Dataset Information

Transfer of cGAMP from neuron to microglia activates microglial type I interferon responses after subarachnoid hemorrhage.

ABSTRACT: Primary subarachnoid hemorrhage (SAH) is a type of acute stroke, accounting for approximately 10% of cases, with high disability and mortality rate. Early brain injury (EBI) is a critical factor in determining SAH mortality; however, there are no effective treatment interventions for EBI. Based on our results, the transmission of cyclic GMP-AMP (cGAMP) from neurons to microglia is a key molecular event that triggers type I interferon response, amplifies neuroinflammation, and leads to neuronal apoptosis. Abnormal intracytoplasmic mitochondrial DNA (mtDNA) is the initiating factor of the cGAS-cGAMP-STING signaling axis. Overall, the cGAS-cGAMP-STING signaling axis is closely associated with neuroinflammation after subarachnoid hemorrhage. Targeting cGAS triggered by cytoplasmic mtDNA may be useful for comprehensive clinical treatment of patients after SAH. Further studies targeting cGAS-specific antagonists for treating SAH are warranted. Video Abstract.

SUBMITTER: Chang H

PROVIDER: S-EPMC10763285 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Transfer of cGAMP from neuron to microglia activates microglial type I interferon responses after subarachnoid hemorrhage.

Chang Hanxiao H Li Zheng Z Zhang Weiwei W Lin Chao C Shen Yuqi Y Zhang Guangjian G Mao Lei L Ma Chencheng C Liu Ning N Lu Hua H

Cell communication and signaling : CCS 20240102 1

Primary subarachnoid hemorrhage (SAH) is a type of acute stroke, accounting for approximately 10% of cases, with high disability and mortality rate. Early brain injury (EBI) is a critical factor in determining SAH mortality; however, there are no effective treatment interventions for EBI. Based on our results, the transmission of cyclic GMP-AMP (cGAMP) from neurons to microglia is a key molecular event that triggers type I interferon response, amplifies neuroinflammation, and leads to neuronal a ...[more]

PMID: 38169382

Similar Datasets

Project description:BackgroundMicroglial activation-mediated neuroinflammation is a major contributor to early brain injury (EBI) after subarachnoid hemorrhage (SAH). MicroRNA-124 (miR-124) is the most abundant miRNAs in the central nervous system (CNS) and plays a vital role in microglial activation by targeting protein CCAAT-enhancer-binding protein α (C/EBPα). It has been reported that the CX3CL1/CX3CR1 axis is involved in the delivery of miR-124 from neurons to microglia.MethodsAn experimental rat SAH model was established by injecting autologous arterial blood into the prechiasmatic cistern, and cultured primary neurons and microglia were exposed to oxyhemoglobin to mimic SAH in vitro. We additionally exploited specific expression plasmids encoding CX3CL1 and CX3CR1.ResultsWe observed significant decreases in CX3CL1 and CX3CR1 in the brain tissues of SAH patients. We also observed decreases in the levels of CX3CL1 in neurons and CX3CR1 in microglia after SAH in rats. Moreover, microglia exhibited an activated phenotype with macrophage-like morphology and high levels of CD45 and major histocompatibility complex (MHC) class II after SAH. After overexpression of CX3CL1/CX3CR1, the level of CD45 and MHC class II and the release of inflammatory factors tumor necrosis factor α, interleukin 1α and complement 1q were significantly decreased. There was also increased neuronal degeneration and behavior dysfunction after SAH, both of which were inhibited by CX3CL1/CX3CR1 overexpression. Additionally, we found that the delivery of exosomal miR-124 from neurons to microglia was significantly reduced after SAH, accompanied by an increase in C/EBPα expression, and was inhibited by CX3CL1/CX3CR1 overexpression. In conclusion, the CX3CL1/CX3CR1 axis may play protective roles after SAH by promoting the delivery of exosomal miR-124 to microglia and attenuate microglial activation and neuroinflammation.ConclusionsCX3CL1/CX3CR1 axis may be a potential intervention target for the inhibition of SAH-induced EBI by promoting exosome transport of miR-124 to microglia.

Project description:BACKGROUND:Interferon ? (IFN?) is a cytokine whose production is increased endogenously in response to viral infection and in autoimmune diseases such as systemic lupus erythematosus (SLE). An elevated IFN? signature has been associated with clinically observed neuro-behavioural deficits such as mild cognitive impairment, fatigue, depression and psychosis in these diseases. However, the mechanisms underlying these neuropsychiatric symptoms remain largely unknown, and it is as yet unclear how IFN? signalling might influence central nervous system (CNS) function. Aberrant microglia-mediated synaptic pruning and function has recently been implicated in several neurodegenerative and neuropsychiatric diseases, but whether and how IFN? modulates these functions are not well defined. METHODS:Using a model of peripheral IFN? administration, we investigated gene expression changes due to IFNAR signalling in microglia. Bulk RNA sequencing on sorted microglia from wild type and microglia-specific Ifnar1 conditional knockout mice was performed to evaluate IFN? and IFNAR signalling-dependent changes in gene expression. Furthermore, the effects of IFN? on microglia morphology and synapse engulfment were assessed, via immunohistochemistry and flow cytometry. RESULTS:We found that IFN? exposure through the periphery induces a unique gene signature in microglia that includes the expected upregulation of multiple interferon-stimulated genes (ISGs), as well as the complement component C4b. We additionally characterized several IFN?-dependent changes in microglial phenotype, including expression of CD45 and CD68, cellular morphology and presynaptic engulfment, that reveal subtle brain region-specific differences. Finally, by specifically knocking down expression of IFNAR1 on microglia, we show that these changes are largely attributable to direct IFNAR signalling on microglia and not from indirect signalling effects through other CNS parenchymal cell types which are capable of IFN?-IFNAR signal transduction. CONCLUSIONS:Peripheral IFN? induces unique genetic and phenotypic changes in microglia that are largely dependent on direct signalling through microglial IFNAR. The IFN?-induced upregulation of C4b could play important roles in the context of aberrant synaptic pruning in neuropsychiatric disease.

Dataset Information

Transfer of cGAMP from neuron to microglia activates microglial type I interferon responses after subarachnoid hemorrhage.

Publications

Transfer of cGAMP from neuron to microglia activates microglial type I interferon responses after subarachnoid hemorrhage.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets