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Liver sinusoidal endothelial cells constitute a major route for hemoglobin clearance

ABSTRACT: Mild hemolysis of senescent erythrocytes occurs physiologically in the spleen resulting in Hb release, whereas pathologic erythrocyte rupture characterizes several diseases. Iron recycling from Hb and Hb detoxification have been attributed to the sequestration of Hb-haptoglobin complexes by macrophages. However, it remained unclear whether other efficient routes of Hb clearance exist. We identified liver sinusoidal endothelial cells (LSECs) as the primary cells responsible for Hb uptake, a process that involves macropinocytosis and operates independently of the Hb-haptoglobin receptor CD163. To further study the functional adaptation of LSECs for Hb clearance, we performed two label-free proteomic analyses: i) using young BALB/C female mice, we compared the proteomes of the following cell types: LSECs, liver macrophages (Kupffer cells), splenic red pulp macrophages, and endothelial cells from the spleen and the heart (set of 15 samples, 5 sample groups, three replicates; ii) we determined changes of protein levels in LSECs after stressed erythrocyte injection in C57BL/6J female mice (set of 10 samples, 2 sample groups, five replicates). In the former analysis, we found that LSECs show high protein levels of enzymes of the heme-catabolic pathway, ferritins, and macropinocytosis regulators. In the later experiment, we identified Hb subunits as the top-increased proteins in LSECs upon erythrocyte injection in mice.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spleen, Kupffer Cell, Splenic Endothelial Cell, Heart, Splenic Red Pulp Macrophage, Cardiac Endothelial Cell, Liver, Endothelial Cell Of Hepatic Sinusoid

DISEASE(S): Hemolysis

SUBMITTER: Remigiusz Serwa

LAB HEAD: Katarzyna Mleczko-Sanecka

PROVIDER: PXD051274 | Pride | 2025-11-12

REPOSITORIES: Pride

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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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	KMS_HEART_ECs1.raw	Raw
	KMS_HEART_ECs2.raw	Raw
	KMS_HEART_ECs3.raw	Raw
	KMS_KC1.raw	Raw
	KMS_KC2.raw	Raw

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Liver sinusoidal endothelial cells constitute a major route for hemoglobin clearance

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