Deletion of Ppard in CD11c⁺ cells attenuates atherosclerosis in ApoE knockout mice.

Ppardδ, one of the lipid-activated nuclear receptor expressed in many cell types to activate gene transcription, also regulates cellular functions other than lipid metabolism. The mechanism regulating the function of antigen-presenting cells during the development of atherosclerosis is not fully understood. Here we aimed to study the involvement of PPARδ in CD11c⁺ cells in atherosclerosis. We used the Cre-loxP approach to make conditional deletion of Ppard in CD11c⁺ cells in mice on Apoe^-/- background, which were fed with high cholesterol diet to develop atherosclerosis. Ppard deficiency in CD11c⁺ cells attenuated atherosclerotic plaque formation and infiltration of myeloid-derived dendritic cells (DCs) and T lymphocytes. Reduced lesion was accompanied by reduced activation of dendritic cells, and also a reduction of activation and differentiation of T cells to Th1 cells. In addition, DC migration to lymph node was also attenuated with Ppard deletion. In bone marrow-derived DCs, Ppard deficiency reduced palmitic acid-induced upregulation of co-stimulatory molecules and pro-inflammatory cytokine IL12 and TNFα. Our results indicated PPARδ activation by fatty acid resulted in the activation of myeloid DCs and subsequent polarization of T lymphocytes, which contributed to atherosclerosis in Apoe^-/- mice. These findings also reveal the potential regulatory role of PPARδ in antigen presentation to orchestrate the immune responses during atherosclerosis.

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