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Deep sequencing reveals an acute inflammatory signature in chronic Peyronie’s disease

ABSTRACT: Background: Peyronie’s disease (PD) is an acquired fibrotic process affecting the tunica albuginea (TA) of the penis. The development of fibrotic plaques can lead to penile curvature/deformities, shortening and erectile dysfunction. Medical treatments are lacking due to limited understanding of disease pathophysiology. Elucidation of molecular pathways and cell types involved could lead to the development of novel disease models and conservative therapeutics. Objective: To characterise the transcriptomic signature of plaques from PD patients and compare it to normal TA using RNA sequencing (RNAseq) and network analysis. Design, setting and participants: We collected surgical TA samples from 6 PD patients and 6 control patients where RNAseq was performed, followed by functional analysis. Our findings were validated through RT-qPCR and immunohistochemistry in other patient samples (biological validation) and tested in an in vitro PD model derived from patient samples. Results and limitations: These findings are the first report of using human samples for transcriptome-wide analysis of genital tract fibrosis. Differential gene expression identified 1294 differentially expressed genes in PD patients. Functional analysis reveals an active inflammatory component in the chronic PD plaque. Moreover, nearly half of all overexpressed genes were regulated by NF-kB and STAT. Further analysis shows that NF-kB is TNFα and TLR-activated and JAK/STAT-signalling occurs through interleukins (IL2/IL6) /interferons (Type I/II)). This data suggests an important macrophage-related response. We validated genes from enriched pathways using RT-qPCR both in the RNAseq samples and 5 additional samples. Immunohistochemical staining for macrophages (CD68) corroborated these findings. Stimulation of PD-derived fibroblasts and myofibroblasts with TNFα revealed expression of macrophage chemoattractant protein-1 (CCL2/MCP-1). Conclusions: Our analysis suggests that, even in an established, chronic PD-plaque, acute inflammatory pathways are still active. We show for the first time that TNFα and TLR-activation could be an important pathway in PD-pathophysiology. Additionally, we suggest that this process is potentially maintained through macrophages. Release of TNFα induce chemoattraction of more macrophages by CCL2 production of (myo)fibroblasts. Both could lead to development of novel druggable targets and more representative disease models.

ORGANISM(S): Homo sapiens

PROVIDER: GSE126005 | GEO | 2022/01/24

REPOSITORIES: GEO

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Project description:Objective: Resident macrophages play an important role in atheromatous plaque rupture. The macrophage gene expression signature associated with plaque rupture is incompletely defined due to the complex cellular heterogeneity in the plaque. We aimed to characterise differential gene expression in resident plaque macrophages from ruptured and stable human atheromatous lesions. A cell-specific approach has the potential to address the question of gene expression differences between particular cell types in stable and unstable plaques with greater precision than approaches based on the study of whole plaques. Using laser micro-dissection, we isolated total RNA from macrophage-rich regions of stable and ruptured human atheromatous plaques derived from carotid endarterectomy samples which were comprehensively characterized using clinical, radiological and histological criteria, and carried out genome-wide gene expression profiling using microarrays. Results: The profiles were characteristic of activated macrophages. At a false discovery rate of 10%, 914 genes were differentially expressed between stable and ruptured plaques. The findings were confirmed in fourteen further stable and ruptured samples for a subset of eleven genes with the highest expression differences (p<0.05). Pathway analysis revealed that components of the PPAR/Adipocytokine signaling pathway were the most significantly upregulated in ruptured compared to stable plaques (p=5.4x10-7). Two key components of the pathway, fatty-acid binding-protein 4 (FABP4) and leptin, showed nine-fold (p=0.0086) and five-fold (p=0.0012) greater expression respectively in macrophages from ruptured plaques. Conclusions: We found differences in gene expression signatures between macrophages isolated from stable and ruptured human atheromatous plaques. Our findings indicate the involvement of FABP4 and leptin in the progression of atherosclerosis and plaque rupture, and suggest that down-regulation of PPAR/adipocytokine signaling within plaques may have therapeutic potential. Methods: We performed genome-wide expression analyses of isolated macrophage-rich regions of stable and ruptured human atherosclerotic plaques. Plaques present in carotid endarterectomy specimens were designated as stable or ruptured using clinical, radiological and histopathological criteria. Macrophage-rich regions were excised from 5 ruptured and 6 stable plaques by laser micro-dissection. Total RNA were subjected to two cycles of linear amplification. Transcriptional profiling was performed using Affymetrix HG-U133 plus 2.0 GeneChip arrays.

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Deep sequencing reveals an acute inflammatory signature in chronic Peyronie’s disease

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