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Microglia aggravate white matter injury via C3/C3aR pathway after experimental subrachnoid hemorrhage

ABSTRACT: Microglia aggravate white matter injury via C3/C3aR pathway after experimental subrachnoid hemorrhage

PROVIDER: PRJNA1069737 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27744360_1.fastq.gz	Fastqsanger.gz
	SRR27744360_2.fastq.gz	Fastqsanger.gz
	SRR27744361_1.fastq.gz	Fastqsanger.gz
	SRR27744361_2.fastq.gz	Fastqsanger.gz
	SRR27744362_1.fastq.gz	Fastqsanger.gz

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Microglia aggravate white matter injury via C3/C3aR pathway after experimental subrachnoid hemorrhage

Project description:Activation of microglia induces neuroinflammation in acute and chronic phase is closely related to the white matter injury (WMI) pathophysiologyafter subrachnoid hemorrhage (SAH). The complement C3a receptor (C3aR) has a dual role in regulating inflammation and plays a role in neurodevelopment, neuroplasticity and neurodegeneration, but it’s effect on WMI during SAH re'mairemains unknown. In this study, 175 male C57BL/6J mice received SAH by endovascular perforation. oxy-Hb was used to simulate SAH in vitro. Multiple technical approaches, including immunohistochemistry, transcriptome sequencing, neurological function assessment, and various molecular biotechnologies, were used to assess the activation of the C3-C3aR pathway after SAH and its effects on microglial polarizations and WMI after SAH. The results showed that abnormal microglial activation after SAH was accompanied by upregulation of complement C3 and C3aR. C3aR inhibition reduced abnormal microglial activation, attenuated neuroinflammation, ameliorated WMI and cognitive deficits after SAH. RNA-Seq revealed that C3aR inhibition downregulated several immune and inflammatory pathways and ameliorated cellular injury by downregulating Pidd1 expression. The adverse effects of C3-C3aR in SAH may be related to Endoplasmic reticulum (ER) stress-dependent cellular injury and formation of inflammasome. PERK agonists exacerbate cellular injury and neuroinflammation attenuated by C3aR inhibition. Intranasal C3a treatment during the subacute phase of SAH helps to reduce astrocyte reactivity and ameliorate cognitive deficits after SAH. In conclusion, these findings suggest that C3aR plays a critical role in the regulation of neuroinflammation and WMI after SAH, providing new therapeutic targets to ameliorate WMI and cognitive deficits after SAH.

2025-01-25 | GSE254320 | GEO

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

Project description: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.

2020-11-24 | GSE141692 | GEO

PS19 and PS19/C3aR KO RNAseq data

Project description:Hippocampal tissue from 9 month old WT, C3aR KO, PS19 and PS19/C3aR KO mice was processed

2018-11-08 | GSE114910 | GEO

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

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

Sedanolide alleviates LPS-induced depressive-like behaviors by modulating the C3a/C3aR signaling axis and microglial glycolysis

Project description:Depression is associated with neuroinflammation and microglial activation. This study investigated the effects of sedanolide in an LPS-induced mouse model of depressive-like behaviors. RNA sequencing of medial prefrontal cortex (mPFC) tissues was performed to identify transcriptomic changes associated with sedanolide treatment. Differential expression analysis revealed candidate genes involved in inflammatory pathways, including C3 and MMP9. Further validation demonstrated that sedanolide regulates neuroinflammation and microglial metabolic reprogramming through the C3a/C3aR signaling axis.

2026-06-25 | GSE335983 | GEO

Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion.

Project description: Not available

| S-EPMC6929610 | biostudies-literature

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

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

Development of gene expression signatures in experimental intracerebral hemorrhage

Project description:To identify the potential lncRNA and mRNA post intracerebral hemorrhage (ICH), we have employed lncRNA microarray expression profiling. 570 mRNAs and 313 lncRNAs were identified in the ICH vs sham group .Expression of six mRNA (Saa3, Col10a1, Mmp13, Oxt, Pcdhb6 and Resp18) and lncRNA (ENSMUT00000141700, AK143011, ENSMUT00000128306, AK030988, ENSMUST00000187076 and ENSMUST00000134129) from this signature was quantified by qPCR.

2023-05-17 | GSE227683 | GEO

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