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.

Abstract-Numerous reports document the role of vascular adhesion molecules in the development and progression of atherosclerosis. Recent novel findings in the field of adhesion molecules require an updated summary of current research. In this review, we highlight the role of vascular adhesion molecules including selectins, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule1 (ICAM-1), PECAM-1, JAMs, and connexins in atherosclerosis. The immune system is important in atherosclerosis, and significant efforts are under way to understand the vascular adhesion molecule-dependent mechanisms of immune cell trafficking into healthy and atherosclerosis-prone arterial walls. This review focuses on the role of vascular adhesion molecules in the regulation of immune cell homing during atherosclerosis and discusses future directions that will lead to better understanding of this disease. (Arterioscler

Atherosclerosis is an inflammatory disease of large arteries. Flow cytometry of aortic cell suspensions showed that B and T lymphocytes and some macrophages and dendritic cells are already present in the adventitia of normal/noninflamed mouse aortas. Adoptively transferred lymphocytes constitutively homed to the aorta and resided within the adventitia up to 7 d after transfer. Lymphocyte trafficking into normal/noninflamed or atherosclerosis-prone aortas was partially L-selectin dependent. Antigen-activated dendritic cells induced increased T lymphocyte proliferation within the aorta 72 h after adoptive transfer. During progression of atherosclerosis in apolipoprotein-E–deficient mice, the total number of macrophages, T cells, and dendritic cells, but not B cells, increased significantly. This alteration in immune cell composition was accompanied by the formation of tertiary lymphoid tissue in the adventitia of atherosclerotic aortas. These results demonstrate that lymphocytes already reside within the normal/noninflamed aorta before the onset atherosclerosis as a consequence of constitutive trafficking. Atherosclerosis induces the recruitment of macrophages and dendritic cells that support antigen presentation.

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 atherosclerosisprone 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 A therosclerosis is the leading cause of cardiovascular disease worldwide. Defined as chronic inflammation of the artery wall, its progression from fatty streaks to more complex lesions and plaque rupture involves a complicated interplay between many different cell types and cytokine networks. Both innate and adaptive immune responses have been shown to regulate local and systemic inflammation during atherogenesis. 1,2 T cells are found within the adventitia of normal/noninflamed vessels as a result of a constitutive T-cell homing into the aorta. 3 Atherosclerosis-prone conditions accelerate T-cell recruitment into the aorta of apolipoprotein E-deficient (Apoe Ϫ/Ϫ ) mice in both the early and advanced stages of atherosclerosis. 3 The majority of aortic T cells are T-cell receptor ␣␤ ϩ CD4 ϩ cells, with few CD8 ϩ and ␥␦ ϩ T cells present. 1,4 Of the CD4 ϩ T cells, T helper 1 (Th1) cells predominate over T helper 2 (Th2) cells during early lesion formation and respond with an elevated production of interferon (IFN)-␥ and interleukin (IL)-6. In the later stages of the disease, a switch to a Th2 response and IL-4 production is evident in the atherosclerotic lesions of Apoe Ϫ/Ϫ mice. 5 Clinical Perspective on p 1755IL-17A is a member of the IL-17 family, which includes IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F. 6 Many lymphocyte subsets secrete IL-17A in response to cytokine or monoclonal antibody stimulation, including CD4 ϩ ␣␤ ϩ (Th17 cells) CD8 ϩ , CD4 Ϫ CD8 Ϫ ␣␤ low , natural killer T cells, and ␥␦ ϩ T cells. 7 The expression of IL-17A is low under normal/noninflamed conditions, in which ␥␦ ϩ T cells are the largest IL-17A-producing T-cell subset. 6 In several murine models of autoimmune diseases, including multiple sclerosis, inflammatory bowel disease, and arthritis, serum IL-17A levels are elevated, and the T helper 17 (Th17) cell population is expanded and plays a highly pathogenic role. 8 Conversely, IL-17A is a protective cytokine in host responses against extracellular pathogens through the induction of proinflammatory cytokines such as IL-6, tumor

The signals required to direct PMN into the different compartments of the lung have not been fully elucidated. In a murine model of LPS-induced lung injury, we investigated the sequential recruitment of PMN into the pulmonary vasculature, lung interstitium, and alveolar space. Mice were exposed to aerosolized LPS and bronchoalveolar lavage fluid (BAL), and lungs were harvested at different time points. We developed a flow cytometry-based technique to assess in vivo trafficking of PMN in the intravascular and extravascular lung compartments. Aerosolized LPS induced consistent PMN migration into all lung compartments. We found that sequestration in the pulmonary vasculature occurred within the first hour. Transendothelial migration into the interstitial space started 1 h after LPS exposure and increased continuously until a plateau was reached between 12 and 24 h. Transepithelial migration into the alveolar air space was delayed, as the first PMN did not appear until 2 h after LPS, reaching a peak at 24 h. Transendothelial migration and transepithelial migration were inhibited by pertussis toxin, indicating involvement of G␣i-coupled receptors. These findings confirm LPS-induced migration of PMN into the lung. For the first time, distinct transmigration steps into the different lung compartments are characterized in vivo. polymorphonuclear leukocytes; pulmonary circulation; chemokines; lipopolysaccharide; flow cytometry; pertussis toxin ACUTE LUNG INJURY (ALI) and acute respiratory distress syndrome (ARDS) are characterized by a disturbance of the alveolar-capillary barrier associated with several clinical disorders. There is no specific therapy, and the mortality of this disease is still high. Our current understanding of the molecular mechanisms of ALI/ARDS has recently been described as "embryonic at best" (27).Migration of activated polymorphonuclear leukocytes (PMN) plays a key role in development of ALI and ARDS (1). Here, we investigate the sequential migration steps from blood to air space (intravascular sequestration, transendothelial migration, transepithelial migration).A variety of stimuli induce PMN migration into the lung. Endotoxin of gram-negative bacteria [lipopolysaccharide (LPS)] induces a range of inflammatory responses. Toll-like receptor-4 (TLR4) is the most important cellular receptor for LPS. LPS stimulates the response to chemoattractants and increases PMN migration at sites of inflammation (14). TLR4 is essential for LPS-induced PMN migration into the lung as shown by the absence of a response in TLR4-deficient mice (3). In the lung, the response to LPS is regulated by radioresistant cells, most likely endothelial cells (2) or alveolar macrophages (28).The administration of LPS alone might not reflect the whole complexity of the human disease, because it does not consider preexisting diseases, fluid resuscitation, or mechanical ventilation (36). However, infections with gram-negative bacteria and exposure to their predominant pathogenic component play a key role in both development and ou...

The diverse leukocyte infiltrate in atherosclerotic mouse aortas was recently analyzed in 9 single cell RNA-Seq (scRNA-Seq) and 2 mass cytometry (CyTOF) studies. In a comprehensive meta-analysis, we demonstrate four macrophage subsets: resident, inflammatory, IFNIC and Trem2 foamy macrophages. We also find that monocytes, neutrophils, dendritic cells, natural killer cells, innate lymphoid cells-2 (ILC2) and CD8 T cells form prominent and separate populations. The CD4 T cells show a large population of Th17-like cells, which also contain γδ T cells. A small number of Tregs and Th1 cells is also identified. The present meta-analysis overcomes limitations of individual studies that, because of their experimental approach, overor under-represent certain cell populations. CyTOF identifies an even larger number of clusters, suggesting that surface markers provide more discriminatory information than transcriptomes. The present analysis provides evidence to further resolve some long-standing controversies in the field. First, Trem2 + foamy macrophages are not pro-inflammatory, but interferon-inducible cell (IFNIC) and inflammatory macrophages are. Second, about half of all foam cells are smooth muscle cell-derived, retaining smooth muscle cell transcripts rather than transdifferentiating to macrophages. Third, Pf4, which had been considered specific for platelets and megakaryocytes, is also prominently expressed in resident vascular macrophages. Finally, the discovery of a prominent ILC2 cluster links the scRNA-Seq work to recent flow cytometry data suggesting a strong atheroprotective role of ILC2 cells. This resolves apparent discrepancies regarding the role of Th2 cells in atherosclerosis based on studies that pre-dated the discovery of ILC2 cells.

Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries characterized by leukocyte accumulation in the vessel wall. Both innate and adaptive immune responses contribute to atherogenesis, but the identity of atherosclerosis-relevant antigens and the role of antigen presentation in this disease remain poorly characterized. We developed live-cell imaging of explanted aortas to compare the behavior and role of APCs in normal and atherosclerotic mice. We found that CD4 + T cells were capable of interacting with fluorescently labeled (CD11c-YFP + ) APCs in the aortic wall in the presence, but not the absence, of cognate antigen. In atherosclerosis-prone Apoe -/-CD11c-YFP + mice, APCs extensively interacted with CD4 + T cells in the aorta, leading to cell activation and proliferation as well as secretion of IFN-γ and TNF-α. These cytokines enhanced uptake of oxidized and minimally modified LDL by macrophages. We conclude that antigen presentation by APCs to CD4 + T cells in the arterial wall causes local T cell activation and production of proinflammatory cytokines, which promote atherosclerosis by maintaining chronic inflammation and inducing foam cell formation.

Different types of activated leukocytes play a crucial role in the pathogenesis of most kidney diseases from acute to chronic stages; however, diabetic nephropathy was not considered an inflammatory disease in the past. This view is changing now because there is a growing body of evidence implicating inflammatory cells at every stage of diabetic nephropathy. Renal tissue macrophages, T cells, and neutrophils produce various reactive oxygen species, proinflammatory cytokines, metalloproteinases, and growth factors, which modulate the local response and increase inflammation within the diabetic kidney. Although the precise mechanisms that direct leukocyte homing into renal tissues are not fully identified, it has been reported that intercellular adhesion molecule-1 and the chemokines CCL2 and CX3CL1 probably are involved in leukocyte migration in diabetic nephropathy. This review focuses on the molecular mechanisms of leukocyte recruitment into the diabetic kidney and the involvement of immigrated immune cells in the damage to renal tissues.J Am Soc Nephrol 17: 368 -377, 2006368 -377, . doi: 10.1681 Diabetic NephropathyDiabetic nephropathy (DN) is the leading case of end-stage renal failure (review in reference [1]). The major features of DN include albuminuria, progressive reduction of GFR, and increased risk for cardiovascular diseases (1-3). DN is associated with the expansion of mesangial cells and development of characteristic features of renal injury, such as thickening of the glomerular basement membrane. In the end, glomerulosclerosis and tubulointerstitial fibrosis are observed in patients with diabetic pathology (4,5). Approximately 30% of patients with type 1 diabetes develop DN (6,7). Barkis et al. (8) reported that approximately 25 to 30% of patients with type 2 diabetes will develop overt DN. Recently, several murine models of DN were developed (review in reference [9]). The well-established streptozotocin (STZ)-induced (10 -14) and nonobese diabetic (NOD) (15-18) mouse models are most commonly used to study type 1 diabetes. A few models of type 2 diabetes include db/db mice (19,20), ob/ob mice (21), agouti mice on different backgrounds (22,23), and C57BL/6 on high-fat diet (24). Although some features such as the absence of renal failure complicate the interpretations of the studies in murine models, several distinct stages of DN can be detected in murine models (9). Genetically deficient mice that lack different inflammatory molecules are expected to help dissect the molecular mechanisms of initiation and development of DN.It is well known that hyperglycemia is a major factor risk for DN (25), but hyperglycemia does not account for all changes that are observed in renal tissues (26). It has been suggested that advanced glycation end products (AGE) (27-30), activation of protein kinase C (31), and overexpression of different growth factors (32) are associated with the pathogenesis of DN. Extracellular matrix accumulation is one of the hallmarks in the development of the disease that leads to the ...