Cathepsin S are involved in human carotid atherosclerotic disease progression, mainly by mediating phagosomes: bioinformatics and in vivo and vitro experiments

Abstract

Background Atherosclerosis emerges as a result of multiple dynamic cell processes including endothelial damage, inflammatory and immune cell infiltration, foam cell formation, plaque rupture, and thrombosis. Animal experiments have indicated that cathepsins (CTSs) mediate the antigen transmission and inflammatory response involved in the atherosclerosis process, but the specific signal pathways and target cells of the CTSs involved in atherosclerosis are unknown. Methods We used the GEO query package to download the dataset GSE28829 from the Gene Expression Omnibus (GEO) and filtered the data to check the standardization of the samples through the box chart. We then used the ‘limma’ package to analyze between-group differences and selected the corresponding differentially expressed genes of CTSs from the protein-protein interaction (PPI) network constructed with the STRING database, and then visualized the CTS-target genes. The best matching pathway and target cells were verified by a male mouse ligation experiment, single-sample GSEA (ssGSEA) analysis, and vitro experiment. Results There were 275 differentially expressed genes (DEGs) selected from the GSE28829 dataset, and the DEGs were identified mainly in the PPI network; 58 core genes (APOE, CD74, CP, AIF1, etc.) target three selected CTS family members (CTSS, CTSB, and CTSC). After the enriched analysis, 15 CTS-target genes were markedly enriched in the phagosome signaling pathway. The mouse experiment results revealed that the percentages and numbers of monocytes and neutrophils and the number of CD68+ cells in CTSS deficiency (CatS−/−) group were lower than those in the wildtype (CatS+/+) group. CTSS mediating phagosome via macrophage were further verified by ssGSEA analysis and vitro experiment. Conclusions CTSS are the main target molecules in the CTS family that are involved in atherosclerosis. The molecule participate in the progression of atherosclerosis by mediating the phagosome via macrophage.

Paired transcriptomic analyses of atheromatous and control vessels reveal novel autophagy and immunoregulatory genes in peripheral artery disease

“…Upregulated gene network analysis had 86 nodes and 91 edges with 2116 average number of neighbors and downregulated gene network analysis had 196 nodes, 452 edges and 4612 average number of neighbors. Gene network analysis of top 100 downregulated genes identified novel interactions among genes such as CD4 and Beclin1 as well as CTSS, which is known to be impaired in atherosclerosis 23 . H4C6, a histone coding gene interacted with STAG1, KIF20A and other histone protein coding genes such as H3-3B (Figure 4A).…”

Identification of co-expressed central genes and transcription factors in acute myocardial infarction and diabetic nephropathy

“…CD163 is expressed only in monocytes and macrophages, and levels of the soluble form of CD163 (sCD163) are elevated in low-grade inflammation [ 26 ], which may be involved in chronic inflammatory responses and possibly in AMI and DN development through the induction of foam cell formation and local inflammatory responses. CTSS degrades damaged or unwanted proteins in lysosomes, regulates antigen presentation in atherosclerosis [ 27 ], and mediates phagosome involvement in atherosclerosis progression through macrophages [ 28 ]. CTSS is also a biomarker of chronic kidney disease, and as the glomerular filtration rate decreases, CTSS increases, exacerbating inflammation-associated endothelial dysfunction [ 29 ].…”

Granulomatous rosacea in Chinese patients: Clinical‐histopathological analysis and pathogenesis exploration

“…Cathepsins (Cat) are a class of proteases responsible for antigen presentation, cell signaling and receptor activation, and Cathepsin S (CTSS) is a cysteine‐like protease that plays an important regulatory role 28–31 . Published animal experiments have shown that the number and percentage of macrophages and neutrophils in mice with Cat gene deficiency were lower than those in the wild‐type group, 32 suggesting that Cat may be involved in the formation of granulomatous structures. Cathepsin Z (CTSZ) participates in the host's immune defense through phagocytosis, signal transduction, proliferation and migration of immune cells such as monocytes, macrophages and dendritic cells 33,34 .…”