Targeting FKBP5 Preserves Mitochondrial Homeostasis through the CaMKKβ/AMPK Pathway to Attenuate Sepsis-Induced Acute Lung Injury
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE335386 | GEO | 2026/08/13
REPOSITORIES: GEO
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Project description:FKBP51, also known as FK506-binding protein 51, is a molecular chaperone and scaffolding protein with significant roles in regulating hormone signaling and stress responding. Genetic variants in FKBP5, which encodes FKBP51, have been implicated in a growing number of neuropsychiatric disorders, which has spurred efforts to target FKBP51 therapeutically. However, the molecular mechanisms by which FKBP51 influences the pathways affected in these disorders are not fully understood. Protein changes in Fkbp5 KO mice, as measured by histology and proteomics, revealed alterations in a brain region- and sex-dependent manner.
2024-09-05 | PXD049439 | Pride
Project description:Targeting FKBP5 Preserves Mitochondrial Homeostasis through the CaMKKβ/AMPK Pathway to Attenuate Sepsis-Induced Acute Lung Injury
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Project description:The disturbance of immune balance at the maternal-fetal interface is a significant contributor to obstetric antiphospholipid syndrome (OAPS); however, the precise mechanisms underlying this disturbance remain unclear. This study investigates the immune regulatory role of FK506-binding protein 5 (FKBP5) to elucidate its molecular mechanisms in pathological pregnancies associated with OAPS. We conducted RNA sequencing (RNA-seq) analysis and immune cell typing on decidual tissue from OAPS patients and healthy controls. The results indicated that the FKBP5 gene and inflammation-related pathways were significantly expressed in the maternal-fetal interface of OAPS patients, characterized by an increase in M1 (iNOS+/CD86+) macrophages and a decrease in M2 (Arg-1+/CD206+) macrophages. In vitro experiments demonstrated that FKBP5 promotes M1-like polarization of macrophages via the JAK1/STAT1 pathway while inhibiting M2-like polarization through the PPARγ/STAT6 pathway. Using a macrophage-trophoblast cell co-culture model, we found that FKBP5-induced abnormal macrophage polarization at the maternal-fetal interface negatively impacted the migration, invasion, and proliferation of trophoblast cells. In a mouse model of OAPS, the knockout of FKBP5 regulated the abnormal polarization of macrophages between M1 and M2 phenotypes, facilitated epithelial-to-mesenchymal transition (EMT), and mitigated antiphospholipid antibodies (aPLs)-mediated placental pathological damage. Notably, SAFit2, a small molecule inhibitor of FKBP5, effectively improved adverse pregnancy outcomes in OAPS mice. The immune microenvironment imbalance at the maternal-fetal interface, driven by FKBP5-regulated macrophage polarization, constitutes a critical immunological basis for aPLs-mediated placental damage. Therefore, FKBP5 presents a potential therapeutic target for OAPS.
2025-04-07 | GSE283798 | GEO
Project description:FK506-binding protein 51 (FKBP51, encoded by FKBP5) is a multisignaling cochaperone that regulates cellular stress responses and inflammatory signaling through the NF-κB pathway. Although FKBP51 is upregulated in reactive astrocytes, its role in epilepsy and excitotoxic neuroinflammation remains unknown. Excessive astrogliosis and impaired glutamate transporter-1 (GLT-1)-mediated glutamate clearance promote excitotoxicity and increase seizure susceptibility. Here, we investigated how both global and astrocyte-specific Fkbp5 deletions influence seizure susceptibility, astrogliosis, neuroinflammation, and cognition in male mice subjected to a kainic acid (KA)-induced epilepsy mouse model. Global Fkbp5 knockout (Fkbp5-KO) presented lower seizure activity along with decreased neuronal loss and astrogliosis in the hippocampus compared with the wild-type mice. Astrocyte-specific Fkbp5 conditional knockout (aFkbp5-cKO) mice similarly attenuated seizure severity, decreased astrogliosis, improved novel object recognition, and preserved GLT-1 expression in hippocampal CA3. Glia-neuron mixed cultures derived from Fkbp5-KO brains showed reduced NMDA-induced neurotoxicity and astrogliosis, accompanied by decreased NF-κB p65 phosphorylation. Notably, overexpression of an Fkbp5 quadruple mutant that disrupts the FKBP51-NF-κB interaction inhibited proinflammatory lipopolysaccharide-induced astrogliosis and NF-κB activation. Transcriptomic analysis of Fkbp5-KO hippocampi further confirmed suppression of NF-κB-driven inflammatory pathways. In summary, astrocytic FKBP51 mediates reactive astrogliosis and GLT-1 downregulation, linking excitotoxic neuroinflammation with seizure susceptibility and cognitive impairment, and represents a potential intervention target for epilepsy.
2026-02-02 | GSE293536 | GEO
Project description:Psychological stress is a risk factor for several diseases. In particular, stressor exposure has been linked with various psychiatric disorders. Since the hypothalamic-pituitary-adrenal (HPA) axis plays a central role in the regulation of stress responses, it has been implicated in the etiology of stress related disorders such as PTSD. The HPA axis regulate synthesis and release of glucocorticoids and its dysregulation cause abnormal response to stress. FK506-binding protein 51 (FKBP5) is a co chaperone of HSP90 in the glucocorticoid receptor (GR) molecular complex and a key regulator of the sensitivity of GR. In this study, we profiled the miRNAs in the prefrontal cortex of FKBP5 knock out mice compared to the wild type. Subsequently, we profiled target mRNAs for differentially expressed miRNAs in the FKBP5 deficient mice using several tools for sequence-based miRNA target prediction such as miRDB, DIANA tool, miRmap and TargetScan. Gene ontology analysis suggested that differentially expressed miRNAs in the brain of FKBP5 deficient mice may be involved in neuron development, cell motion, endocytosis, and cell-cell adhesion. These results suggest that Nfasc could be a new target for understanding of the pathophysiology of PTSD.
2020-10-31 | GSE139502 | GEO
Project description:Normal children, children with SIRS, children with sepsis, and children with septic shock. Objectives: To advance our biological understanding of pediatric septic shock, we measured the genome-level expression profiles of critically ill children representing the systemic inflammatory response syndrome (SIRS), sepsis, and septic shock spectrum. Experiment Overall Design: Prospective observational study involving microarray-based bioinformatics.
2009-01-05 | E-GEOD-13904 | biostudies-arrayexpress
Project description:While the paradigm that genetic predisposition and environmental exposures interact to shape development and function of the human brain and ultimately the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not been elucidated yet. Here we show that a functional polymorphism altering chromatin interaction between the transcription start site and long range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increases the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements (GREs) of FKBP5. This demethylation is linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global impact on the function of immune cells and brain areas associated with stress regulation. This first identification of molecular mechanisms of genotype-directed long-term environmental reactivity will also critically contribute to designing more effective treatment strategies for stress-related disorders. Effects of FKBP5 rs1360780 genotype x environment interaction on peripheral blood mRNA expression of GR responsive genes, as measured by gene expression arrays, were explored in 129 individuals (child abuse/risk allele carrier N = 40, child abuse/protective allele carrier N = 15; and no child abuse/risk allele carrier N = 60, no child abuse/protective allele carrier N = 14). In all 129 individuals, 1627 transcripts showed a significant correlation with plasma cortisol concentrations, suggesting their GR responsiveness. The correlation of 76 of these transcripts with cortisol plasma levels showed significant differences when stratifying by FKBP5 genotype in individuals with child abuse (Fisher z score ≥ 1.96) For these 76 transcripts, the mean absolute correlation coefficient with plasma cortisol was R = 0.23 in the risk allele carriers with child abuse, that is those exhibiting a demethylation of FKBP5 intron 7 as compared to R = 0.74 in the carriers of the protective genotype with child abuse where intron 7 methylation remains largely stable. This indicates a relative GR-resistance in the trauma exposed FKBP5 risk allele vs. protective genotype carriers. These 76 transcripts did not show a genotype-dependent difference in correlation coefficients in non-trauma exposed individuals suggesting that exposure to early trauma enhances FKBP5 genotype-dependent effect of GR sensitivity, most likely by epigenetic mechanisms. These findings suggest that the combination of FKBP5 risk allele carrier status and early trauma exposure alters the stress hormone-dependent regulation of several genes in peripheral blood cells, and might thereby enhance the reported association of early trauma with immune and inflammatory dysregulation, further promoting system-wide symptoms of stress-related disorders.
2012-11-03 | E-GEOD-42002 | biostudies-arrayexpress
Project description:Fkbp5 encodes the FK506 binding protein 5, a glucocorticoid receptor (GR) binding protein which is an important factor in stress responses that form coping behavior. However, the results of previous studies have been controversial about the relationships between variants in Fkbp5 and stress have been controversial. To clarify the effects of the loss of Fkbp5 on the stress response, we conducted behavior test with mice following chronic restraint stress with homozygous wild type (WT) and knock-out (KO) genotypes. WT mice showed anhedonia, one of depressive-like behaviors, but KO mice did not show this symptom in sucrose preference test (SPT). To examine the molecular mechanism of this stress resilience, we performed RNAseq analysis. The results of differentially expressed gene (DEG) analysis showed that diverse biological processes related with cell-cell communication are changed by chronic stress. Weighted gene co-expression network analysis detected 60 gene modules which show varied correlation patterns with stress or Fkbp5 genotype. The expression pattern of M55 module correlated with SPT results and the gene ontology (GO) enrichment analysis in this module revealed that the genes in this module are involved in nervous system development, gland morphogenesis and inflammatory response. We identify the role of Fkbp5 KO in stress response and the transcriptome study provide insight into stress-related biological processes.
2019-11-06 | GSE138240 | GEO
Project description:Normal children, children with SIRS, children with sepsis, and children with septic shock. Objectives: To advance our biological understanding of pediatric septic shock, we measured the genome-level expression profiles of critically ill children representing the systemic inflammatory response syndrome (SIRS), sepsis, and septic shock spectrum. Keywords: Normal vs diseased
2008-12-12 | GSE13904 | GEO
Project description:While the paradigm that genetic predisposition and environmental exposures interact to shape development and function of the human brain and ultimately the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not been elucidated yet. Here we show that a functional polymorphism altering chromatin interaction between the transcription start site and long range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increases the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements (GREs) of FKBP5. This demethylation is linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global impact on the function of immune cells and brain areas associated with stress regulation. This first identification of molecular mechanisms of genotype-directed long-term environmental reactivity will also critically contribute to designing more effective treatment strategies for stress-related disorders. Effects of FKBP5 rs1360780 genotype x environment interaction on peripheral blood mRNA expression of GR responsive genes, as measured by gene expression arrays, were explored in 129 individuals (child abuse/risk allele carrier N = 40, child abuse/protective allele carrier N = 15; and no child abuse/risk allele carrier N = 60, no child abuse/protective allele carrier N = 14).
2012-11-03 | GSE42002 | GEO