aR2 KO cell lines, implicating C5aR2 as a regulator of the IFN-β response to cGAS-STING pathway activation. Transcriptomic analysis by RNAseq revealed that nucleic acid sensing and antiviral signalling pathways were significantly up-regulated in C5aR2 KO THP-1 cell lines. These results suggest that C5aR2 is a negative regulator of nucleic acid sensing in macrophages, with potential relevance for viral infection and anti-tumour immunity.

2023-10-22 | GSE245973 | GEO

Deficiency of C3a receptor attenuates the development of diabetic nephropathy (Diabetic Group)

Project description:Diabetic nephropathy (DN) is the leading cause of chronic kidney disease and end-stage renal disease. Emerging evidence suggests that complement activation is involved in the pathogenesis of DN. The aim of this study was to investigate the pathogenic role of C3a and C3a receptor (C3aR) in DN. The expression of C3aR was examined in the renal specimen of DN patients. Using a C3aR gene knockout mice (C3aR-/-), we evaluated kidney injury in diabetic mice. The mouse gene expression microarray was performed to further explore the pathogenic role of C3aR. Then the underlying mechanism was investigated in vitro with macrophage treated with C3a. Compared with normal controls, the renal expression of C3aR was significantly increased in DN patients. C3aR-/- diabetic mice developed less severe diabetic renal damage compared with WT diabetic mice, exhibiting significantly lower level of albuminuria and milder renal pathological injury. Microarray profiling uncovered significantly suppressed inflammatory responses and T cell adaptive immunity in C3aR-/- diabetic mice compared with WT diabetic mice and this result was further verified by immunohistochemical staining of renal CD4+, CD8+ T cells and macrophages infiltration. In vitro study demonstrated C3a can enhance macrophages secreted cytokines which could induce inflammatory responses and differentiation of T cell lineage. In conclusion, C3aR deficiency could attenuate diabetic renal damage through suppressing inflammatory responses and T cell adaptive immunity, possibly by influencing macrophages secreted cytokines. Thus, C3aR may be a promising therapeutic target for DN.

2020-04-10 | GSE133597 | GEO

Deficiency of C3a receptor attenuates the development of diabetic nephropathy (Control Group)

2020-04-10 | GSE133596 | GEO

Intracellular activation of complement C3 leads to PD-L1 antibody treatment resistance via modulating tumor-associated macrophages

Project description:Mounting evidence has highlighted the importance of complement in the construction of an immunosuppressive tumor microenvironment (TME). Tumor cell-derived C3 has been previously reported, however, whether and how it acts on anti-tumor immunity remains to be elucidated. Here, we describe a unique role of tumor cell-derived C3 in suppressing anti-tumor immunity. Tumor cell-derived C3 was activated intracellularly, which results in generation of C3a. C3a could modulate tumor-associated macrophages (TAMs) via C3a-C3aR-PI3Kγ signaling, thereby repressing anti-tumor immunity. More importantly, deletion of C3 in tumor cells with high C3 expression is sufficient to enhance the efficacy of ɑPD-L1 treatment. Collectively, our present results suggest tumor cell-derived C3 may serve as a novel target in cancer immunotherapy, specifically targeting C3 in tumor cells to enhance anti-tumor immunity.

2018-09-21 | GSE120274 | GEO

COMPLEMENT C3aR ACTS AS AN ONCOSUPPRESSOR IN COLORECTAL CANCER BY MODULATING GUT MICROBIOTA

Project description:Several lines of evidence suggest that inflammation plays a pivotal role in the development and progression of CRC and can be unleashed by the loss of innate immunosurveillance. The complement system is a well characterized first line of defense against pathogens and a central component of the immune responses. As such, the complement system is an important determinant in the maintenance of intestinal homeostasis and emerging evidences suggest that complement dysregulation is involved in the development and progression of CRC. Here we show that in CRC patients CpG island methylation occurs in the gene encoding for the complement anaphylatoxin C3a receptor (c3aR) and strong C3aR down-regulation resulted in decreased overall survival and events-free survival in CRC patients. Ablation of c3ar in mouse models of CRC resulted in the establishment of a pro-inflammatory microbial flora, which fostered strong Th1/Th17 immune responses and a striking increase in tumor incidence and growth that were both dependent on the microbiota. Our findings highlight a previously unrecognized tumor oncosuppressive role for C3aR in CRC that could be exploited as a biomarker for more effective therapeutic intervention.

2020-02-01 | E-MTAB-8500 | biostudies-arrayexpress

Complement C3aR depletion reverses HIF-1α induced metabolic impairment and improves microglial phagocytic and barrier function in response to Aβ pathology.

Project description:Complement C3aR is primarily expressed in microglial cells in the brain. Our study found elevated expression of C3aR in microglia in Alzheimer's disease. To understand the underlying molecular mechanism, we sorted microglia based on their C3aR expression from 9-month-old wild-type and APP-KI mice. Through RNA-seq analysis, we identified metabolic perturbations in C3aR-positive microglia from 9-month-old APP-KI mice. Furthermore, we performed RNA-seq on sorted microglial cells from wild-type, C3aR knockout, APP-KI, and APP-KI;C3aR knockout mice. This analysis revealed a dampening of metabolic dysfunction in the absence of C3aR.

2023-06-25 | GSE228258 | GEO

Discovery-Based Protein Expression Profiling Identifies Distinct Subgroups and Pathways in Leiomyosarcomas

Project description:20 tumor samples run in duplicates, consisting of pleomorphic sarcomas; classfied as leiomyosarcoma or high-grade undifferentiated pleomorphic sarcoma.

2020-01-27 | PXD000616 | Pride

Comparison of the transcriptomic profiles of WT and complement C3-deficient mice with rhabdomyolysis-induced acute kidney injury

Project description:Rhabdomyolysis is a severe condition caused by skeletal muscle damage, leading to acute kidney injury (AKI). We demonstrate that complement has a direct pathogenic role in rhabdomyolysis-induced AKI. Deposition of C3d in the tubules of patients and mice correlated with rhabdomyolysis-induced AKI. Moreover, C3-defiient mice with rhabdomyolysis had preserved renal function. Mechanistically, C3-deficiency attenuated strongly inflammatory and apoptotic components of the renal transcriptome, perturbed by rhabdomyolysis. Complement was activated intrarenal by the lectin pathway via collectin-11. It proceeded in a C4-bypass manner and was amplified by heme-activated alternative pathway. Therefore, complement and heme are promising therapeutic targets for rhabdomyolysis-induced AKI.

2020-11-01 | GSE153507 | GEO

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