Interleukin-6 (IL-6) plays a paradoxical role in inflammation and metabolism. The pro-inflammatory effects of IL-6 are mediated via IL-6 "trans-signaling," a process where the soluble form of the IL-6 receptor (sIL-6R) binds IL-6 and activates signaling in inflammatory cells that express the gp130 but not the IL-6 receptor. Here we show that trans-signaling recruits macrophages into adipose tissue (ATM). Moreover, blocking trans-signaling with soluble gp130Fc protein prevents high-fat diet (HFD)-induced ATM accumulation, but does not improve insulin action. Importantly, however, blockade of IL-6 trans-signaling, unlike complete ablation of IL-6 signaling, does not exacerbate obesity-induced weight gain, liver steatosis, or insulin resistance. Our data identify the sIL-6R as a critical chemotactic signal for ATM recruitment and suggest that selectively blocking IL-6 trans-signaling may be a more favorable treatment option for inflammatory diseases, compared with current treatments that completely block the action of IL-6 and negatively impact upon metabolic homeostasis.
Background-Immunoinflammatory mechanisms are implicated in the atherogenic process. The polarization of the immune response and the nature of the immune cells involved, however, are major determinants of the net effect, which may be either proatherogenic or antiatherogenic. Dendritic cells (DCs) are central to the regulation of immunity, the polarization of the immune response, and the induction of tolerance to antigens. The potential role of DCs in atherosclerosis, however, remains to be defined. Methods and Results-We created a mouse model in which the lifespan and immunogenicity of conventional DCs are enhanced by specific overexpression of the antiapoptotic gene hBcl-2 under the control of the CD11c promoter. When studied in either low-density lipoprotein receptor-deficient or apolipoprotein E-deficient backgrounds, DC-hBcl2 mice exhibited an expanded DC population associated with enhanced T-cell activation, a T-helper 1 and T-helper 17 cytokine expression profile, and elevated production of T-helper 1-driven IgG2c autoantibodies directed against oxidationspecific epitopes. This proatherogenic signature, however, was not associated with acceleration of atherosclerotic plaque progression, because expansion of the DC population was unexpectedly associated with an atheroprotective decrease in plasma cholesterol levels. Conversely, depletion of DCs in hyperlipidemic CD11c-diphtheria toxin receptor/ apolipoprotein E-deficient transgenic mice resulted in enhanced cholesterolemia, thereby arguing for a close relationship between the DC population and plasma cholesterol levels. Conclusions-Considered together, the present data reveal that conventional DCs are central to the atherosclerotic process, because they are directly implicated in both cholesterol homeostasis and the immune response. Key Words: atherosclerosis Ⅲ immune system Ⅲ homeostasis Ⅲ dendritic cells Ⅲ lymphocytes D endritic cells (DCs) are the most potent antigen-presenting cells. Indeed, DCs possess a markedly elevated capacity to stimulate T cells, B cells, and natural killer T cells and to drive T-cell differentiation along both T-helper 1 (Th1) and T-helper 2 (Th2) pathways. 1 Moreover, DCs are known to favor tolerance to antigens, possibly via the generation of regulatory T cells. 2 As major regulators of immune responses and T-cell polarization, DCs are potentially key players in chronic inflammatory diseases such as atherosclerosis. Indeed, available evidence suggests that immune responses are directly implicated in the pathogenesis of atherosclerosis. 3,4 Although the presence of DCs has been reported in atherosclerotic plaques, 5-7 no mechanistic insight into the potential central immunoregulatory role of DCs in the immunoinflammatory dimension of atherosclerosis has been provided in atherosclerosis-prone mice. Modulation of the capacity of DCs to induce an immune response may facilitate evaluation of their impact on the pathogenesis of atherosclerosis. Indeed, enhancement of the lifespan of DCs has been reported to increase their immunogen...
Our loss- and gain-of-function findings provide definitive evidence that NK cells are atherogenic and their production of perforin and granzyme B contributes to atherosclerosis and the expansion of necrotic cores.
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