Macrophage LXRα gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR−/− mice

Abstract

Liver X receptors (LXRs) are implicated in the regulation of cholesterol homeostasis, inflammatory response and atherogenesis. Administration of LXR agonists inhibits the progress of atherosclerosis, and also increases plasma triglyceride levels, representing an obstacle to their use in treating this disease. The objective of this study was to develop an alternative approach that could overcome this obstacle. Eight-week-old low-density lipoprotein receptor-deficient (LDLR À/À ) mice were transplanted with hematopoietic stem cell (HSC)-enriched bone marrow cells transduced with lentivectors expressing either green fluorescent protein (GFP) (Lenti-SP-GFP, control) or LXRa (Lenti-SP-LXRa) driven by a synthetic macrophage promoter. At 4 weeks post-transplant, the mice were fed with a Western diet for 8 weeks and then killed. Compared with Lenti-SP-GFP mice, the Lenti-SP-LXRa mice had a 30% reduction in atherosclerotic lesions, which was accompanied by increases in levels of macrophage expression of cholesterol efflux genes apolipoprotein E and ATP-binding cassette A1, as well as decreases in plasma inflammatory cytokines interleukin-6 and tumor necrosis factor-a. Intriguingly, a 50% reduction of plasma triglyceride level was also observed. We conclude that HSC-based macrophage LXRa gene therapy ameliorates the development of atherosclerosis along with an unexpected concomitant reduction of plasma triglyceride levels in LDLR À/À mice. These findings highlight the potential value of macrophage LXR expression as an avenue for therapeutic intervention against atherosclerosis.

The nuclear receptor LXRα controls the functional specialization of splenic macrophages

“…To gain insight into the cellular mechanisms controlled by LXRα signaling that lead to the development of MZ macrophages, we overexpressed LXRα in hematopoietic stem cells (HSCs) using a myeloid specific lentiviral system 27,28 . First, we examined the expression of the green fluorescent protein (GFP) in blood monocytes obtained from mice transplanted with HSC-enriched BM cells that were previously transduced with the myeloid specific lentivirus.…”

Bone marrow-derived microglia-based neurturin delivery protects against dopaminergic neurodegeneration in a mouse model of Parkinson's disease

“…These constructs were driven by the MSP, thereby favoring enhancement of both the therapeutic efficacy and safety of neurotrophic factor gene therapy by restricting the expression of the transgene to microglial precursor cells (monocyte/macrophage) [2]. To confirm the expression of NTN in the transduced marrow cells aliquots of MSP-NTN and MSP-GFP transduced cells were cultured in macrophage medium [17] for seven days to transform them into macrophages. Immunocytochemical staining revealed that >95% of the MSP-NTN transduced macrophages expressed NTN in their cytoplasm, whereas no NTN staining was observed in MSP-GFP transduced macrophages (Fig.…”

Emerging role of liver X receptors in cardiac pathophysiology and heart failure

“…LXR agonist activation inhibits the induction of pro-inflammatory cytokines through a mechanism involving transrepression [ 63 ]. In atherogenic Ldlr −/− mice, selectively increasing LXRα in macrophages leads to reductions in plasma inflammatory cytokines, IL6 and TNFα, and atherosclerotic lesion development [ 82 ]. Moreover, in the absence of cholesterol efflux pathways mediated by Abca1/g1 -deficient macrophages, LXR agonism nonetheless decreased lesion area, complexity, and inflammatory cell infiltration, including plasma levels of the chemokine, MCP1 [ 67 ].…”