Resolvin D2-GPR18 Enhances Bone Marrow Function and Limits Steatosis and Hepatic Collagen Accumulation in Aging

Autor: Fitzgerald, Hannah, Bonin, Jesse L., Khan, Sayeed, Eid, Maya, Sadhu, Sudeshna, Rahtes, Allison, Lipscomb, Masharh, Biswas, Nirupam, Decker, Christa, Nabage, Melisande, Ramos, Ramon Bossardi, Duarte, Giesse Albeche, Marinello, Michael, Chen, Anne, Aydin, Hasan Basri, Mena, Hebe Agustina, Gilliard, Kurrim, Spite, Matthew, DiPersio, C. Michael, Adam, Alejandro, MacNamara, Katherine C., Fredman, Gabrielle
Zdroj: American Journal of Pathology; 20230101, Issue: Preprints
Abstrakt: Aging is associated with non-resolving inflammation and tissue dysfunction. Resolvin D2 (RvD2) is a pro-resolving ligand that acts through the G-protein coupled receptor (GPCR) called GPR18. Unbiased RNA sequencing revealed increased Gpr18expression in macrophages from old mice, and in livers from elderly humans, which was associated with increased steatosis and fibrosis in middle-aged (MA) and old mice. MA mice that lack GPR18 on myeloid cells had exacerbated steatosis and hepatic fibrosis, which was associated with a decline in Mac2+macrophages. Treatment of MA mice with RvD2 reduced steatosis and decreased hepatic fibrosis, correlating with increased Mac2+macrophages, monocyte-derived macrophages, and elevated numbers of monocytes in the liver, blood, and bone marrow. RvD2 acted directly upon the bone marrow to increase monocyte-macrophage progenitors. A transplantation assay further demonstrated that bone marrow from old mice facilitated hepatic collagen accumulation in young mice, and transient RvD2 treatment to mice transplanted with bone marrow from old mice prevented hepatic collagen accumulation. Together, this study demonstrates that RvD2-GPR18 signaling controls steatosis and fibrosis and provides a mechanistic-based therapy for promoting liver repair in aging.
Databáze: Supplemental Index