Liver sinusoidal endothelial cells show reduced scavenger function and downregulation of Fc gamma receptor IIb, yet maintain a preserved fenestration in the Glmpgt/gt mouse model of slowly progressing liver fibrosis

Antwi, Milton Boaheng; Dumitriu, Gianina; Simón-Santamaria, Jaione; Romano, Javier Sánchez; Li, Ruomei; Smedsrød, Bård; Vik, Anders; Eskild, Winnie; Sørensen, Karen Kristine

doi:10.1371/journal.pone.0293526

Cited by 5 publications

(1 citation statement)

References 87 publications

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“…S3). As previously observed ( 28 ), KCs did not rapidly internalize FSA 647 like LSECs, and colocalization with phage-positive vacuoles could not be evaluated. After 10 and 24 h of continuous phage challenge, intense green fluorescence in both LSECs and KCs confirmed persistent internalization of phages ( Fig.…”

Section: Resultsmentioning

confidence: 65%

Liver sinusoidal cells eliminate blood-borne phage K1F

Sánchez Romano,

Simón-Santamaría,

McCourt

et al. 2024

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Phage treatment has regained attention due to an increase in multiresistant bacteria. For phage therapy to be successful, phages must reach their target bacteria in sufficiently high numbers. Blood-borne phages are believed to be captured by macrophages in the liver and spleen. Since liver sinusoids also consist of specialized scavenger liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs), this study investigated the contribution of both cell types in the elimination of Escherichia coli phage K1Fg10b::gfp (K1F gfp ) in mice. Circulatory half-life, organ, and hepatocellular distribution of K1F gfp were determined following intravenous administration. Internalization of K1F gfp and effects of phage opsonization on uptake were explored using primary mouse and human LSEC and KC cultures. When inoculated with 10 7 virions, >95% of the total K1F gfp load was eliminated from the blood within 20 min, and 94% of the total retrieved K1F gfp was localized to the liver. Higher doses resulted in slower elimination, possibly reflecting temporary saturation of liver scavenging capacity. Phage DNA was detected in both cell types, with a KC:LSEC ratio of 12:1 per population following cell isolation. Opsonization with plasma proteins increased time-dependent cellular uptake in both LSECs and KCs in vitro . Internalized phages were rapidly transported along the endocytic pathway to lysosomal compartments. Reduced viability of intracellular K1F gfp corroborated inactivation following endocytosis. This study is the first to identify phage distribution in the liver at the hepatocellular level, confirming clearance of K1F gfp performed mostly by KCs with a significant uptake also in LSECs. IMPORTANCE Faced with the increasing amounts of bacteria with multidrug antimicrobial resistance, phage therapy has regained attention as a possible treatment option. The phage field has recently experienced an emergence in commercial interest as research has identified new and more efficient ways of identifying and matching phages against resistant superbugs. Currently, phages are unapproved drugs in most parts of the world. For phages to reach broad clinical use, they must be shown to be clinically safe and useful. The results presented herein contribute to increased knowledge about the pharmacokinetics of the T7-like phage K1F in the mammalian system. The cell types of the liver that are responsible for rapid phage blood clearance are identified. Our results highlight the need for more research about appropriate dose regimens when phage therapy is delivered intravenously and advise essential knowledge about cell systems that should be investigated further for detailed phage pharmacodynamics.

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Section: Resultsmentioning

confidence: 65%

Liver sinusoidal cells eliminate blood-borne phage K1F

Sánchez Romano,

Simón-Santamaría,

McCourt

et al. 2024

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PPARα-ERRα crosstalk mitigates metabolic dysfunction-associated steatotic liver disease progression

Antwi,

Lefere,

Clarisse

et al. 2024

Metabolism

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Early and late phases of liver sinusoidal endothelial cell (LSEC) defenestration in mouse model of systemic inflammation

Czyzynska-Cichon,

Kotlinowski,

Blacharczyk

et al. 2024

Cell Mol Biol Lett

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Background Liver sinusoidal endothelial cells (LSECs) have transcellular pores, called fenestrations, participating in the bidirectional transport between the vascular system and liver parenchyma. Fenestrated LSECs indicate a healthy phenotype of liver while loss of fenestrations (defenestration) in LSECs is associated with liver pathologies. Methods We introduce a unique model of systemic inflammation triggered by the deletion of Mcpip1 in myeloid leukocytes (Mcpip1fl/flLysMCre) characterised by progressive alterations in LSEC phenotype. We implement multiparametric characterisation of LSECs by using novel real-time atomic force microscopy supported with scanning electron microscopy and quantitative fluorescence microscopy. In addition, we provide genetic profiling, searching for characteristic genes encoding proteins that might be connected with the structure of fenestrations. Results We demonstrate that LSECs in Mcpip1fl/flLysMCre display two phases of defenestration: the early phase, with modest defenestration that was fully reversible using cytochalasin B and the late phase, with severe defenestration that is mostly irreversible. By thorough analysis of LSEC porosity, elastic modulus and actin abundance in Mcpip1fl/flLysMCre and in response to cytochalasin B, we demonstrate that proteins other than actin must be additionally responsible for inducing open fenestrations. We highlight several genes that were severely affected in the late but not in the early phase of LSEC defenestration shedding a light on complex structure of individual fenestrations. Conclusions The presented model of LSEC derived from Mcpip1fl/flLysMCre provides a valuable reference for developing novel strategies for LSEC refenestration in the early and late phases of liver pathology.

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Liver sinusoidal endothelial cells show reduced scavenger function and downregulation of Fc gamma receptor IIb, yet maintain a preserved fenestration in the Glmpgt/gt mouse model of slowly progressing liver fibrosis

Cited by 5 publications

References 87 publications

Liver sinusoidal cells eliminate blood-borne phage K1F

Liver sinusoidal cells eliminate blood-borne phage K1F

PPARα-ERRα crosstalk mitigates metabolic dysfunction-associated steatotic liver disease progression

Early and late phases of liver sinusoidal endothelial cell (LSEC) defenestration in mouse model of systemic inflammation

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