Evaluation of immune status in testis and macrophage polarization associated with testicular damage in patients with nonobstructive azoospermia

Zheng, Wenzhong; Zhang, Shiqiang; Jiang, Shaoqin; Huang, Zhangcheng; Chen, Xiaobao; Guo, Huan; Li, Mengqiang

doi:10.1111/aji.13481

Cited by 25 publications

(19 citation statements)

References 70 publications

(132 reference statements)

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“…In accordance with previous findings ( 34 ), our in-depth analysis of multiple-subtype data sets in NOA indicated that macrophages were involved in its pathogenesis. Macrophages constitute a common type of immune cell that reside in multiple organs and maintain overall bodily homeostasis ( 35 ).…”

Section: Discussionsupporting

confidence: 92%

Identification of biomarkers associated with macrophage infiltration in non-obstructive azoospermia using single-cell transcriptomic and microarray data

Luo¹,

Zheng²,

Nai³

et al. 2023

Ann Transl Med

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Background Non-obstructive azoospermia (NOA) is a common clinical cause of male infertility. Research suggests that macrophages are linked to testicular function; however, their involvement in NOA remains unknown. Methods To evaluate the importance of macrophages infiltration in NOA and identify the macrophage-related biomarkers, the gene-expression microarray data GSE45885 and the single-cell transcriptomic data GSE149512 were utilized from the Gene Expression Omnibus (GEO). A single-sample gene set enrichment analysis (ssGSEA) was conducted to investigate immune cell proliferation. The Seurat package was used for the single-cell data analysis, and the limma package was used to identify the differentially expressed genes between the NOA and normal samples. Moreover, we conducted a weighted gene co-expression network analysis (WGCNA) to identify the macrophage-related key modules and genes, and conducted Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses for the functional exploration. To identify the macrophage-related biomarkers, we conducted least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) analyses. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to verify the marker genes present in NOA. Results We confirmed that open reading frame 72 gene on chromosome 9 ( C9orf72 ) [area under the curve (AUC) =0.861] and cartilage-associated protein ( CRTAP ) (AUC =0.917) were the hub genes of NOA, and the RT-qPCR analysis revealed the critical expression of both genes in NOA. Conclusions Through the combination of tissue transcriptomic and single-cell RNA-sequencing analyses, we concluded that macrophage infiltration is significant in different subtypes of NOA, and we hypothesized that C9orf72 and CRTAP play critical roles in NOA due to their high expression in macrophages.

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Section: Discussionsupporting

confidence: 92%

Identification of biomarkers associated with macrophage infiltration in non-obstructive azoospermia using single-cell transcriptomic and microarray data

Luo¹,

Zheng²,

Nai³

et al. 2023

Ann Transl Med

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“…A report has suggested that macrophages were increasingly present in NOA men, and inhibitory paracrine function of macrophages on Leydig cells may partially lead to the deficit of steroidogenesis and testosterone within the testis ( 72 ). More recently, one report showed that NOA testis tissue had significantly elevated immune score and more M1 and M2 macrophages in comparison with the normal testis, which was appreciated as the evidence for the vital role of macrophage polarization in NOA development ( 73 ). NK cells are traditionally divided into two subsets (CD56 bright and CD56 dim ) in humans.…”

Section: Discussionmentioning

confidence: 99%

Aberrant Gene Expression Profiling in Men With Sertoli Cell-Only Syndrome

et al. 2022

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Sertoli cell-only syndrome (SCOS) is the most severe and common pathological type of non-obstructive azoospermia. The etiology of SCOS remains largely unknown to date despite a handful of studies reported in this area. According to the gene expression of testicular tissue samples in six datasets from the Gene Expression Omnibus, we detected 1441 differentially expressed genes (DEGs) between SCOS and obstructive azoospermia (OA) testicular tissue samples. Enriched GO terms and KEGG pathways for the downregulated genes included various terms and pathways related to cell cycle and reproduction, while the enrichment for the upregulated genes yielded many inflammation-related terms and pathways. In accordance with the protein-protein interaction (PPI) network, all genes in the most critical module belonged to the downregulated DEGs, and we obtained nine hub genes, including CCNB1, AURKA, CCNA2, BIRC5, TYMS, UBE2C, CDC20, TOP2A, and OIP5. Among these hub genes, six were also found in the most significant SCOS-specific module obtained from consensus module analysis. In addition, most of SCOS-specific modules did not have a consensus counterpart. Based on the downregulated genes, transcription factors (TFs) and kinases within the upstream regulatory network were predicted. Then, we compared the difference in infiltrating levels of immune cells between OA and SCOS samples and found a significantly higher degree of infiltration for most immune cells in SCOS than OA samples. Moreover, CD56bright natural killer cell was significantly associated with six hub genes. Enriched hallmark pathways in SCOS had remarkably more upregulated pathways than the downregulated ones. Collectively, we detected DEGs, significant modules, hub genes, upstream TFs and kinases, enriched downstream pathways, and infiltrated immune cells that might be specifically implicated in the pathogenesis of SCOS. These findings provide new insights into the pathogenesis of SCOS and fuel future advances in its theranostics.

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“…Evaluating the transcriptional profile of testicular macrophages showed high expression levels of anti-inflammatory factor ( IL10 ) and low levels of inflammatory factors ( IL1A , IL17C , IL12A , IL22 , IL11 and IL6 ), suggesting an enrichment of M2 macrophages in men with normal spermatogenesis. Interestingly, these cells show high expression levels of the inflammatory factor receptors IL13RA1 and IL1R2 suggesting the potential to quickly respond to inflammatory stimuli ( Zheng et al , 2021 ). ScRNA-seq analyses of testicular tissues from men with iNOA, cryptozoospermic and Klinefelter syndrome all showed similar signs of inflammation.…”

Section: A Single-cell View Of Testicular Somatic Cells In (In)fertil...mentioning

confidence: 99%

Human spermatogonial stem cells and their niche in male (in)fertility: novel concepts from single-cell RNA-sequencing

Persio

Neuhaus

2022

Human Reproduction

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The amount of single-cell RNA-sequencing (scRNA-seq) data produced in the field of human male reproduction has steadily increased. Transcriptional profiles of thousands of testicular cells have been generated covering the human neonatal, prepubertal, pubertal and adult period as well as different types of male infertility; the latter include non-obstructive azoospermia, cryptozoospermia, Klinefelter syndrome and azoospermia factor deletions. In this review, we provide an overview of transcriptional changes in different testicular subpopulations during postnatal development and in cases of male infertility. Moreover, we review novel concepts regarding the existence of spermatogonial and somatic cell subtypes as well as their crosstalk and provide corresponding marker genes to facilitate their identification. We discuss the potential clinical implications of scRNA-seq findings, the need for spatial information and the necessity to corroborate findings by exploring other levels of regulation, including at the epigenetic or protein level.

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Evaluation of immune status in testis and macrophage polarization associated with testicular damage in patients with nonobstructive azoospermia

Cited by 25 publications

References 70 publications

Identification of biomarkers associated with macrophage infiltration in non-obstructive azoospermia using single-cell transcriptomic and microarray data

Identification of biomarkers associated with macrophage infiltration in non-obstructive azoospermia using single-cell transcriptomic and microarray data

Aberrant Gene Expression Profiling in Men With Sertoli Cell-Only Syndrome

Human spermatogonial stem cells and their niche in male (in)fertility: novel concepts from single-cell RNA-sequencing

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