PI3K signaling promotes formation of lipid-laden foamy macrophages at the spinal cord injury site
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ABSTRACT:
PROVIDER: PRJNA995560 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25304652_1.fastq.gz | Fastqsanger.gz | |||
| SRR25304652_2.fastq.gz | Fastqsanger.gz | |||
| SRR25304653_1.fastq.gz | Fastqsanger.gz | |||
| SRR25304653_2.fastq.gz | Fastqsanger.gz | |||
| SRR25304654_1.fastq.gz | Fastqsanger.gz |
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Project description:After spinal cord injury (SCI), infiltrating macrophages undergo excessive phagocytosis of myelin and cellular debris, forming lipid-laden foamy macrophages. To understand their role in the cellular pathology of SCI, investigation of foamy macrophage phenotype in vitro revealed a unique inflammatory profile, increased reactive oxygen species (ROS) production, and mitochondrialdysfunction. Bioinformatic analysis identified PI3K as a regulator of inflammation in foamy macrophages, and pharmacological inhibition of this pathway decreased lipid content and inflammatory cytokine and ROS production in these cells. Macrophage-specific inhibition of PI3K using liposomes significantly decreased foamy macrophages at the injury site after a mid-thoracic contusive SCI in mice. RNA sequencing and in vitro analysis of foamy macrophages revealed increased autophagy after PI3K inhibition as a potential mechanism for reduced cellular lipid accumulation. Together, our data suggest that formation of pro-inflammatory foamy macrophages after SCI is due to activation of PI3K signaling that leads to decreased autophagy.
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Project description:Atherosclerosis-associated vascular disease is the leading cause of death worldwide. Clinical and experimental data demonstrated that circulating monocytes internalize plasma lipoproteins and become lipid-laden foamy cells in hypercholesterolemic subjects. This study was designed to identify the endocytic mechanisms responsible for foamy monocyte formation, perform functional and transcriptomic analysis of foamy and non-foamy monocytes, and characterize specific monocyte subsets in the circulation from normocholesterolemic controls and hypercholesterolemic patients. The presence of foamy monocytes was confirmed in hypercholesterolemic mice and humans via flow cytometry analysis. High resolution scanning electron microscopy (SEM) and quantification of FITC/TRITC-dextran internalization demonstrated macropinocytosis stimulation in human (THP-1) and wild type murine monocytes in vitro. Stimulation of macropinocytosis induced foamy monocyte formation in the presence of unmodified, native LDL (nLDL) and oxidized LDL (ox-LDL) in vitro. Genetic blockade of macropinocytosis (LysMCre+ Nhe1f/f) inhibited foamy monocyte formation in hypercholesterolemic mice in vivo and attenuated monocyte adhesion to atherosclerotic aortas ex vivo. qRT-PCR quantified mRNA levels of major scavenger receptors (SR) in foamy and non-foamy monocytes and identified CD36 as a major SR increasing in response to lipid loading. Deletion of CD36 (Cd36-/-) inhibited foamy monocyte formation in hypercholesterolemic mice. Mechanistic studies identified NADPH oxidase 2 (Nox2)-derived superoxide (O2⋅−) as an important downstream signaling molecule stimulating macropinocytosis in monocytes. Bulk RNA-sequencing characterized transcriptional differences between non-foamy and foamy monocytes and macrophages. Flow cytometry analysis of CD14 and CD16 expression demonstrated a significant increase in intermediate monocytes in hypercholesterolemic patients compared to normocholesterolemic controls. These results provide novel insights into the mechanisms of foamy monocyte formation and potentially identify new therapeutic targets in the treatment of atherosclerosis.
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Project description:Macrophages in atherosclerotic aorta are major population in lesion and contributes to lesion formation by becoming foam cells. To investigate in vivo transcriptome profiles of those macrophages, we extracted foamy and non-foamy macrophages from atherosclerotic aorta using lipid probe-based flow cytometry sorting. Our data indicates that intima non-foamy and foamy macrophages show different mRNA expressions. Rather than non-foamy macrophages, foamy macrophages expressed more genes related to cholesterol metabolism, oxidative phosphorylation, lysosome and so on. The non-foamy macrophages expressed more genes related to immune response (Il-1b related pathways, TNF, TLR signaling pathways) than foamy macrophages.
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Project description:Adult zebrafish have the ability to recover from spinal cord injury and exhibit re-growth of descending axons from the brainstem to the spinal cord. We performed gene expression analysis using microarray to find damage-induced genes after spinal cord injury, which shows that Sox11b mRNA is up-regulated at 11 days after injury. However, the functional relevance of Sox11b for regeneration is not known. Here, we report that the up-regulation of Sox11b mRNA after spinal cord injury is mainly localized in ependymal cells lining the central canal and in newly differentiating neuronal precursors or immature neurons. Using an in vivo morpholino-based gene knockout approach, we demonstrate that Sox11b is essential for locomotor recovery after spinal cord injury. In the injured spinal cord, expression of the neural stem cell associated gene, Nestin, and the proneural gene Ascl1a (Mash1a), which are involved in the self-renewal and cell fate specification of endogenous neural stem cells, respectively, is regulated by Sox11b. Our data indicate that Sox11b promotes neuronal determination of endogenous stem cells and regenerative neurogenesis after spinal cord injury in the adult zebrafish. Enhancing Sox11b expression to promote proliferation and neurogenic determination of endogenous neural stem cells after injury may be a promising strategy in restorative therapy after spinal cord injury in mammals. Spinal cord injury or control sham injury was performed on adult zebrafish. After 4, 12, or 264 hrs, a 5 mm segment of spinal cord was dissected and processed (as a pool from 5 animals) in three replicate groups for each time point and treatment.
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Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to find the potential molecular mechanism of traditional Chinese medicine in the treatment of spinal cord injury Methods: Total RNA was isolated and purified using TRIzol reagent following the manufacturer's procedure. The RNA amount and purity of each sample was quantified using NanoDrop ND-1000 . The RNA integrity was assessed by Bioanalyzer 2100 with RIN number >7.0, and confirmed by electrophoresis with denaturing agarose gel. Poly (A) RNA is purified from 1μg total RNA using Dynabeads Oligo (dT)25-61005 using two rounds of purification. Then the poly(A) RNA was fragmented into small pieces using Magnesium RNA Fragmentation Module under 94℃ 5-7min. Then the cleaved RNA fragments were reverse-transcribed to create the cDNA by SuperScript™ II Reverse Transcriptase , which were next used to synthesise U-labeled second-stranded DNAs with E. coli DNA polymerase I, RNase H and dUTP Solution . An A-base is then added to the blunt ends of each strand, preparing them for ligation to the indexed adapters. Each adapter contains a T-base overhang for ligating the adapter to the A-tailed fragmented DNA. Single- or dual-index adapters are ligated to the fragments, and size selection was performed with AMPureXP beads. After the heat-labile UDG enzyme (NEB, cat.m0280, USA) treatment of the U-labeled second-stranded DNAs, the ligated products are amplified with PCR by the following conditions: initial denaturation at 95℃ for 3 min; 8 cycles of denaturation at 98℃ for 15 sec, annealing at 60℃ for 15 sec, and extension at 72℃ for 30 sec; and then final extension at 72℃ for 5 min. The average insert size for the final cDNA library was 300±50 bp. At last, we performed the 2×150bp paired-end sequencing (PE150) on an Illumina Novaseq™ 6000 following the vendor's recommended protocol. Results:In this study, we obtained: chromosome: 23, Genes (G): 32623, Transcripts (T): 40808, GO Annoated: 20795, KEGG Annoated: 8299; in further pathway analysis, it was shown that PI3K-AKT signaling pathway may be the underlying molecular mechanism. Conclusions: Our study represents the first detailed analysis of the spinal cord transcriptome generated by RNA-seq technology with biological replicates. Our results suggest that Modified Erxian decoction may mediate spinal cord repair through the PI3K-AKT pathway.
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