Lymphotoxin-β-receptor (LTβR) signaling on hepatocytes is required for liver regeneration after partial hepatectomy.

Ursula R Sorg,Julia Mock,Patrick Petzsch,Nicole Küpper,Karl Köhrer,Anne Tersteegen,Klaus Pfeffer,Thomas Hehlgans

doi:10.1515/hsz-2021-0152

Ursula R Sorg, Julia Mock + Show 6 more

Open Access

https://doi.org/10.1515/hsz-2021-0152

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Abstract

Lymphotoxin-β-receptor deficient (LTβR-/-) and Tumor Necrosis Factor Receptor p55 deficient (TNFRp55-/-) mice show defects in liver regeneration (LR) after partial hepatectomy (PHx) with significantly increased mortality. LTβR and TNFRp55 belong to the core members of the TNF/TNFR superfamily. Interestingly, combined failure of LTβR and TNFRp55 signaling after PHx leads to a complete defect in LR. Here, we first addressed the question which liver cell population crucially requires LTβR signaling for efficient LR. To this end, mice with a conditionally targeted LTβR allele (LTβRfl/fl) were crossed to AlbuminCre and LysozymeMCre mouse lines to unravel the function of the LTβR on hepatocytes and monocytes/macrophages/Kupffer cells, respectively. Analysis of these mouse lines clearly reveals that LTβR is required on hepatocytes for efficient LR while no deficit in LR was found in LTβRfl/fl×LysMCre mice. Second, the molecular basis for the cooperating role of LTβR and TNFRp55 signaling pathways in LR was investigated by transcriptome analysis of etanercept treated LTβR-/- (LTβR-/-/ET) mice. Bioinformatic analysis and subsequent verification by qRT-PCR identified novel target genes (Cyclin-L2, Fas-Binding factor 1, interferon-related developmental regulator 1, Leucyl-tRNA Synthetase 2, and galectin-4) that are upregulated by LTβR/TNFRp55 signaling after PHx and fail to be upregulated after PHx in LTβR-/-/ET mice.

Highlights

LTβR, TNFRp55 and TNFRp75 as well as their corresponding ligands lymphotoxin β (LTα1β2), LIGHT, tumor necrosis factor (TNF) and lymphotoxin α (LTα3) are core members of the TNF/TNFR superfamily (Hehlgans and Pfeffer 2005)
Analysis of these mouse lines clearly reveals that LTβR is required on hepatocytes for efficient liver regeneration (LR) while no deficit in LR was found in LTβRfl/fl × LysMCre mice
Bioinformatic analysis and subsequent verification by qRT-PCR identified novel target genes (Cyclin-L2, Fas-Binding factor 1, interferon-related developmental regulator 1, Leucyl-tRNA Synthetase 2, and galectin-4) that are upregulated by LTβR/TNFRp55 signaling after PHx and fail to be upregulated after PHx in LTβR−/−/ET mice

Summary

Introduction

LTβR, TNFRp55 and TNFRp75 as well as their corresponding ligands lymphotoxin β (LTα1β2), LIGHT (homologous to lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T lymphocytes), tumor necrosis factor (TNF) and lymphotoxin α (LTα3) are core members of the TNF/TNFR superfamily (Hehlgans and Pfeffer 2005) They are essential for the organogenesis of secondary lymphoid organs, for the maintenance of the architectural integrity of lymphoid tissues (De Togni et al 1994; Futterer et al 1998; Neumann et al 1996; Pfeffer et al 1993) and, importantly, for liver regeneration (LR) (Anders et al 2005; Sorg et al 2016). Expression of Gadd45γ was lower in LTβR−/−/ET mice but not significantly so (Figure 4)

Discussion

Materials and methods