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Phase separation of endothelial PML drives inflammatory macrophage infiltration during liver fibrosis [RNA-Seq 2]

ABSTRACT: PML directly binds with BRD4 in the nucleus and facilitates BRD4 protein accumulation to amplify pro-inflammatory gene expression through phase separation-dependent SE-activation via PML/BRD4 condensate formation. In the preclinical mouse models, LSEC-specific deletion of PML/BRD4 complex mitigates liver inflammation and fibrosis. Utilizing single-cell RNA-sequencing, we show that epigenetically aberrant LSECs exhibit a reprogramed pro-inflammatory angiocrine landscape in mouse fibrotic livers and establish that TIMP1+ LSECs promote the recruitment of CD63+ monocyte-derived macrophages (MoMFs) during the progression of liver fibrosis. Thereby, we demonstrate that PML/BRD4 in LSECs govern inflammatory immune cell recruitment in liver fibrosis, and that pharmacological BRD4 inhibition or epigenetic repression of PML SE alleviates liver inflammation and fibrosis. In conclusion, we highlight in this study that PML/BRD4-mediated SE activation via phase separation drives pro-inflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300028 | GEO | 2026/03/10

REPOSITORIES: GEO

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Project description:Liver sinusoidal endothelial cells (LSECs) are specialized fenestrated scavenger endothelial cells involved in the elimination of modified plasma proteins and tissue turnover waste macromolecules from blood. LSECs also participate in liver immune responses. A challenge when studying LSEC biology is the rapid loss of the in vivo cell phenotype in culture. In this study, we have examined biological processes and pathways affected during early-stage primary culture of rat LSECs and checked for cell responses to the pro-inflammatory cytokine interleukin (IL)-1 and the anti-inflammatory drug dexamethasone. Methods: LSECs from male Sprague Dawley rats were cultured on type I collagen in a 5% oxygen atmosphere in DMEM with serum-free supplements for 2 and 24 h. Quantitative proteomics using tandem mass tag technology were used to examine proteins in cells and supernatants. Validation was done with ELISA and multiplex immunobead assays, cell ultrastructure was examined by scanning electron microscopy, and scavenger function by quantitative endocytosis assays. Results: LSECs cultured for 24 h showed a characteristic pro-inflammatory phenotype both in the presence and absence of IL-1, displaying upregulation of cellular responses to cytokines and interferon-, cell-cell adhesion, and glycolysis, and downregulation of membrane/endocytosis receptors (MCAM, STAB1, STAB2, LYVE1, CLEC4G) and proteins involved in pyruvate metabolism, citric acid cycle, fatty acid elongation, amino acid metabolism, and oxidation-reduction processes. Dexamethasone improved LSEC viability in culture and repressed the culture-induced stimulation of glycolysis, inflammatory and immune regulatory pathways, and secretion of pro-inflammatory cytokines while increasing IL-10 secretion compared to time-matched control. The number of sieve plates in LSECs was reduced at 24 h both in the presence and absence of dexamethasone but the dexamethasone-treated cells showed a more quiescent phenotype. Conclusion: Rat LSECs become activated towards a pro-inflammatory phenotype during early culture. Dexamethasone represses LSEC activation and improves cell viability.

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Phase separation of endothelial PML drives inflammatory macrophage infiltration during liver fibrosis [RNA-Seq 2]

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