β-Catenin Signaling in Dendritic Cells Reduces Atherosclerosis

Objective A driving force behind atherosclerotic disease is the chronic inflammatory response. It has been shown that immunomodulation by tolerogenic dendritic cell (DC) therapy is a feasible approach to reduce atherosclerosis. While it is mostly unclear what molecular pathways induce tolerogenic DCs, β-catenin has been implicated in this process. We therefore assessed whether induction of tolerogenic DCs, by means of β-catenin stabilization (CD11c-βcatEX3 DCs), can reduce atherosclerosis. Methods and Results CD11c-βcatEX3 DCs possess similar antigen uptake capacities, but displayed enhanced CD40, CD86 and CCR7 expression and reduced production of pro-inflammatory cytokines TNF-α and IL-6 upon LPS exposure. Consequently, CD11c-βcatEX3 DCs inhibited T cell responses by 90% as a result of a 33% increased regulatory T cell (Treg) response. To establish the effect on atherosclerosis, we generated CD11c-βcatEX3/ LDLr-/bone marrow chimera and for a more clinical approach adoptively transferred CD11c-βcatEX3 DCs into LDLr-/mice. Both CD11c-βcatEX3/LDLr-/chimeras and CD11cβcatEX3 DC-treated mice experienced significantly less atherosclerosis (26% and 21% reduction, respectively). Additionally, CD11c-βcatEX3/LDLr-/chimeras had reduced necrotic cores and more stable collagen-rich lesions, while this was not observed after adoptive transfer of CD11c-βcatEX3 DCs. In both experiments we detected reduced splenic T cell proliferative capacity indicating reduced T cell responses. While CD11cβcatEX3/LDLr-/chimeras showed an overall significant 1.6-fold increase of circulating Tregs, CD11c-βcatEX3 DC-treated mice only showed a significant 2-fold increase directly after treatment. Conclusion We show here for the first time that β-catenin stabilization in DCs can effectively generate tolerogenic DCs that have the capacity to inhibit atherosclerotic lesion formation. This provides a new strategy to increase the potential of tolerogenic DC therapies for any inflammatory autoimmune disease.