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Although high-fat diet (HFD)-induced gut microbiota dysbiosis is known to affect atherosclerosis, the underlying mechanisms remain to be fully explored. Here, we show that the progression of atherosclerosis depends on a gut microbiota shaped by an HFD but not a high-cholesterol (HC) diet and, more particularly, on low fiber (LF) intake. Mechanistically, gut lymphoid cells impacted by HFD- or LF-induced microbiota dysbiosis highly proliferate in mesenteric lymph nodes (MLNs) and migrate from MLNs to the periphery, which fuels T cell accumulation within atherosclerotic plaques. This is associated with the induction of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) within plaques and the presence of enterotropic lymphocytes expressing β7 integrin. MLN resection or lymphocyte deficiency abrogates the pro-atherogenic effects of a microbiota shaped by LF. Our study shows a pathological link between a diet-shaped microbiota, gut immune cells, and atherosclerosis, suggesting that a diet-modulated microbiome might be a suitable therapeutic target to prevent atherosclerosis. [Display omitted] • HFD and high-cholesterol diet differentially impact microbiota composition • Fecal microbiota transfer from mice fed HFD or LF diet aggravates atherosclerosis • HFD- or LF-shaped microbiota promotes gut lymphocyte proliferation in MLNs • HFD- or LF-shaped microbiota aggravates atherosclerosis through gut lymphocytes Laurans et al. investigate the impact of fecal microbiota transfer from mice fed an HFD or LF on atherosclerosis and find that these microbiota alterations induce gut lymphocyte proliferation and thus increase gut lymphocytes in the periphery, which aggravates atherosclerosis. [ABSTRACT FROM AUTHOR]

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The obesogenic diet (HFD) is responsible for intestinal dysbiosis observed especially in obesity. Indoleamine 2,3-dioxygenase 1 (IDO) is the main enzyme responsible for the degradation of Tryptophan (Trp), an essential amino acid, in extra-hepatic organs. Our team has shown that the total invalidation of IDO in the presence of HFD contributes to the reduction of metabolic complications. However, the specific role of intestinal IDO locally in the gut as well as its systemic effects on the development of atherosclerosis are unknown. Study of the impact of HFD (High Fat Diet) and HC (High Cholesterol), in the context of a specific invalidation of IDO in intestinal epithelial cells (IEC) on intestinal homeostasis and atherosclerosis. Mice genetically deficient for IDO in IEC and for LDLr (low density lipoprotein receptor) were created. They were subjected to HFD + HC or HC diet for 8 or 13 weeks, to develop atherosclerosis. Feces were collected to characterize microbiota. The heart and the aorta were harvested to analyze the development of atheromatous plaques as well as the inflammatory infiltrate. The invalidation of IDO in IEC contributes to a significant decrease in its expression in the intestine, indicating the importance of IEC in the intestinal expression of IDO. This invalidation in HFD + HC condition but not HC condition contributes to a significant increase in the size of atherosclerotic plaques in the aortic sinus as well as lymphocyte accumulation within the plaques, without any significant changes in plasma cholesterol. It also contributes to dysbiosis as well as intestinal inflammation. The expression of IDO in IEC has a local protective role at the intestine and on the systemic development of atherosclerosis, in the HFD condition. We will continue this project by determining the impact of other pathways of intestinal tryptophan catabolism on atherosclerosis. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To determine the effects of interleukin (IL)-17A inhibition on experimental atherosclerosis. Methods and results: ApoE−/− mice were treated with either rat anti-mouse IL-17A, mouse anti-mouse IL-17A or isotype-matched control antibodies for 12 weeks (n =8–10 per group). Ldlr −/− mice were transplanted with IL-17A-deficient or wild type bone marrow (n =8 per group). Rat anti-mouse IL-17A treatment obviously reduced plaque size by 43% (p <0.01) without evidence of reduced IL-17A signaling. In contrast, mouse anti-mouse IL-17A treatment and IL-17A deficiency in bone marrow cells did not alter lesion size despite significant reduction of IL-17A production. Conclusions: Inhibition of IL-17A signaling does not alter lesion development in Th1-biased C57BL/6 ApoE−/− and Ldlr −/− mice with already low levels of IL-17A production. Alteration of lesion development after repeated injections of rat anti-mouse IL-17A antibody in ApoE−/− mice could not be attributed to blockade of IL-17A signaling. [Copyright &y& Elsevier]

Atherosclerosis is a chronic inflammatory disease of the arterial wall where both innate and adaptive immune responses contribute to disease initiation and progression. Initial studies have focused on the role of T helper-1 (Th1) and Th2 responses in atherosclerosis, and more recently evidence has been published supporting a protective role of regulatory T cells in this disease. A third member of the T helper set, IL-17-producing T cells, now called Th17 cells, was recently described as a distinct lineage that play important role in autoimmune diseases. Here, we review the current knowledge on the role of effector and regulatory T cell responses in atherosclerosis and discuss the contribution of the Th17 to this disease. [Copyright &y& Elsevier]

Background: Innate immune responses activated through myeloid cells contribute to the initiation, progression, and complications of atherosclerosis in experimental models. However, the critical upstream pathways that link innate immune activation to foam cell formation are still poorly identified.Objectives: This study sought to investigate the hypothesis that activation of the triggering receptor expressed on myeloid cells (TREM-1) plays a determinant role in macrophage atherogenic responses.Methods: After genetically invalidating Trem-1 in chimeric Ldlr-/-Trem-1-/- mice and double knockout ApoE-/-Trem-1-/- mice, we pharmacologically inhibited Trem-1 using LR12 peptide.Results: Ldlr-/- mice reconstituted with bone marrow deficient for Trem-1 (Trem-1-/-) showed a strong reduction of atherosclerotic plaque size in both the aortic sinus and the thoracoabdominal aorta, and were less inflammatory compared to plaques of Trem-1+/+ chimeric mice. Genetic invalidation of Trem-1 led to alteration of monocyte recruitment into atherosclerotic lesions and inhibited toll-like receptor 4 (TLR 4)-initiated proinflammatory macrophage responses. We identified a critical role for Trem-1 in the upregulation of cluster of differentiation 36 (CD36), thereby promoting the formation of inflammatory foam cells. Genetic invalidation of Trem-1 in ApoE-/-/Trem-1-/- mice or pharmacological blockade of Trem-1 in ApoE-/- mice using LR-12 peptide also significantly reduced the development of atherosclerosis throughout the vascular tree, and lessened plaque inflammation. TREM-1 was expressed in human atherosclerotic lesions, mainly in lipid-rich areas with significantly higher levels of expression in atheromatous than in fibrous plaques.Conclusions: We identified TREM-1 as a major upstream proatherogenic receptor. We propose that TREM-1 activation orchestrates monocyte/macrophage proinflammatory responses and foam cell formation through coordinated and combined activation of CD36 and TLR4. Blockade of TREM-1 signaling may constitute an attractive novel and double-hit approach for the treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]