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Apolipoprotein E deficiency potentiates macrophage resistance to staphylococcus aureus osteomyelitis via regulating cholesterol metabolism

ABSTRACT: To explore how APOE functions in the mechanism of regulation of cholesterol metabolism during S. aureus osteomyelitis, we established S. aureus osteomyelitis models in WT mice and APOE knockout mice. We then performed gene expression profiling analysis using data obtained from RNA-seq of bone marrow from mice mentioned above at day 7 after operation.

ORGANISM(S): Mus musculus

PROVIDER: GSE227521 | GEO | 2023/07/09

REPOSITORIES: GEO

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Apolipoprotein E deficiency potentiates macrophage resistance to staphylococcus aureus osteomyelitis via regulating cholesterol metabolism

Project description:Apolipoprotein E deficiency potentiates macrophage resistance to staphylococcus aureus osteomyelitis via regulating cholesterol metabolism

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Project description:We aimed to elucidate the mechanism of IL-27/ IL-27 receptor signaling effects on S. aureus osteomyelitis via gene expression studies.

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Osteocytes are not able to eliminate intracellular S. aureus and serves as a main reservoir for osteomyelitis

Project description:The main reservoir for Staphylococcus aureus osteomyelitis is the bone tissue where this pathogen can persist and form small colony variants for long periods within osteoblasts and osteocytes. Recently the osteocytes were described as a main reservoir for this pathogen in bone tissue. However, the mechanisms involved in the persistence of S. aureus within these cells are still unknown. Here we investigated the intrinsic relation between S. aureus and both bone cells during infection. The infection of osteoblasts and osteocytes by this pathogen generates the functional bifurcation of these cells into two different responders. Whereas osteoblasts are able to induce a strong antimicrobial respond, the osteocytes trigger signals to recruit immune cells and enhance the inflammation. Moreover, we found that extracellular signals from osteocytes enhance the intracellular bacterial clearance on osteoblasts but not on osteocytes. Even that both cells contain TLR2, the main toll receptor responsible of S. aureus recognition, only osteoblasts were able to increase its expression after infection. Although the expression of TLR2 was not altered in osteocytes, these cells secrete higher lipid mediators and cytokines than osteoblasts. In addition, we found by proteomic analysis that the reduced intracellular bacterial killing of osteocytes is related to a low expression of antimicrobial peptides and reactive oxygen species (ROS) in these cells. Our results suggest that osteocytes contribute to the high inflammation observed in osteomyelitis and at the same time, provide the main niche for S. aureus persistence due to their poor intracellular antimicrobial response. Collectively, these findings reveal the roles of bone cells upon S. aureus infection and provide new insight on the treatment failure of osteomyelitis.

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mRNA transcriptome analysis of bone in a mouse model of implant-associated Staphylococcus aureus osteomyelitis

Project description:Objective: To investigate the molecular pathogenesis of bone with implant-associated osteomyelitis (IAOM) in early and chonic stages. Methods: After a 2 mm sterile stainless pin (0.3 mm in diameter) was inserted into the bone marrow cavity, 2 μl S. aureus solution at 1 × 10e6 CFU/ml was slowly injected into the bone marrow cavity using a micro-syringe to create IAOM mice while only an equal volume of sterile PBS to create controls. Transcriptomic sequencing was performed on day 3 and 14 post-operation, respectively. Differential expression analyses of IAOM_3D vs Ctrl_3D and of IAOM _14D vs Ctrl_14D were performed using the DESeq2 R package (1.16.1); P-values were adjusted using the Benjamini and Hochberg’s approach to control the false discovery rate. The genes with an adjusted P-value < 0.05 and |log2 (Fold Change)| > 1 were recognized as differentially expressed genes (DEGs). GO, KEGG and PPI analysis of DEGs were performed to identify key genes. Results: Differential expression analyses detected a total of 101 DEGs, among which 96 were up-regulated and 5 down-regulated in the femur, when the IAOM and control groups were compared by day 3 post-infection. The number of DEGs significantly increased up to 1,702 by day 14 post-operation, with 1,065 up-regulated and 637 down-regulated in the IAOM femurs compared with controls. Further GO, KEGG and PPI analyses of DEGs suggested that IL-6, CXCL10, IFN-γ and CXCL9 were associated with early development of IAOM. Conclusions: Our study has revealed transcriptomic characteristics of IAOM and suggested that IL-6, CXCL10, IFN-γ and CXCL9 might play an important role in the early stage of IAOM.

2021-02-11 | GSE166522 | GEO

osteomyelitis

Project description:High-resolution transcriptomic analysis of the adaptive response of Staphylococcus aureus during acute and chronic phases of osteomyelitis infection

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Apolipoprotein E deficiency potentiates macrophage against <i>Staphylococcus aureus</i> in mice with osteomyelitis via regulating cholesterol metabolism.

Project description:IntroductionStaphylococcus aureus (S. aureus) osteomyelitis causes a variety of metabolism disorders in microenvironment and cells. Defining the changes in cholesterol metabolism and identifying key factors involved in cholesterol metabolism disorders during S. aureus osteomyelitis is crucial to understanding the mechanisms of S. aureus osteomyelitis and is important in designing host-directed therapeutic strategies.MethodsIn this study, we conducted in vitro and in vivo experiments to define the effects of S. aureus osteomyelitis on cholesterol metabolism, as well as the role of Apolipoprotein E (ApoE) in regulating cholesterol metabolism by macrophages during S. aureus osteomyelitis.ResultsThe data from GSE166522 showed that cholesterol metabolism disorder was induced by S. aureus osteomyelitis. Loss of cholesterol from macrophage obtained from mice with S. aureus osteomyelitis was detected by liquid chromatography-tandem mass spectrometry(LC-MS/MS), which is consistent with Filipin III staining results. Changes in intracellular cholesterol content influenced bactericidal capacity of macrophage. Subsequently, it was proven by gene set enrichment analysis and qPCR, that ApoE played a key role in developing cholesterol metabolism disorder in S. aureus osteomyelitis. ApoE deficiency in macrophages resulted in increased resistance to S. aureus. ApoE-deficient mice manifested abated bone destruction and decreased bacteria load. Moreover, the combination of transcriptional analysis, qPCR, and killing assay showed that ApoE deficiency led to enhanced cholesterol biosynthesis in macrophage, ameliorating anti-infection ability.ConclusionWe identified a previously unrecognized role of ApoE in S. aureus osteomyelitis from the perspective of metabolic reprogramming. Hence, during treating S. aureus osteomyelitis, considering cholesterol metabolism as a potential therapeutic target presents a new research direction.

| S-EPMC10387542 | biostudies-literature

Effect of squalene on liver transcriptome of mice lacking apolipoprotein E

Project description:The hypothesis that the squalene of olive oil might influence hepatic gene expression in an apoE and sex-dependent ways was tested in mice. Gene expression was analyzed using DNA microarrays in male apoE-deficient mice that received 1 g/kg/day of squalene for 10 weeks. As initial screening of potential candidate genes involved in a differential response, only genes with remarkably modified expression (signal log2 ratio > 1.5 or < -1.5) were further considered

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Effect of squalene on liver transcriptome of mice lacking apolipoprotein E

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Effect of Oleanolic acid on liver transcriptome of mice lacking apolipoprotein E

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2014-03-20 | E-GEOD-43589 | biostudies-arrayexpress

Microarray gene expression profiling of heart failure induced in apolipoprotein E-deficient mice by treatment with rosiglitazone

Project description:The anti-diabetic drug and agonist of the peroxisome proliferator-activated receptor gamma (Pparg), rosiglitazone, was recently withdrawn in many countries because the drug use was associated with an increased risk of heart failure. To investigate underlying pathomechanisms, we chose 6-month-old apolipoprotein E (apoE)-deficient mice, which are prone to atherosclerosis and insulin resistance, and thereby mimic the risk profile of patients with cardiovascular disease. After 8 weeks of rosiglitazone treatment (30 mg/kg/day), echocardiography and histology analyses demonstrated that rosiglitazone had induced heart failure with cardiac dilation. Concomitantly, cardiac lipid overload and lipid-induced cardiomyocyte death developed. The microarray gene expression study of heart tissue from rosiglitazone-treated apoE-deficient mice relative to untreated apoE-deficient mice and non-transgenic B6 mice identified cardiac Pparg-dependent lipid metabolism genes in rosiglitazone-treated mice, which seem to trigger a major heart failure promoting pathway. Microarray gene expression profiling was performed with heart tissue isolated from three study groups: (i) rosiglitazone-treated 8-month-old apolipoprotein (apoE)-deficient mice with symptoms of heart failure, (ii) untreated 8-month-old apoE-deficient mice, and (iii) age-matched, untreated, non-transgenic B6 control mice.

2011-03-18 | E-GEOD-28031 | biostudies-arrayexpress

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