Indoleamine 2,3-Dioxygenase-Expressing Aortic Plasmacytoid Dendritic Cells Protect against Atherosclerosis by Induction of Regulatory T Cells

Abstract

Plasmacytoid dendritic cells (pDCs) are unique bone-marrow-derived cells that produce large amounts of type I interferon in response to microbial stimulation. Furthermore, pDCs also promote T cell tolerance in sterile-inflammation conditions. However, the immunomodulatory role of aortic pDCs in atherosclerosis has been poorly understood. Here, we identified functional mouse and human pDCs in the aortic intima and showed that selective, inducible pDC depletion in mice exacerbates atherosclerosis. Aortic pDCs expressed CCR9 and indoleamine 2,3-dioxygenase 1 (IDO-1), an enzyme involved in driving the generation of regulatory T cells (Tregs). As a consequence, loss of pDCs resulted in decreased numbers of Tregs and reduced IL-10 levels in the aorta. Moreover, antigen presentation by pDCs expanded antigen-specific Tregs in the atherosclerotic aorta. Notably, Tregs ablation affected pDC homeostasis in diseased aorta. Accordingly, pDCs in human atherosclerotic aortas colocalized with Tregs. Collectively, we identified a mechanism of atheroprotection mediated by tolerogenic aortic pDCs.

B-Cell Depletion Promotes Aortic Infiltration of Immunosuppressive Cells and Is Protective of Experimental Aortic Aneurysm

“…Our data is in consistent with a model that B cells control immunosuppressive effects of pDC by limiting IDO+ pDC population and regulate inflammation and AAA as shown the graphic abstract. In support of this model, recently, Yun et al demonstrate that aortic pDCs expressing IDO protects against atherosclerosis via generation of Tregs 34 .…”

“…In support of our finding, Mellak et al have reported that angiotensin II mobilizes monocytes from spleen to aorta in a B cell-dependent manner and promote AAA formation in the Apolipoprotein E KO mice 7 . As far as atherosclerosis is concerned, there are reports supporting 34, 36 and contradicting 37 protective role of IDO expressing pDCs. Therefore, generation of pDC-specific IDO knock-out mouse is required to confirm that IDO expressing pDCs protect B cell depleted mice from AAA.…”

IDO1 and TGF-β Mediate Protective Effects of IFN-α in Antigen-Induced Arthritis

“…Thus, pDC are an important source of IDO1 expression activated by IFN-a, and this has also been observed in humans treated with IFN-a (25). An anti-inflammatory effect of IDO1-expressing pDC has earlier been anticipated in a number of experimental studies, including prevention of atherosclerosis (26), regulation of HIV responses (27,28), and amelioration of experimental encephalitis (29), to name a few. In line with such observations, we showed in this work that pDC were critically involved in IFN-a-mediated protection against AIA (Fig.…”

The Importance of Dendritic Cells in Maintaining Immune Tolerance

“…In vascularized grafts, as in GVHD, pDCs promote the development of Treg and prevent allograft rejection (162). pDCs similarly contribute to prevent atherosclerosis, where specific depletion of pDCs leads to a reduction in Tregs and an exacerbation of atherosclerosis lesions (163). This latter study demonstrates that pDCs induce antigen-specific Treg via the production of IDO.…”