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Protective role of aconitate decarboxylase 1 in neuroinflammation-induced dysfunctions of the paraventricular thalamus and sleepiness

ABSTRACT: Protective role of aconitate decarboxylase 1 in neuroinflammation-induced dysfunctions of the paraventricular thalamus and sleepiness

PROVIDER: PRJNA1176163 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31074656_1.fastq.gz	Fastqsanger.gz
	SRR31074656_2.fastq.gz	Fastqsanger.gz
	SRR31074657_1.fastq.gz	Fastqsanger.gz
	SRR31074657_2.fastq.gz	Fastqsanger.gz
	SRR31074658_1.fastq.gz	Fastqsanger.gz

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Protective role of aconitate decarboxylase 1 in neuroinflammation-induced dysfunctions of the paraventricular thalamus and sleepiness

Project description:Sleepiness is commonly associated with neuroinflammation; however, the underlying neuroregulatory mechanisms remain unclear. Previous research suggests that the paraventricular thalamus (PVT) plays a crucial role in regulating sleep‐wake dynamics; thus, neurological abnormalities in the PVT may contribute to neuroinflammation-induced sleepiness. To test this hypothesis, we performed electroencephalography recordings in mice treated with lipopolysaccharide (LPS) and found that the mice exhibited temporary sleepiness lasting for 7 days. Using the Fos-TRAP method, fiber photometry recordings, and immunofluorescence staining, we detected temporary PVT neuron hypoactivation and microglia activation from day 1 to day 7 post-LPS treatment. Combining the results of bulk and single-cell RNA sequencing, we found upregulation of aconitate decarboxylase 1 (Acod1) in PVT microglia post-LPS treatment. To investigate the role of Acod1, we manipulated Acod1 gene expression in PVT microglia via stereotactic injection of short hairpin RNA adenovirus. Knockdown of Acod1 exacerbated inflammation, neuronal hypoactivation, and sleepiness. Itaconate is a metabolite synthesized by the enzyme encoded by Acod1. Finally, we confirmed that exogenous administration of an itaconate derivative, 4-octyl itaconate, could inhibit microglia activation, alleviate neuronal dysfunction, and relieve sleepiness. In summary, our findings highlight PVT’s role in inflammation-induced sleepiness and suggest Acod1 as a potential therapeutic target for neuroinflammation.

2024-10-23 | GSE280081 | GEO

Wild type (WT) and Aconitate decarboxylase 1 knockout (Acod1-/-) BMDM treated with Imiquimod for 12h

Project description:The Krebs cycle enzyme Aconitate Decarboxylase 1 (ACOD1) mediates itaconate synthesis in monocytes and macrophages. Here, we explore the role of endogenous ACOD1-itaconate pathway in the activation of BMDM after imiquimod treatment.

2024-04-17 | GSE250384 | GEO

Aconitate decarboxylase 1 mediates acute airway inflammatory response to environmental exposures

Project description:Aconitate decarboxylase 1 mediates acute airway inflammatory response to environmental exposures

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Molecular and spatial profiling of the paraventricular nucleus of the thalamus

Project description:The paraventricular nucleus of the thalamus (PVT) is known to regulate various cognitive and behavioral processes. However, while functional diversity among PVT circuits has often been linked to cellular differences, the molecular identity and spatial distribution of PVT cell types remains unclear. To address this gap, here we used single nucleus RNA sequencing (snRNA-seq) and identified five molecularly distinct PVT neuronal subtypes. Additionally, multiplex fluorescent in situ hybridization of top marker genes revealed that PVT subtypes are organized by a combination of previously unidentified molecular gradients. Lastly, comparing our dataset with a recently published single-cell sequencing atlas of thalamus yielded novel insight into the PVT’s connectivity with cortex, including unexpected innervation of auditory and visual areas. This comparison also revealed that our data contains a largely non-overlapping transcriptomic map of multiple midline thalamic nuclei. Collectively, our findings uncover previously unknown features of the molecular diversity and anatomical organization of the PVT and provide a valuable resource for future investigations.

2023-03-06 | GSE208707 | GEO

Neutrophils Resist Ferroptosis and Promote Breast Cancer Metastasis through Aconitate Decarboxylase 1

Project description:Neutrophils Resist Ferroptosis and Promote Breast Cancer Metastasis through Aconitate Decarboxylase 1

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Astrocytes modulate a specific paraventricular thalamus-prefrontal cortex projection to enhance consciousness recovery from sevoflurane anesthesia in mice

Project description:Previous studies have proved that astrocytes may be a key neural substrate that regulates wakefulness and consciousness recovery from general anesthesia, while the exact molecular target in astrocytes is still unclear. Using virus injection and in vivo fiber photometry in mice, we found both activating astrocytes and knocking down astrocytic Kir4.1 in paraventricular thalamus (PVT) promotes the consciousness recovery from sevoflurane anesthesia. Single-cell RNA sequencing of PVT reveals two distinct cellular subtypes of glutamatergic neurons: PVTGRM and PVTChAT neurons. Patch-clamp recording results proved that Astrocytic Kir4.1-mediated modulation of sevoflurane on PVT mainly works on PVTChAT neurons. Moreover, we found that PVTChAT neurons project mainly to the mPFC. This specific paraventricular thalamus to prefrontal cortex projection is involved in recovery of consciousness from sevoflurane anesthesia indirectly through modulation of astrocytes. In summary, our findings support the novel conception that the volatile anesthetic sevoflurane can inhibit PVT astrocytic Kir 4.1 to maintain and/or increase neuronal firing of PVTChAT neurons, which mainly projects to mPFC and promotes consciousness recovery from anesthesia.

2024-07-20 | GSE240388 | GEO

Molecular and spatial profiling of the paraventricular nucleus of the thalamus

Project description:Molecular and spatial profiling of the paraventricular nucleus of the thalamus

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Aconitate decarboxylase 1 participates in the control of pulmonary Brucella infection in mice

Project description:Brucellosis is one of the most widespread bacterial zoonoses worldwide. Here, our aim was to identify the effector mechanisms controlling the early stages of intranasal infection with Brucella in C57BL/6 mice. During the first 48 hours of infection, alveolar macrophages (AMs) are the main cells infected in the lungs. Using RNA sequencing, we identified the aconitate decarboxylase 1 gene (Acod1; also known as Immune responsive gene 1), as one of the genes most upregulated in murine AMs in response to B. melitensis infection at 24 hours post-infection. Upregulation of Acod1 was confirmed by RT-qPCR in lungs infected with B. melitensis and B. abortus. We observed that Acod1-/- C57BL/6 mice display a higher bacterial load in their lungs than wild-type (wt) mice following B. melitensis or B. abortus infection, demonstrating that Acod1 participates in the control of pulmonary Brucella infection. The ACOD1 enzyme is mostly produced in mitochondria of macrophages, and converts cis-aconitate, a metabolite in the Krebs cycle, into itaconate. Dimethyl itaconate (DMI), a chemically-modified membrane permeable form of itaconate, has a dose-dependent inhibitory effect on Brucella growth in vitro. Interestingly, modelling studies suggest the binding of itaconate into the binding site of isocitrate lyase. DMI does not inhibit multiplication of the isocitrate lyase deletion mutant ∆aceA B. abortus in vitro. Finally, we observed that, unlike the wt strain, the ∆aceA B. abortus strain multiplies similarly in wt and Acod1-/- C57BL/6 mice. These data suggest that bacterial isocitrate lyase might be a target of itaconate in AMs.

2021-09-21 | GSE180699 | GEO

Aconitate decarboxylase 1 participates in the control of pulmonary Brucella infection in mice

Project description:Aconitate decarboxylase 1 participates in the control of pulmonary Brucella infection in mice

| PRJNA749252 | ENA

Neutrophils Resist Ferroptosis and Promote Breast Cancer Metastasis through Aconitate Decarboxylase 1

Project description:Lung metastasis is the principal cause of breast cancer-related mortality. Neutrophils have emerged as an important component of the tumor microenvironment (TME), supporting tumor proliferation and mediating immunosuppression. Here, we show that aconitate decarboxylase 1 (Acod1) is highly expressed in tumor-infiltrating neutrophils and promotes breast cancer lung metastasis by supporting neutrophil survival in the TME. Acod1 expression is regulated by tumor-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) through the JAK/STAT signaling pathway and CCAAT/enhancer-binding protein beta (C/EBPβ) transcription factor activity. Acod1 loss in tumor-infiltrating neutrophils leads to ferroptosis-like cell death, resulting in decreased frequency of neutrophils in the TME. Mechanistically, itaconate, the product of Acod1, activates nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in upregulated antioxidant responses and decreased lipid-reactive oxygen species. Genetical deletion of Acod1 in neutrophils suppresses lung metastasis of breast cancer in mouse models by decreasing neutrophil-lymphocyte ratio and elevating cytotoxic T cell response. Importantly, genetic targeting of Acod1 enhances the anti-tumor efficacy of immune checkpoint blockade. Overall, our findings reveal a mechanism of how immunosuppressive neutrophils survive in the harsh TME and support Acod1-targeting approaches for cancer treatment.

2023-09-13 | GSE216425 | GEO

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