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

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. © 2021 Ursula R. Sorg et al., published by De Gruyter, Berlin/Boston.

Citation

Ursula R Sorg, Nicole Küpper, Julia Mock, Anne Tersteegen, Patrick Petzsch, Karl Köhrer, Thomas Hehlgans, Klaus Pfeffer. Lymphotoxin-β-receptor (LTβR) signaling on hepatocytes is required for liver regeneration after partial hepatectomy. Biological chemistry. 2021 Aug 26;402(9):1147-1154

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PMID: 34087963

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