Several lines of preclinical and clinical research have confirmed that chronic low-grade inflammation of adipose tissue is mechanistically linked to metabolic disease and organ tissue complications ...in the overweight and obese organism. Despite this widely confirmed paradigm, numerous open questions and knowledge gaps remain to be investigated. This is mainly due to the intricately intertwined cross-talk of various pro- and anti-inflammatory signaling cascades involved in the immune response of expanding adipose depots, particularly the visceral adipose tissue. Adipose tissue inflammation is initiated and sustained over time by dysfunctional adipocytes that secrete inflammatory adipokines and by infiltration of bone marrow-derived immune cells that signal via production of cytokines and chemokines. Despite its low-grade nature, adipose tissue inflammation negatively impacts remote organ function, a phenomenon that is considered causative of the complications of obesity. The aim of this review is to broadly present an overview of adipose tissue inflammation by highlighting the most recent reports in the scientific literature and summarizing our overall understanding of the field. We also discuss key endogenous anti-inflammatory mediators and analyze their mechanistic role(s) in the pathogenesis and treatment of adipose tissue inflammation. In doing so, we hope to stimulate studies to uncover novel physiological, cellular, and molecular targets for the treatment of obesity.
Cardiovascular disease remains a major medical and socioeconomic burden in developed and developing countries and will increase with an aging and increasingly sedentary society. Many vascular ...diseases and atherosclerotic vascular disease, in particular, are essentially inflammatory disorders, involving multiple cell types. Communication between these cells is initiated and sustained by a complex network of cytokines and their receptors. The interleukin (IL)-20 family members, IL-19, IL-20, IL-22, and IL-24, initiate, sustain, and drive the progression of vascular disease. They are important in vascular disease as they facilitate a bidirectional cross-talk between resident vascular cells with immune cells. These cytokines are grouped into the same family based on shared common receptor subunits and signaling pathways. This communication is varied and can result in exacerbation, attenuation, and even repair of the vasculature. We will briefly review what is known about IL-20, IL-22, and IL-24 in cardiovascular biology. Because IL-19 is the most studied member of this family in terms of its role in vascular pathophysiological processes, the major emphasis of this review will focus on the expression and atheroprotective roles of IL-19 in vascular inflammatory disease.
The inflammatory response is a complex, tightly regulated process activated by tissue wounding, foreign body invasion, and sterile inflammation. Over the decades, great progress has been made to ...advance our understanding of this process. One often overlooked aspect of inflammation is its sequel: resolution. We know that dysregulated resolution often results in numerous chronic degenerative diseases such as arthritis, cancer, and asthma. However, identification of components and mechanisms of resolving pathways lags behind those of proinflammatory processes, yet represents overlooked therapeutic opportunities. One approach is identification of endogenous, negative compensatory mechanisms, which are activated in response to inflammation for the purpose of resolution of that inflammatory stimuli. This review will focus on literature that describes expression and function of interleukin-19, a proposed anti-inflammatory cytokine, in numerous inflammatory diseases. The literature concerning IL-19 is complex, context-dependent, and often contradictory. The expression and function of IL-19 in the inflammatory response are in no way settled. We will attempt to clarify the role that this interesting and understudied cytokine plays in resolution of inflammation and discuss its mechanisms of action in different cell types. We will present a hypothesis that endogenous IL-19 expression in response to inflammatory stimuli is a cellular compensatory mechanism to dampen inflammation. We further present studies suggesting that while endogenously expressed IL-19 may be a response to inflammation, pharmacological levels may be necessary to effectively resolve the inflammatory cascade.
Despite advances in prevention and treatment, vascular diseases continue to account for significant morbidity and mortality in the developed world. Incidence is expected to worsen as the number of ...patients with common co-morbidities linked with atherosclerotic vascular disease, such as obesity and diabetes, continues to increase, reaching epidemic proportions. Atherosclerosis is a lipid-driven vascular inflammatory disease involving multiple cell types in various stages of inflammation, activation, apoptosis, and necrosis. One commonality among these cell types is that they are activated and communicate with each other in a paracrine fashion via a complex network of cytokines. Cytokines mediate atherogenesis by stimulating expression of numerous proteins necessary for induction of a host of cellular responses, including inflammation, extravasation, proliferation, apoptosis, and matrix production. Cytokine expression is regulated by a number of transcriptional and post-transcriptional mechanisms. In this context, proteins that control and fine-tune cytokine expression can be considered key players in development of atherosclerosis and also represent targets for rational drug therapy to combat this disease. This review will describe the cellular and molecular mechanisms that drive atherosclerotic plaque progression and present key cytokines that participate in this process. We will also describe RNA binding proteins that mediate cytokine mRNA stability and regulate cytokine abundance. Identification and characterization of the cytokines and proteins that regulate their abundance are essential to our ability to identify therapeutic approaches to ameliorate atherosclerotic vascular disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Visceral adipose tissue is a primary site of chronic inflammation in obesity and may contribute to systemic inflammation and development of atherosclerotic vascular disease. Few studies identify ...molecular mechanisms and secretory pathways which mediate this process. In this edition of Clinical Science, Kwok et al. utilize a transgenic mouse in which dominant-negative c-Jun NH2 terminal kinase (dnJNK) expression is restricted to adipose tissue to implicate JNK-driven expression of adipocyte fatty acid binding protein (A-FABP) in visceral adipose tissue as a key secretory pathway to exacerbate development of atherosclerosis in ApoE-/- mice. They further demonstrate that ApoE-/- mice transplanted with visceral adipose tissue in which JNK has been inactivated display less systemic inflammation and develop significantly less atherosclerosis compared with control mice. Together, the findings of the present study reinforce our understanding of visceral adipose tissue as a secretory organ and the importance of the JNK/A-FABP pathway in mediating adipose vascular cross-talk and exacerbation of atherosclerosis.
Angiogenesis is a vital biological process, and neovascularization is essential for the development, wound repair, and perfusion of ischemic tissue. Neovascularization and inflammation are ...independent biological processes that are linked in response to injury and ischemia. While clear that pro-inflammatory factors drive angiogenesis, the role of anti-inflammatory interleukins in angiogenesis remains less defined. An interleukin with anti-inflammatory yet pro-angiogenic effects would hold great promise as a therapeutic modality to treat many disease states where inflammation needs to be limited, but revascularization and reperfusion still need to be supported. As immune modulators, interleukins can polarize macrophages to a pro-angiogenic and reparative phenotype, which indirectly influences angiogenesis. Interleukins could also potentially directly induce angiogenesis by binding and activating its receptor on endothelial cells. Although a great deal of attention is given to the negative effects of pro-inflammatory interleukins, less is described concerning the potential protective effects of anti-inflammatory interleukins on various disease processes. To focus this review, we will consider IL-4, IL-10, IL-13, IL-19, and IL-33 to be anti-inflammatory interleukins, all of which have recognized immunomodulatory effects. This review will summarize current research concerning anti-inflammatory interleukins as potential drivers of direct and indirect angiogenesis, emphasizing their role in future therapeutics.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cardiovascular disease is the leading cause of morbidity and mortality in the Western and developing world, and the incidence of cardiovascular disease is increasing with the longer lifespan afforded ...by our modern lifestyle. Vascular diseases including coronary heart disease, high blood pressure, and stroke comprise the majority of cardiovascular diseases, and therefore represent a significant medical and socioeconomic burden on our society. It may not be surprising that these conditions overlap and potentiate each other when we consider the many cellular and molecular similarities between them. These intersecting points are manifested in clinical studies in which lipid lowering therapies reduce blood pressure, and anti-hypertensive medications reduce atherosclerotic plaque. At the molecular level, the vascular smooth muscle cell (VSMC) is the target, integrator, and effector cell of both atherogenic and the major effector protein of the hypertensive signal Angiotensin II (Ang II). Together, these signals can potentiate each other and prime the artery and exacerbate hypertension and atherosclerosis. Therefore, VSMCs are the fulcrum in progression of these diseases and, therefore, understanding the effects of atherogenic stimuli and Ang II on the VSMC is key to understanding and treating atherosclerosis and hypertension. In this review, we will examine studies in which hypertension and atherosclerosis intersect on the VSMC, and illustrate common pathways between these two diseases and vascular aging.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cardiovascular disease remains a major medical and socioeconomic burden in developed and developing societies, and will increase with an aging and increasingly sedentary society. Vascular disease and ...atherosclerotic vascular syndromes are essentially inflammatory disorders, and transcriptional and post-transcriptional processes play essential roles in the ability of resident vascular and inflammatory cells to adapt to environmental stimuli. The regulation of mRNA translocation, stability, and translation are key processes of post-transcriptional regulation that permit these cells to rapidly respond to inflammatory stimuli. For the most part, these processes are controlled by elements in the 3'-UTR of labile, proinflammatory transcripts. Since proinflammatory transcripts almost exclusively contain AU-rich elements (AREs), this represents a tightly regulated and specific mechanism for initiation and maintenance of the proinflammatory phenotype. RNA-binding proteins (RBPs) recognize cis elements in 3'-UTR, and regulate each of these processes, but there is little literature exploring the concept that RBPs themselves can be directly regulated by inflammatory stimuli. Conceptually, inflammation-responsive RBPs represent an attractive target of rational therapies to combat vascular inflammatory syndromes. Herein we briefly describe the cellular and molecular etiology of atherosclerosis, and summarize our current understanding of RBPs and their specific roles in regulation of inflammatory mRNA stability. We also detail RBPs as targets of current anti-inflammatory modalities and how this may translate into better treatment for vascular inflammatory diseases.
Dyslipidemia, vascular inflammation, obesity, and insulin resistance often overlap and exacerbate each other. Mutations in low density lipoprotein receptor adaptor protein-1 (LDLRAP1) lead to LDLR ...malfunction and are associated with the autosomal recessive hypercholesterolemia disorder in humans. However, direct causality on atherogenesis in a defined preclinical model has not been reported. The objective of this study was to test the hypothesis that deletion of LDLRAP1 will lead to hypercholesteremia and atherosclerosis. LDLRAP1
mice fed a high-fat Western diet had significantly increased plasma cholesterol and triglyceride concentrations accompanied with significantly increased plaque burden compared with wild-type controls. Unexpectedly, LDLRAP1
mice gained significantly more weight compared with controls. Even on a chow diet, LDLRAP1
mice were insulin-resistant, and calorimetric studies suggested an altered metabolic profile. The study showed that LDLRAP1 is highly expressed in visceral adipose tissue, and LDLRAP1
adipocytes are significantly larger, have reduced glucose uptake and AKT phosphorylation, but have increased CD36 expression. Visceral adipose tissue from LDLRAP1
mice was hypoxic and had gene expression signatures of dysregulated lipid storage and energy homeostasis. These data are the first to indicate that lack of LDLRAP1 directly leads to atherosclerosis in mice and also plays an unanticipated metabolic regulatory role in adipose tissue. LDLRAP1 may link atherosclerosis and hypercholesterolemia with common comorbidities of obesity and insulin resistance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Interleukin-17 (IL-17)-secreting T helper 17 cells were recently identified as a CD4+ T helper subset and implicated in various inflammatory and autoimmune diseases. The issues of whether and by what ...mechanism hyperlipidemic stress induces IL-17A to activate aortic endothelial cells (ECs) and enhance monocyte adhesion remained largely unknown. Using biochemical, immunological, microarray, experimental data mining analysis, and pathological approaches focused on primary human and mouse aortic ECs (HAECs and MAECs) and our newly generated apolipoprotein E (ApoE)−/−/IL-17A−/− mice, we report the following new findings. 1) The hyperlipidemia stimulus oxidized low density lipoprotein up-regulated IL-17 receptor(s) in HAECs and MAECs. 2) IL-17A activated HAECs and increased human monocyte adhesion in vitro. 3) A deficiency of IL-17A reduced leukocyte adhesion to endothelium in vivo. 3) IL-17A activated HAECs and MAECs via up-regulation of proinflammatory cytokines IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), chemokine CXC motif ligand 1 (CXCL1), and CXCL2. 4) IL-17A activated ECs specifically via the p38 mitogen-activated protein kinases (MAPK) pathway; the inhibition of p38 MAPK in ECs attenuated IL-17A-mediated activation by ameliorating the expression of the aforementioned proinflammatory cytokines, chemokines, and EC adhesion molecules including intercellular adhesion molecule 1. Taken together, our results demonstrate for the first time that IL-17A activates aortic ECs specifically via p38 MAPK pathway.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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