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Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs
Manikandan Subramanian, … , Goran K. Hansson, Ira Tabas
Manikandan Subramanian, … , Goran K. Hansson, Ira Tabas
Published December 21, 2012
Citation Information: J Clin Invest. 2013;123(1):179-188. https://doi.org/10.1172/JCI64617.
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Research Article Cardiology

Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs

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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.

Authors

Manikandan Subramanian, Edward Thorp, Goran K. Hansson, Ira Tabas

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Figure 6

Evidence of a link between decreased TGF-β and increased MCP1 in lesions of WD-fed Ldlr–/– mice transplanted with bone marrow from Cre+ mice.

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Evidence of a link between decreased TGF-β and increased MCP1 in lesions...
(A) LCM RT-qPCR analysis of Tgfb mRNA in RNA obtained from CD11chi, CD11clo, and sm-actin+ regions of atherosclerotic lesions of Cre– and Cre+ mice (n = 5 mice per group). (B) ELISA-based measurement of latent TGF-β from extracts of atherosclerotic lesions of Cre– and Cre+ mice (n = 5 mice per group). (C) Col1a1, Col3a1, and Egr1 mRNA in RNA obtained from sm-actin+ regions of atherosclerotic lesions of Cre– and Cre+ mice (n = 5 mice per group). (D) Analysis of MCP1 mRNA expression in RNA obtained from the intima of atherosclerotic lesions of 10-week WD-fed Ldlr–/– mice treated with rat IgG (rIgG) or a neutralizing rat IgG antibody against TGF-β (TGF-β nAb) (100 μg per mouse) on days 1, 3, and 8 prior to sacrifice. The data were normalized to expression of Gapdh (n = 6 mice per group). For all panels, *P < 0.05. Symbols represent individual mice; horizontal bars indicate the mean.

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