GITRL impairs hepatocyte repopulation by liver progenitor cells to aggravate inflammation and fibrosis by GITR+CD8+ T lymphocytes in CDE Mice

Abstract

As an alternative pathway for liver regeneration, liver progenitor cells and their derived ductular reaction cells increase during the progression of many chronic liver diseases. However, the mechanism underlying their hepatocyte repopulation after liver injury remains unknown. Here, we conducted progenitor cell lineage tracing in mice and found that fewer than 2% of hepatocytes were derived from liver progenitor cells after 9 weeks of injury with a choline-deficient diet supplemented with ethionine (CDE), and this percentage increased approximately three-fold after 3 weeks of recovery. We also found that the proportion of liver progenitor cells double positive for the ligand of glucocorticoid-induced tumour necrosis factor receptor (GITRL, also called Tnfsf18) and SRY-related HMG box transcription 9 (Sox9) among nonparenchymal cells increased time-dependently upon CDE injury and reduced after recovery. When GITRL was conditionally knocked out from hepatic progenitor cells, its expression in nonparenchymal cells was downregulated by approximately fifty percent, and hepatocyte repopulation increased by approximately three folds. Simultaneously, conditional knockout of GITRL reduced the proportion of liver-infiltrating CD8+ T lymphocytes and glucocorticoid-induced tumour necrosis factor receptor (GITR)-positive CD8+ T lymphocytes. Mechanistically, GITRL stimulated cell proliferation but suppressed the differentiation of liver progenitor organoids into hepatocytes, and CD8+ T cells further reduced their hepatocyte differentiation by downregulating the Wnt/β-catenin pathway. Therefore, GITRL expressed by liver progenitor cells impairs hepatocyte differentiation, thus hindering progenitor cell-mediated liver regeneration.

Can Nutraceuticals Support the Treatment of MASLD/MASH, and thus Affect the Process of Liver Fibrosis?

“…One of the groups involved in fibrinogenesis is CD8+ T lymphocytes, which are essential for the annihilation of tumors and infected cells. Although these cells can stimulate cell proliferation, they reduce the differentiation of liver progenitor cells into hepatocytes [37]. On the other hand, Bonilla et al in their work indicate that this type of lymphocytes producing interferon gamma (IFNg) is associated with a low rate of the progression of liver fibrosis [38].…”