Abstract 592: Constitutive CD40-Signaling in Dendritic Cells Limits Atherosclerosis by Provoking Inflammatory Bowel Disease and Ensuing Cholesterol Malabsorption

Abstract

The co-stimulatory molecule CD40 is a major driver of atherosclerosis. It is expressed on a wide variety of cell types including mature dendritic cells (DCs) and required for optimal T cell activation and expansion. It remains undetermined if and how CD40 on DCs impacts the pathogenesis of atherosclerosis. Here we examined the effects of constitutively active CD40 in DCs on atherosclerosis, using low-density lipoprotein-deficient (Ldlr -/- ) bone-marrow chimeras that express an engineered latent membrane protein 1 (LMP)/CD40 fusion protein conferring constitutive CD40 signaling under control of the CD11c promoter ( DC-CD40ca ). As expected, DC-CD40ca/Ldlr -/- chimeras showed increased antigen presenting capacity on DCs and increased T cell numbers. However, they developed extensive neutrophilia compared to wt / ldlr -/- chimeras. Despite overt T cell expansion and neutrophilia we observed a reduction in cDC frequency and a dramatic reduction in atherosclerosis ( CD40wt/ldlr -/- 22076±3763 μm 2 vs. DC-CD40ca/ldlr -/- 2511±1256 μm 2 ). Further analyses revealed that cholesterol and triglyceride levels decreased by 37% and 60%, respectively, in DC-CD40ca/Ldlr -/- chimeras. Moreover, DC-CD40ca/Ldlr -/- chimeras developed inflammatory bowel disease characterized by massive transmural influx of leukocytes and lymphocytes, resulting in villous degeneration and lipid malabsorption. Constitutive activation of CD40 in DCs results in inflammation of the gastrointestinal tract, thereby impairing lipid uptake, which consequently results in attenuated atherosclerosis.