Cirrhosis is the end result of chronic liver disease. Hepatic stellate cells (HSC) are believed to be the major source of collagenproducing myofibroblasts in cirrhotic livers. Portal fibroblasts, bone marrow-derived cells, and epithelial to mesenchymal transition (EMT) might also contribute to the myofibroblast population in damaged livers. Fibroblast-specific protein 1 (FSP1, also called S100A4) is considered a marker of fibroblasts in different organs undergoing tissue remodeling and is used to identify fibroblasts derived from EMT in several organs including the liver. The aim of this study was to characterize FSP1-positive cells in human and experimental liver disease. FSP1-positive cells were increased in human and mouse experimental liver injury including liver cancer. However, FSP1 was not expressed by HSC or type I collagenproducing fibroblasts. Likewise, FSP1-positive cells did not express classical myofibroblast markers, including αSMA and desmin, and were not myofibroblast precursors in injured livers as evaluated by genetic lineage tracing experiments. Surprisingly, FSP1-positive cells expressed F4/80 and other markers of the myeloid-monocytic lineage as evaluated by double immunofluorescence staining, cell fate tracking, flow cytometry, and transcriptional profiling. Similar results were obtained for bone marrow-derived and peritoneal macrophages. FSP1-positive cells were characterized by increased expression of COX2, osteopontin, inflammatory cytokines, and chemokines but reduced expression of MMP3 and TIMP3 compared with Kupffer cells/macrophages. These findings suggest that FSP1 is a marker of a specific subset of inflammatory macrophages in liver injury, fibrosis, and cancer.tumor microenvironment

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.

Most leukocytes can roll along the walls of venules at low shear stress (1 dyn/cm 2 ), but neutrophils have the ability to roll at 10-fold higher shear stress in microvessels in vivo 1 , 2 . The mechanisms involved in this shear-resistant rolling are known to involve cell flattening 3 and pulling of long membrane tethers at the rear 4 – 6 . Here, we show that these long tethers do not retract as postulated 6 , 7 , but instead persist and appear as ‘slings’ at the front of rolling cells. We demonstrate slings in a model of acute inflammation in vivo and on P-selectin in vitro , where P-selectin-glycoprotein-ligand-1 (PSGL-1) is presented as discrete sticky patches while LFA-1 is expressed over the entire length on slings. As neutrophils roll forward, slings wrap around the rolling cells and undergo a step-wise peeling from the P-selectin substrate enabled by the failure of PSGL-1 patches under hydrodynamic forces. The ‘step-wise peeling of slings’ is distinct from the ‘pulling of tethers’ reported previously 4 – 6 , 8 . Each sling effectively lays out a cell-autonomous adhesive substrate in front of neutrophils rolling at high shear stress during inflammation.

Atherosclerosis contributes to the development of many cardiovascular diseases, which remain the leading cause of death in developed countries. Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries. It is caused by dyslipidemia and mediated by both innate and adaptive immune responses. Inflammation is a key factor at all stages of atherosclerosis progression. Cells involved in pathogenesis of atherosclerosis were shown to be activated by soluble factors, cytokines that strongly influence the disease development. Pro-inflammatory cytokines accelerate atherosclerosis progression, while anti-inflammatory cytokines ameliorate the disease. In this review, we discuss the latest findings on the role of cytokines in the development and progression of atherosclerosis.

Summary While commensal flora is involved in the regulation of immunity, the interplay between cytokine signaling and microbiota in atherosclerosis remains unknown. We found that interleukin (IL)-23 and its downstream target IL-22 restricted atherosclerosis by repressing pro-atherogenic microbiota. Inactivation of IL-23-IL-22 signaling led to deterioration of the intestinal barrier, dysbiosis and expansion of pathogenic bacteria with distinct biosynthetic and metabolic properties, causing systemic increase in pro-atherogenic metabolites such as lipopolysaccharide (LPS) and trimethylamine N-oxide (TMAO). Augmented disease in the absence of the IL-23-IL-22 pathway was mediated in part by pro-atherogenic osteopontin, controlled by microbial metabolites. Microbiota transfer from IL-23 deficient mice accelerated atherosclerosis, whereas microbial depletion or IL-22 supplementation reduced inflammation and ameliorated disease. Our work uncovers the IL-23-IL-22 signaling as a regulator of atherosclerosis that restrains expansion of pro-atherogenic microbiota, and argues for informed use of cytokine blockers to avoid cardiovascular side effects driven by microbiota and inflammation.

Atherosclerosis is an inflammatory disease of the arteries, which results in major morbidity and mortality. Immune cells initiate and sustain local inflammation. Here we focus on how DC-mediated processes might be relevant to atherosclerosis. Although only small numbers of DCs are detected in healthy arteries, these numbers dramatically increase during atherosclerosis development. In the earliest fatty streaks, DCs are found next to the vascular endothelium. During plaque growth, new DCs are actively recruited, and their egress from the vessel wall is dampened. In the adventitia next to mature atherosclerotic lesions, tertiary lymphoid organs develop, which also contain DCs. Thus, DCs likely participate in all stages of atherosclerosis from fatty streaks to mature lesions.

Cardiovascular diseases (CVD) are the major cause of death in developed countries. Various risk factors including host genetics and, more importantly, environmental factors such as lifestyle, diet and smoking influence CVD progression. Two common forms of CVD are atherosclerosis and abdominal aortic aneurysm (AAA). Emerging evidence suggests that inflammation plays a pivotal role in CVD. However, it remains unclear whether the same inflammatory pathways prove essential for atherosclerosis and AAA because, in some cases, the same mechanisms uniformly promote both diseases, while in others they function in opposite ways. Cytokines, key mediators of inflammation, play an important role in the development of atherosclerosis but have only been scarcely studied in AAA. In this review, we discuss the importance of immune‐mediated mechanisms and cytokines in the pathogenesis of atherosclerosis and AAA.

Rationale Atherosclerosis is a major cause of death in patients with chronic kidney disease. Chronic inflammation of the arterial wall including invasion, proliferation and differentiation of leukocytes is important in atherosclerotic lesion development. How atherosclerotic inflammation is altered in renal impairment is incompletely understood. Objective This study analyzed leukocytes of the atherosclerotic aorta in mice with impaired and normal renal function and studied a mechanism for the alteration in aortic myeloid leukocytes. Methods and Results Unilateral nephrectomy significantly decreased glomerular filtration rate and increased atherosclerotic lesion size and aortic leukocyte numbers in two murine atherosclerosis models, Apolipoprotein E (Apoe−/−) and LDL receptor (LDLr−/−) deficient mice. The number of aortic myeloid cells increased significantly. They took up less oxidized LDL, while CD11c expression, interaction with T cells and aortic T cell proliferation were significantly enhanced in renal impairment. In human PBMC cultures, chronic kidney disease serum decreased lipid uptake and increased HLAII expression. Supplementation with Interleukin (IL)-17A similarly increased HLAII and CD11c expression and impaired oxLDL uptake. IL-17A expression was increased in atherosclerotic mice with renal impairment. Ablation of IL-17A in LDLr−/− mice by lethal irradiation and reconstitution with Il17a−/− bone marrow abolished the effect of renal impairment on aortic CD11b+ myeloid cell accumulation, CD11c expression and cell proliferation. Atherosclerotic lesion size was decreased to levels observed in normal kidney function. Conclusions Kidney function modifies arterial myeloid cell accumulation and phenotype in atherosclerosis. Our results suggest a central role for IL-17A in aggravation of vascular inflammation and atherosclerosis in renal impairment.