Mild Hypoxia Accelerates Cerebral Cavernous Malformation Disease Through CX3CR1-CX3CL1 Signaling

BackgroundCerebral Cavernous Malformations (CCMs) are neurovascular abnormalities in the central nervous system (CNS) caused by loss of function mutations in KRIT1 (CCM1), CCM2, or PDCD10 (CCM3) genes. One of the most common symptoms in CCM patients is associated with motor disability, weakness, seizures, stress, and anxiety, and the extent of the symptom or symptoms may be due to the location of the lesion within the CNS or whether multiple lesions are present. Previous studies have primarily focused on understanding the pathology of CCM using animal models. However, more research has yet to explore the potential impact of CCM lesions on behavioral deficits in animal models, including effects on short-term and long-term memory, motor coordination, and function.MethodsWe used the accelerating RotaRod test to assess motor and coordination deficits. We also used the open field test to assess locomotor activity and pathology-related behavior and Pavlovian fear conditioning to assess short—and long-term memory deficits. Our behavioral studies were complemented by proteomics, histology, immunofluorescence, and imaging techniques. We found that neuroinflammation is crucial in behavioral deficits in male and female mice with neurovascular CCM lesions (Slco1c1-iCreERT2; Pdcd10fl/fl; Pdcd10BECKO).ResultsFunctional behavior tests in male and femalePdcd10BECKOmice revealed that CCM lesions cause sudden motor coordination deficits associated with the manifestation of profound neuroinflammatory lesions. Our findings indicate that maturation of CCM lesions inPdcd10BECKOmice also experienced a significant change in short- and long-term memory compared to their littermate controls,Pdcd10fl/flmice. Proteomic experiments reveal that as CCM lesions mature, there is an increase in pathways associated with inflammation, coagulation, and angiogenesis, and a decrease in pathways associated with learning and plasticity. Therefore, our study shows thatPdcd10BECKOmice display a wide range of behavioral deficits due to significant lesion formation in their central nervous system and that signaling pathways associated with neuroinflammation and learning impact behavioral outcomes.ConclusionsOur study found that CCM animal models exhibited behavioral impairments such as decreased motor coordination and amnesia. These impairments were associated with the maturation of CCM lesions that displayed a neuroinflammatory pattern.

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Identification and experimental validation of diagnostic and prognostic genes CX3CR1, PID1 and PTGDS in sepsis and ARDS using bulk and single-cell transcriptomic analysis and machine learning

Jiang,

Chen,

et al. 2024

Front. Immunol.

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BackgroundSepsis is an uncontrolled reaction to infection that causes severe organ dysfunction and is a primary cause of ARDS. Patients suffering both sepsis and ARDS have a poor prognosis and high mortality. However, the mechanisms behind their simultaneous occurrence are unclear.MethodsWe acquired sepsis and ARDS datasets from GEO and Arrayexpress databases and screened hub genes by WGCNA and machine learning algorithm. For diagnosis and prognosis, ROC curve and survival analysis were used. We performed GO, KEGG, GSEA, immune cell infiltration, drug prediction, molecular docking, transcription factor prediction, and constructed PPI and ceRNA networks to explore these genes and the common mechanisms of sepsis and ARDS. Single-cell data analysis compared immune cell profiles and hub gene localization. Finally, RT-qPCR and H&E staining confirmed the reliability of hub genes using PBMCs samples and mouse models.ResultsWe identified 242 common differentially expressed genes in sepsis and ARDS. WGCNA analysis showed that the turquoise module in GSE95233 is strongly linked to sepsis occurrence and poor prognosis, while the black module in GSE10474 is associated with ARDS. Using WGCNA and three machine learning methods (LASSO, random forest and Boruta), we identified three key genes CX3CR1, PID1 and PTGDS. Models built with them showed high AUC values in ROC curve evaluations and were validated by external datasets, accurately predicting the occurrence and mortality. We further explored the immunological landscape of these genes using immune infiltration and single-cell analysis. Then, the ceRNA, predicted drugs and molecular docking were analyzed. Ultimately, we demonstrated that these genes are expressed differently in human and mouse samples with sepsis and ARDS.ConclusionThis study identified three molecular signatures (CX3CR1, PID1 and PTGDS) linked to the diagnosis and poor prognosis of sepsis and ARDS, validated by RT-qPCR and H&E staining in both patient and mouse samples. This research may be valuable for identifying shared biological mechanisms and potential treatment targets for both diseases.

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Mild Hypoxia Accelerates Cerebral Cavernous Malformation Disease Through CX3CR1-CX3CL1 Signaling

Cited by 4 publications

References 82 publications

Tobacco use increases lesion burden in familial cerebral cavernous malformation syndrome

Tobacco use increases lesion burden in familial cerebral cavernous malformation syndrome

Behavioral impairments are linked to neuroinflammation in mice with Cerebral Cavernous Malformation disease

Identification and experimental validation of diagnostic and prognostic genes CX3CR1, PID1 and PTGDS in sepsis and ARDS using bulk and single-cell transcriptomic analysis and machine learning

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