Immunological investigations · 2025
Unveiling the Role of Sdc4+ Monocytes in NASH: A Single-Cell RNA Sequencing Study.
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Li Jing-Ze, Mao Ting, Gao Yu-Xuan, Xu Ming-Yi, Li Hui-Yi
Аннотация
BACKGROUND: Nonalcoholic steatohepatitis (NASH) involves liver inflammation and fibrosis. Monocytes, key immune cells differentiating into macrophages and dendritic cells, are understudied in NASH using single-cell RNA sequencing (scRNA-seq).
METHODS: Liver nonparenchymal cells from NASH and control mice underwent scRNA-seq to identify monocyte subsets and transcriptional profiles. Findings were validated via transfection, coculture, immunofluorescence, and qPCR.
RESULTS: scRNA-seq analysis revealed that Ly6chi monocytes in Cluster 0 appeared to be converted into macrophages in the liver, potentially contributing to the progression of NASH inflammation. Similarly, Ly6clo monocytes in Cluster 1 seemed to differentiate into dendritic cells, possibly mediating T-cell immune responses in NASH. Notably, Sdc4 was uniquely abundant in Cluster 0. Sdc4+ monocytes were elevated in NASH patients and mice versus controls. Under lipotoxic conditions, Sdc4-deficient (sh-Sdc4) monocytes exhibited upregulated expression of CD206 (an M2 marker) and IL-10. When cocultured with sh-Sdc4 monocytes under palmitic acid stimulation, HepG2 cells accumulated fewer lipid droplets and produced less TNF-α protein, along with increased IL-10 genes, compared to controls.
CONCLUSION: Our study elucidates the heterogeneity and functional transformation of two major monocyte subsets in NASH. We foundSdc4+ monocytes may exacerbate NASH through pro-inflammatory mechanisms.
METHODS: Liver nonparenchymal cells from NASH and control mice underwent scRNA-seq to identify monocyte subsets and transcriptional profiles. Findings were validated via transfection, coculture, immunofluorescence, and qPCR.
RESULTS: scRNA-seq analysis revealed that Ly6chi monocytes in Cluster 0 appeared to be converted into macrophages in the liver, potentially contributing to the progression of NASH inflammation. Similarly, Ly6clo monocytes in Cluster 1 seemed to differentiate into dendritic cells, possibly mediating T-cell immune responses in NASH. Notably, Sdc4 was uniquely abundant in Cluster 0. Sdc4+ monocytes were elevated in NASH patients and mice versus controls. Under lipotoxic conditions, Sdc4-deficient (sh-Sdc4) monocytes exhibited upregulated expression of CD206 (an M2 marker) and IL-10. When cocultured with sh-Sdc4 monocytes under palmitic acid stimulation, HepG2 cells accumulated fewer lipid droplets and produced less TNF-α protein, along with increased IL-10 genes, compared to controls.
CONCLUSION: Our study elucidates the heterogeneity and functional transformation of two major monocyte subsets in NASH. We foundSdc4+ monocytes may exacerbate NASH through pro-inflammatory mechanisms.