Atherosclerosis is an inflammatory disease of the wall of large- and medium-sized arteries that is precipitated by elevated levels of low-density lipoprotein (LDL) cholesterol in the blood. Although dendritic cells (DCs) and lymphocytes are found in the adventitia of normal arteries, their number is greatly expanded and their distribution changed in human and mouse atherosclerotic arteries. Macrophages, DCs, foam cells, lymphocytes, and other inflammatory cells are found in the intimal atherosclerotic lesions. Beneath these lesions, adventitial leukocytes organize in clusters that resemble tertiary lymphoid tissues. Experimental interventions can reduce the number of available blood monocytes, from which macrophages and most DCs and foam cells are derived, and reduce atherosclerotic lesion burden without altering blood lipids. Under proatherogenic conditions, nitric oxide production from endothelial cells is reduced and the burden of reactive oxygen species (ROS) and advanced glycation end products (AGE) is increased. Incapacitating ROS-generating NADPH oxidase or the receptor for AGE (RAGE) has beneficial effects. Targeting inflammatory adhesion molecules also reduces atherosclerosis. Conversely, removing or blocking IL-10 or TGF-β accelerates atherosclerosis. Regulatory T cells and B1 cells secreting natural antibodies are atheroprotective. This review summarizes our current understanding of inflammatory and immune mechanisms in atherosclerosis.

Background— T cells play an important role during the immune response that accompanies atherosclerosis. To date, the role for interleukin (IL)-17A in atherogenesis is not well defined. Here, we tested the hypothesis that atherosclerosis-prone conditions induce the differentiation of IL-17A–producing T cells, which in turn promote atherosclerosis. Methods and Results— IL-17A was found to be elevated in the plasma and tissues of apolipoprotein E–deficient ( Apoe ^−/− ) mice. IL-17A–expressing T cells were significantly increased in the aortas, spleen, and lamina propria of aged Apoe ^−/− mice compared with age-matched C57BL/6 mice. IL-17A ⁺ T cells resided in both adventitia and aortas of aged Apoe ^−/− mice fed a chow diet. Elevated levels of IL-17A ⁺ T cells were also detected in the aortas of 21-week-old Apoe ^−/− mice fed a Western diet for 15 weeks. IL-17A ⁺ T cells were characterized as predominantly CD4 ⁺ T helper 17 (Th17) cells and γδ ⁺ T cells. Blockade of IL-17A in Apoe ^−/− mice by use of adenovirus-produced IL-17 receptor A reduced plaque burden in Apoe ^−/− mice fed a Western diet for 15 weeks. In addition, the treatment diminished circulating IL-6 and granulocyte colony-stimulating factor levels and limited CXCL1 expression and macrophage content within the aortas. Conversely, IL-17A treatment of whole aorta isolated from Apoe ^−/− mice promoted aortic CXCL1 expression and monocyte adhesion in an ex vivo adhesion assay. Conclusions— These results demonstrate that atherosclerosis-prone conditions induce the differentiation of IL-17A–producing T cells. IL-17A plays a proatherogenic inflammatory role during atherogenesis by promoting monocyte/macrophage recruitment into the aortic wall.

Rationale:: Forkhead box P3 ⁺ T regulatory cells (Tregs) are key players in maintaining immune homeostasis. Evidence suggests that Tregs respond to environmental cues to permit or suppress inflammation. In atherosclerosis, Th1-driven inflammation affects Treg homeostasis, but the mechanisms governing this phenomenon are unclear. Objective:: Here, we address whether atherosclerosis impacts Treg plasticity and functionality in Apoe ^{− /−} mice, and what effect Treg plasticity might have on the pathology of atherosclerosis. Methods and Results:: We demonstrate that atherosclerosis promotes Treg plasticity, resulting in the reduction of CXCR3 ⁺ Tregs and the accumulation of an intermediate Th1-like interferon (IFN)-γ ⁺ CCR5 ⁺ Treg subset (Th1/Tregs) within the aorta. Importantly, Th1/Tregs arise in atherosclerosis from bona fide Tregs, rather than from T-effector cells. We show that Th1/Tregs recovered from atherosclerotic mice are dysfunctional in suppression assays. Using an adoptive transfer system and plasticity-prone Mir146a ^−/− Tregs, we demonstrate that elevated IFNγ ⁺ Mir146a ^−/− Th1/Tregs are unable to adequately reduce atherosclerosis, arterial Th1, or macrophage content within Apoe ^−/− mice, in comparison to Mir146a ^+/+ Tregs. Finally, via single-cell RNA-sequencing and real-time -polymerase chain reaction, we show that Th1/Tregs possess a unique transcriptional phenotype characterized by coexpression of Treg and Th1 lineage genes and a downregulation of Treg-related genes, including Ikzf2 , Ikzf4, Tigit, Lilrb4 , and Il10 . In addition, an ingenuity pathway analysis further implicates IFNγ, IFNα, interleukin-2, interleukin-7, CTLA-4 (cytotoxic T-lymphocyte–associated protein 4), T-cell receptor, and Csnk2b-related pathways in regulating Treg plasticity. Conclusions:: Atherosclerosis drives Treg plasticity, resulting in the accumulation of dysfunctional IFNγ ⁺ Th1/Tregs that may permit further arterial inflammation and atherogenesis.

Rationale:: Atherosclerosis is a disease of large- and medium-sized arteries that is characterized by chronic vascular inflammation. While the role of Th1, Th2, and T-regulatory subsets in atherogenesis is established, the involvement of IL-17A-producing cells remains unclear. Objective:: To investigate the role of the IL-17A/IL-17RA axis in atherosclerosis. Methods and Results:: We bred apolipoprotein-E-deficient ( Apoe ^−/− ) mice with IL-17A-deficient and IL-17 receptor A-deficient mice to generate Il17a ^−/− Apoe ^−/− and Il17ra ^−/− Apoe ^−/− mice. Western diet fed Il17a ^−/− Apoe ^−/− and Il17ra ^−/− Apoe ^−/− mice had smaller atherosclerotic plaques in the aortic arch and aortic roots, but showed little difference in plaque burden in the thoracoabdominal aorta in comparison with Apoe ^−/− controls. Flow cytometric analysis of Il17a ^−/− Apoe ^−/− and Il17ra ^−/− Apoe ^−/− aortas revealed that deficiency of IL-17A/IL-17RA preferentially reduced aortic arch, but not thoracoabdominal aortic T cell, neutrophil, and macrophage content in comparison with Apoe ^−/− aortic segments. In contrast to ubiquitous IL-17RA expression throughout the aorta, IL-17A was preferentially expressed within the aortic arch of WD-fed Apoe ^−/− mice. Deficiency of IL-17A or IL-17RA reduced aortic arch, but not thoracoabdominal aortic TNFα and CXCL2 expression. Aortic vascular IL-17RA supports monocyte adherence to explanted aortas in ex vivo adhesion assays. Short-term homing experiments revealed that the recruitment of adoptively transferred monocytes and neutrophils to the aortas of Il17ra ^−/− Apoe ^−/− mice is impaired in comparison with Apoe ^−/− recipients. Conclusions:: The IL-17A/IL-17RA axis increases aortic arch inflammation during atherogenesis through the induction of aortic chemokines, and the acceleration of neutrophil and monocyte recruitment to this site.

Atherosclerosis continues to be the leading cause of cardiovascular disease. Development of atherosclerosis depends on chronic inflammation in the aorta and multiple immune cells are involved in this process. Importantly, resident macrophages and dendritic cells (DCs) are present within the healthy aorta, but the functions of these cells remain poorly characterized. Local inflammation within the aortic wall promotes the recruitment of monocytes and DC precursors to the aorta and micro-environmental factors direct the differentiation of these emigrated cells into multiple subsets of macrophages and DCs. Recent data suggest that several populations of macrophages and DCs can co-exist within the aorta. Although the functions of M1, M2, Mox, and M4 macrophages are well characterized in vitro, there is a limited set of data on the role of these populations in atherogenesis in vivo. Recent studies on the origin and the potential role of aortic DCs provide novel insights into the biology of aortic DC subsets and prospective mechanisms of the immune response in atherosclerosis. This review integrates the results of experiments analyzing heterogeneity of DCs and macrophage subsets in healthy and diseased vessels and briefly discusses the known and potential functions of these cells in atherogenesis.