Biology subjects

Marinello, M.

Publications and source records attributed to Marinello, M..

3 recordsLinked to original sources

bioRxiv2023

Resolvin D2-GPR18 Signaling on Myeloid Cells Limits Plaque Necrosis

Introduction/ObjectiveDysregulated inflammation-resolution programs are associated with atherosclerosis progression. Inflammation-resolution is in part mediated by Resolvins, including Resolvin D2 (RvD2). RvD2, which activates a G-protein coupled receptor (GPCR) called GPR18, limits plaque progression. Cellular targets of RvD2 are not known. Approach and ResultsHere we developed humanized GPR18 floxed ("fl/fl") and a myeloid (Lysozyme M Cre) GPR18 knockout (mKO) mouse. We functionally validated this model by assessing efferocytosis in bone marrow derived macrophages (BMDMs) and found that RvD2 enhanced efferocytosis in the fl/fl, but not in the mKO BMDMs. We employed two different models to evaluate the role of GPR18 in atherosclerosis. We first used the PCSK9-gain of function approach and found increased necrosis in the plaques of the mKO mice compared with fl/fl mice. Next, we performed a bone marrow transfer of fl/fl or mKO bone marrow into Ldlr-/- recipients. For these experiments, we treated each genotype with either Veh or RvD2 (25 ng/mouse, 3 times/week for 3 weeks). Myeloid loss of GPR18 resulted in significantly more necrosis and cleaved caspase-3+ cells compared with fl/fl transplanted mice. RvD2 treatment decreased plaques necrosis and cleaved caspase-3+ cells in fl/fl, but not in the mKO transplanted mice. ConclusionsThese results are the first to suggest a causative role for endogenous RvD2 signaling on myeloid cells in limiting plaque necrosis. Moreover, these results provide a mechanistic basis for RvD2 as a therapy limiting plaque necrosis.

immunology↗

bioRxiv2023

The Resolvin D2-GPR18 Axis Enhances Bone Marrow Function and Limits Hepatic Fibrosis in Aging

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 GRP18. Using an unbiased screen, we report increased Gpr18 expression in macrophages from old mice and in livers from elderly humans that is 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. Using a transplantation assay we 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, our study demonstrates that RvD2-GPR18 signaling controls steatosis and fibrosis and provides a mechanistic-based therapy for promoting liver repair in aging.

physiology↗

bioRxiv2021

Sub-lethal radiation-induced senescence impairs resolution programs and drives cardiovascular inflammation

Radiation is associated with tissue damage and increased risk of atherosclerosis but there are currently no treatments and a very limited mechanistic understanding of how radiation impacts tissue repair mechanisms. We uncovered that radiation significantly delayed temporal resolution programs that was associated with decreased efferocytosis in vivo. Resolvin D1 (RvD1), a known pro-resolving ligand, promoted swift resolution and restored efferocytosis in sub-lethally irradiated mice. Irradiated macrophages exhibited several features of senescence, including increased expression of p16INK4A and p21, heightened levels of SA-{beta}-gal, COX-2, and oxidative stress (OS) in vitro, and when transferred to mice exacerbated inflammation in vivo. Mechanistically, heightened OS in senescent macrophages led to impairment in their ability to carry out efficient efferocytosis and treatment with RvD1 reduced OS and improved efferocytosis. Sub-lethally irradiated Ldlr-/- mice exhibited increased plaque necrosis and p16INK4A cells compared with non-irradiated controls and treatment with RvD1 significantly reduced these endpoints. Removal of p16INK4A hematopoietic cells during advanced atherosclerosis with p16-3MR mice reduced plaque necrosis and increased production of key intraplaque resolving mediators. Our results demonstrate that sub-lethal radiation drives macrophage senescence and efferocytosis defects and suggest that RvD1 may be a new therapeutic strategy to limit radiation-induced tissue damage.

immunology↗