Adipose tissue inflammation mediates the association between excessive body fat accumulation and several chronic inflammatory diseases. A high prevalence of obesity-associated adipose tissue inflammation was observed not only in patients with cardiovascular conditions but also in patients with inflammatory bowel diseases, abdominal aortic aneurysm, or cardiorenal syndrome. In addition to excessive caloric intake, other triggers promote visceral adipose tissue inflammation followed by chronic, low-grade systemic inflammation. The infiltration and accumulation of immune cells in the inflamed and hypertrophied adipose tissue promote the production of inflammatory cytokines, contributing to target organ damages. This comorbidity seems to delimit subgroups of individuals with systemic adipose tissue inflammation and more severe chronic inflammatory diseases that are refractory to conventional treatment. This review highlights the association between adipose tissue immune response and the pathophysiology of visceral adiposity-related chronic inflammatory diseases, while suggesting several new therapeutic strategies.

Background and Purpose— The concept of “vulnerable plaque” has been extended to the more recent definition of the “cardiovascular vulnerable patient,” in which “intraplaque” and “systemic” factors contribute to the cumulative risk of acute cardiovascular events. Thus, we investigated the possible role of systemic and intraplaque inflammation in patients asymptomatic versus symptomatic for ischemic stroke. Methods— Regions upstream and downstream the blood flow were isolated from internal carotid plaques of patients asymptomatic (n=63) or symptomatic (n=18) for ischemic stroke. Specimens were analyzed for lipid, collagen, macrophage, lymphocyte, neutrophil, mast cell and smooth muscle cell content, and chemokine and cytokine mRNA expression. Chemokine receptors and adhesion molecules were assessed on circulating leukocytes by flow cytometry. Systemic inflammatory markers and biochemical parameters were measured on total blood, plasma, and serum. Results— Tumor necrosis factor-α and CCL5 serum levels as well as intercellular adhesion molecule-1 expression on circulating neutrophils were increased in symptomatic as compared with asymptomatic patients. Collagen content and smooth muscle cell infiltration were decreased in symptomatic plaques. In upstream regions of symptomatic plaques, lipid content and lymphocyte infiltration were increased. In downstream regions of symptomatic plaques, macrophage, neutrophil, and mast cell infiltration were increased. Intraplaque collagen content was positively correlated with smooth muscle cell infiltration and inversely correlated with macrophages, neutrophils, or serum tumor necrosis factor-α. Collagen reduction in downstream regions and serum tumor necrosis factor-α were independently associated with the likelihood of being symptomatic. Conclusions— Inflammatory mediators are increased in ischemic stroke. Despite statistically significant, the correlation between tumor necrosis factor-α serum level and intraplaque vulnerability was weak and probably of limited biological importance.

Anti-Apolipoprotein A-1 auto-antibodies (anti-ApoA-1 IgG) represent an emerging prognostic cardiovascular marker in patients with myocardial infarction or autoimmune diseases associated with high cardiovascular risk. The potential relationship between anti-ApoA-1 IgG and plaque vulnerability remains elusive. Thus, we aimed to investigate the role of anti-ApoA-1 IgG in plaque vulnerability. Potential relationship between anti-ApoA-1 IgG and features of cardiovascular vulnerability was explored both in vivo and in vitro. In vivo, we investigated anti-ApoA-1 IgG in patients with severe carotid stenosis (n = 102) and in ApoE−/− mice infused with polyclonal anti-ApoA-1 IgG. In vitro, anti-ApoA-1 IgG effects were assessed on human primary macrophages, monocytes, and neutrophils. Intraplaque collagen was decreased, while neutrophil and matrix metalloprotease (MMP)-9 content were increased in anti-ApoA-1 IgG-positive patients and anti-ApoA-1 IgG-treated mice when compared with corresponding controls. In mouse aortic roots (but not in abdominal aortas), treatment with anti-ApoA-1 IgG was associated with increased lesion size when compared with controls. In humans, serum anti-ApoA-1 IgG levels positively correlated with intraplaque macrophage, neutrophil, and MMP-9 content, and inversely with collagen. In vitro, anti-ApoA-1 IgG increased macrophage release of CCL2, CXCL8, and MMP-9, as well as neutrophil migration towards TNF-α or CXCL8. These results suggest that anti-ApoA-1 IgG might be associated with increased atherosclerotic plaque vulnerability in humans and mice.

The activation of cannabinoid receptor type 2 (CB₂)-mediated pathways might represent a promising anti-atherosclerotic treatment. Here, we investigated the expression of the endocannabinoid system in human carotid plaques and the impact of CB₂ pharmacological activation on markers of plaque vulnerability in vivo and in vitro. The study was conducted using all available residual human carotid tissues (upstream and downstream the blood flow) from our cohort of patients symptomatic (n = 13) or asymptomatic (n = 27) for ischaemic stroke. Intraplaque levels of 2-arachidonoylglycerol, anandamide N-arachidonoylethanolamine, N-palmitoylethanolamine, N-oleoylethanolamine, and their degrading enzymes (fatty acid amide hydrolase and monoacylglycerol lipase) were not different in human plaque portions. In the majority of human samples, CB₁ (both mRNA and protein levels) was undetectable. In downstream symptomatic plaques, CB₂ protein expression was reduced when compared with asymptomatic patients. In these portions, CB₂ levels were inversely correlated (r = −0.4008, P = 0.0170) with matrix metalloprotease (MMP)-9 content and positively (r = 0.3997, P = 0.0174) with collagen. In mouse plaques, CB₂ co-localized with neutrophils and MMP-9. Treatment with the selective CB₂ agonist JWH-133 was associated with the reduction in MMP-9 content in aortic root and carotid plaques. In vitro, pre-incubation with JWH-133 reduced tumour necrosis factor (TNF)-α-mediated release of MMP-9. This effect was associated with the reduction in TNF-α-induced ERK1/2 phosphorylation in human neutrophils. Cannabinoid receptor type 2 receptor is down-regulated in unstable human carotid plaques. Since CB₂ activation prevents neutrophil release of MMP-9 in vivo and in vitro, this treatment strategy might selectively reduce carotid vulnerability in humans.

Angiotensin (Ang)-(1–7), acting through the receptor Mas, has atheroprotective effects; however, its role on plaque vulnerability has been poorly studied. Here, we investigated the expression of the renin-angiotensin system (RAS) components in stable and unstable human carotid plaques. In addition, we evaluated the effects of the chronic treatment with an oral formulation of Ang-(1–7) in a mouse model of shear stress-determined carotid atherosclerotic plaque. Upstream and downstream regions of internal carotid plaques were obtained from a recently published cohort of patients asymptomatic or symptomatic for ischaemic stroke. Angiotensinogen and renin genes were strongly expressed in the entire cohort, indicating an intense intraplaque modulation of the RAS. Intraplaque expression of the Mas receptor mRNA was increased in the downstream portion of asymptomatic patients as compared to corresponding region in symptomatic patients. Conversely, AT1 receptor gene expression was not modified between asymptomatic and symptomatic patients. Treatment with Ang-(1–7) in ApoE^-/- mice was associated with increased intraplaque collagen content in the aortic root and low shear stress-induced carotid plaques, and a decreased MMP-9 content and neutrophil and macrophage infiltration. These beneficial effects were not observed in the oscillatory shear stress-induced plaque. In vitro incubation with Ang-(1–7) did not affect ICAM-1 expression and apoptosis on cultured endothelial cells. In conclusion, Mas receptor is up regulated in the downstream portions of human stable carotid plaques as compared to unstable lesions. Treatment with the oral formulation of Ang-(1–7) enhances a more stable phenotype in atherosclerotic plaques, depending on the local pattern of shear stress forces.