Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs

Abstract

TLR activation on CD11c + DCs triggers DC maturation, which is critical for T cell activation. Given the expansion of CD11c + DCs during the progression of atherosclerosis and the key role of T cell activation in atherogenesis, we sought to understand the role of TLR signaling in CD11c + DCs in atherosclerosis. To this end, we used a mouse model in which a key TLR adaptor involved in DC maturation, MYD88, is deleted in CD11c + DCs. We transplanted bone marrow containing Myd88-deficient CD11c + DCs into Western diet-fed LDL receptor knockout mice and found that the transplanted mice had decreased activation of effector T cells in the periphery as well as decreased infiltration of both effector T cells and Tregs in atherosclerotic lesions. Surprisingly, the net effect was an increase in atherosclerotic lesion size due to an increase in the content of myeloid-derived inflammatory cells. The mechanism involves increased lesional monocyte recruitment associated with loss of Treg-mediated suppression of MCP-1. Thus, the dominant effect of MYD88 signaling in CD11c + DCs in the setting of atherosclerosis is to promote the development of atheroprotective Tregs. In the absence of MYD88 signaling in CD11c + DCs, the loss of this protective Treg response trumps the loss of proatherogenic T effector cell activation.

Control of the T Follicular Helper–Germinal Center B-Cell Axis by CD8 + Regulatory T Cells Limits Atherosclerosis and Tertiary Lymphoid Organ Development

“…[25][26][27][28] Initial studies 1,29,30 indicated the atheroprotective potential of the B-cell compartment that relies on B1a cells and germ-line-encoded immunoglobulins. In contrast, recent studies have identified T-dependent B cells (B2 cells) as potent proatherogenic mediators in the ApoE° and low-density lipoprotein receptor-knockout mouse models.…”

CAMKIIγ suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis

“…Experimentation was carried out as previously described by our laboratory (10,72). In brief, aortic root sections were stained with TUNEL (Roche) followed by Mac-3 (BD BiosciencesPharmingen) to label lesional macrophages.…”

“…Aortic root lesional material from 5 mice was captured (twelve 5-μm sections per mouse) using a PALM LCM microscope as previously described (72). RNA was isolated using the RNeasy Mini Kit (QIAGEN, catalog 74106) and linearly amplified using the Message Amp II aRNA Kit (Ambion, catalog AM1751).…”

Toll-Like Receptor, Lipotoxicity and Chronic inflammation: The Pathological Link Between Obesity and Cardiometabolic Disease

“…Modified from reference 19) . ＋ DCs is required for the differentiation of both effecter T cells and Treg cells, the net result in Ldlr −/− mice is the enhanced recruitment of monocytes to the plaque lesion due to the loss of the Treg-mediated suppression of MCP-1 68) . These results indicate that the role of TLR4 signaling in atherogenesis is likely to be ligand-, timing-and cell type-dependent.…”