Abstract 509: Critical Role of the Transcriptional Repressor BCL-6 in Bone Marrow-Derived Inflammation and Atherosclerosis
The transcription factor BCL-6 has been extensively implicated in non-Hodgkin lymphoma and B-cell development. More recent studies reveal additional roles for BCL-6 in the macrophage lineage to repress chemokine expression and physically interact with the nuclear receptor PPARδ. To investigate the role of macrophage BCL-6 in atherosclerosis and its functional interplay with PPARδ, we performed bone marrow transplantation (BMT) studies in low-density lipoprotein receptor-deficient (LDLR−/−) mice. Three month-old LDLR−/−mice were lethally irradiated, transplanted with wild type or BCL-6−/− bone marrow, reconstituted and fed a Western diet supplemented with or without the PPARδ ligand GW1516 (4 mg/kg/day) for 4 months. Results demonstrate a significant reduction in the body and adipose tissue weights of BCL-6−/− BMT mice compared to control BMT LDLR−/− mice. Although plasma lipids were not altered, profiling of plasma cytokines in BCL-6−/− BMT mice revealed selectively altered systemic inflammation with elevated levels of the BCL-6 target chemokine MCP-3. The impact of BCL-6 deficiency in bone marrow cells on atherosclerosis was quantified by en face method. BCL6−/− BMT LDLR−/− mice developed substantially more (70% increased) atherosclerosis compared to control BMT LDLR−/− mice (P<0.001). Administration of GW1516 had no significant impact on atherosclerosis in control BMT LDLR−/− mice but reduced atherosclerosis in BCL-6−/− BMT LDLR−/− mice by 32% (P<0.01). Interestingly, BCL-6−/− BMT mice exhibit chronic, cholesterol-dependent tendonitis of the fore and hind limbs, reminiscent of findings in humans with familial hypercholesterolemia. These results provide the first evidence that BCL-6 expression in bone marrow-derived cells plays a critical role in the control atherosclerosis, identify BCL-6 and PPARδ as convergent inflammatory regulators, and reveal BCL-6 as an anti-atherogenic therapeutic target.