Abstract 134: Myeloid Disabled Homolog 2 (Dab2) Controls Liver Inflammation and Atherosclerosis
Inflammatory (M1) macrophages contribute to the pathogenesis of atherosclerosis, but the intracellular mediators of macrophage polarization are not fully understood. We identified the adaptor protein disabled homolog 2 (Dab2) as a novel regulator of phenotypic switching in macrophages. Dab2 expression is upregulated in M2 and suppressed in M1 macrophages. Dab2 in macrophages dampens NF-κB signaling by binding to TRAF6. Genetic deletion of Dab2 predisposes macrophages to adopt a proinflammatory M1 phenotype, and mice with myeloid cell-specific deletion of Dab2 (Dab2fl/flLysMCre mice) show increased inflammation upon challenge with lipopolysaccharide. To test the role of myeloid Dab2 in the pathogenesis of atherosclerosis we performed a bone marrow transplant of WT and Dab2 null bone marrow into LDLR-/- mice followed by western diet feeding for 9 or 20 weeks. Surprisingly, after 20 weeks of western diet feeding, Dab2-null chimeric mice had decreased lesion area by en face analysis of aortic arches and a trend toward decreased Oil red O positive area in aortic root lesions; however, aortic root lesions in Dab2 null-chimeric mice had increased macrophage content and caspase staining, indicative of lesion instability. Serum total cholesterol and triglyceride levels were significantly decreased in Dab2 null-chimeric mice after 20 weeks of western diet, and analysis of mRNA in liver tissue revealed increased levels of inflammatory cytokines. Histological analysis of livers of Dab2 null-chimeric mice showed large patches of cells that were positive for B220, a marker present on B cells and some dendritic-like cells. We conclude that myeloid Dab2 deficiency exacerbates hepatic immune responses which in turn control atherosclerotic lesion development.
Author Disclosures: S.E. Adamson: None. K. Marqueen: None. J. Angdisen: None. I. Schulman: None. N. Leitinger: None.
This research has received full or partial funding support from the American Heart Association.
- © 2015 by American Heart Association, Inc.