Cytokine–ontogeny interaction shapes macrophage transcriptional states (GM-CSF–derived macrophages)
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE304645 | GEO | 2025/09/30
REPOSITORIES: GEO
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Project description:In M-CSF–derived macrophages, bulk RNA-seq was performed on five biological replicates per cytokine condition (IL‑4, IFN‑γ, IL‑10, TGF‑β). IL‑4 dominated PC1 (54% variance) driving a reparative module with EMT, UPR, and mTORC1 signatures, while IFN‑stimulated genes (Gbp4, Ifi44) were repressed. PC2 (26% variance) spanned an inflammatory‑to‑remodeling continuum: IFN‑γ anchored the chemokine‑rich, IFN‑responsive pole (Ccl7, Ccl2, Ccl12), whereas TGF‑β anchored a matrix‑remodeling/angiogenic pole (Mmp14, Cav1, Cspg4); IL‑10 shifted modestly toward the IFN‑low quadrant.
2025-09-30 | GSE304647 | GEO
Project description:To account for the within-state heterogeneity of GM-CSF compared to M-CSF macrophages (Helft et al. 2015), we performed multiplexed scRNA-seq on 49,441 GM-CSF–derived macrophages stimulated with IL‑4, IFN‑γ, IL‑10, or TGF‑β. Cells were visualized by principal component analysis (PC1 = 13.21%, PC2 = 4.65%), which recapitulated patterns previously observed in bulk RNA-seq. IL‑4 displaced cells farthest along PC1 towards a cell cluster enriched for NfkB controlled gene expression with high Ccl22 and Ccr7, consistent with a dendritic‑cell‑like, T‑cell‑activating phenotype. IFN‑γ dominated PC2, retaining high MHC-II expression while adding a complement/interferon module (C1qb, C1qc, Gbp2, Irf1), and showed enrichment for IRF1/8 and STAT1 transcription factor signatures. TGF‑β and IL‑10 co-clustered in the PC1/PC2 low quadrant and shared expression of reparative markers including Chil3 and Cd24, forming an immunosuppressive, trophic branch distinct from either inflammatory pole. Together, these data show that within the GM-CSF lineage, IL‑4 and IFN‑γ drive orthogonal inflammatory trajectories, whereas IL‑10 and TGF‑β consolidate a shared remodeling program.
2025-09-30 | GSE304596 | GEO
Project description:We generated eight macrophage states using a cytokine–ontogeny matrix, combining two macrophage ontogenies (M-CSF and GM-CSF) with four cytokines (IL‑4, IFN‑γ, IL‑10, TGF‑β). Bulk RNA‑seq on five biological replicates per condition revealed that PC1 (54% variance) segregated ontogeny: GM‑CSF states loaded negatively, M‑CSF states positively. Gene‑set enrichment analysis of negative PC1 loadings highlighted NfkB programs, confirming the intrinsic inflammatory bias of GM‑CSF macrophages (Hamilton 2008; Hamilton et al. 2016)
2025-09-30 | GSE304646 | GEO
Project description:Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of ESRD. Affected individuals inherit a defective copy of either the PKD1 or PKD2 gene, encoding the proteins polycystin?1 (PC1) or polycystin?2 (PC2) respectively. PC1 and PC2 are secreted on urinary exosome?like vesicles (ELVs) (100nm diameter vesicles), where PC1 is present in a cleaved form and may be complexed with PC2. Label free quantitative proteomic studies of urine ELVs in an initial discovery cohort (13 PKD1 and 18 Normals), revealed that of 2008 ELV proteins, nine (0.32%) showed a statistically significant difference between PKD1 and normals at a p<0.025. PC1 was reduced to 54% of the normal level (p<0.02) and PC2 reduced to 53% (p<0.001). TMEM2, a protein with homology to fibrocystin, the product of the polycystic hepatic and kidney disease (PKHD1) gene, is increased 2.1 fold (p<0.025). The PC1/TMEM2 ratio correlated inversely with height adjusted total kidney volume (HtTKV) in the discovery cohort and the ratio of PC1/TMEM2 or PC2/TMEM2 could be used to distinguish PKD1 from normals in a confirmation cohort. In summary, this study suggests that a test based on the urine exosomal PC1/TMEM2 or PC2/TMEM2 ratio may have utility in the diagnosis and perhaps monitoring of PKD1.
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2024-02-14 | PXD027716 | Pride
Project description:Background: Autosomal dominant polycystic kidney disease (PKD) is characterized by extensive cyst formation and progressive fibrosis. However, the molecular mechanisms whereby the loss/loss-of-function of polycystin 1 or 2 (PC1/2) provokes fibrosis are largely unknown. The small GTPase RhoA has been implicated in cystogenesis, while we have shown that the RhoA/cytoskeleton/myocardin-related transcription factor (MRTF) pathway is a key inducer of epithelium-induced fibrogenesis. Therefore, we hypothesized that MRTF 1) is activated by PC1/2 loss, and 2) plays a critical role in fibrogenic repogramming of the epithelium and the subsequent induction of fibrosis. Methods: PC1/2 loss was achieved by gene silencing in tubular cells (in vitro) and in PKD1 (RC/RC) and PKD2 (ws25/-) mice (in vivo). RhoA activation was measured by pull-down assays and immunofluorescence. MRTF localization (nuclear/cytosolic ratio, intensity) was quantified in large cell populations and in renal tissue using automated image analysis. PC1/PC2 loss-promoted, MRTF-dependent gene expression was followed by qPCR, RNAseq and RNAscope. MRTF-dependent paracrine effects were assessed by a bioassay. Results: Loss of PC1 or PC2 activated RhoA in vitro and in vivo, resulting in cytoskeletal remodelling and robust nuclear MRTF translocation, accompanied by increased MRTF expression. Nuclear translocation occurred predominantly in dilated tubules, while overexpression in the cyst-lining epithelium. A large cohort of PC1/PC2 downregulation-induced genes was MRTF-dependent, including cytoskeletal, integrin-related, and matricellular/fibrogenic proteins. Epithelial MRTF was necessary for paracrine priming of fibroblast-myofibroblast transition. Conclusion: The Rho/MRTF pathway is a critical novel mediator of PC1/2 loss-induced acquisition of the profibrotic epithelial phenotype and the ensuing fibrosis.
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