Immune surveillance: a balance between protumor and antitumor immunity

Precancerous and malignant cells can induce an immune response which results in the destruction of transformed and/or malignant cells, a process known as immune surveillance. However, immune surveillance is not always successful, resulting in 'edited' tumors that have escaped immune surveillance. Immunoediting is not simply because of the absence of antitumor immunity, but is because of protumor immunity that blocks antitumor adaptive and innate responses, and promotes conditions that favor tumor progression. Several immune protumor effector mechanisms are upregulated by chronic inflammation, leading to the hypothesis that inflammation promotes carcinogenesis and tumor growth by altering the balance between protumor and antitumor immunity, thereby preventing the immune system from rejecting malignant cells, and providing a tumor-friendly environment for progressive disease.     

脂肪细胞与免疫细胞在脂肪组织炎症与代谢失调中的作用

肥胖和超重的患病率继续上升,发病率和死亡率日益增长,是造成高血压、高脂血症、动脉粥样硬化、2型糖尿病等疾病的关键因素之一。目前,针对肥胖的研究已经深入到分子层面。结果提示,肥胖状态下内脏脂肪组织中的低度、慢性炎症反应被认为是其导致胰岛素抵抗的重要病理生理机制。这篇评论的目的是总结目前先天性免疫细胞和适应性免疫细胞在脂肪组织炎症和免疫细胞失调在肥胖和胰岛素抵抗中的作用,认识免疫炎症与代谢之间关系可能为临床治疗肥胖提供靶向。     

Antagonistic effects of thiazolidinediones and cytokines in lipotoxicity

Ectopic lipid accumulation is promoted by obesity and an impaired ability to accumulate triglycerides in the subcutaneous depots. The adipose tissue is dysregulated in hypertrophic obesity, i.e., when the adipose cells have become enlarged. In some individuals, however, obesity is a consequence of a recruitment of new adipocytes, i.e., a hyperplastic obesity. This form of obesity is usually not associated with the metabolic complications and is termed “obese but metabolically normal”. We here review recent findings showing that hypertrophic obesity is associated with an impaired differentiation of committed preadipocytes. This may be a primary (genetic?) event, thus leading to hypertrophic fat cells and the associated inflammation. However, it is also possible that the inflammation is a primary event allowing, in particular, TNFα to inhibit preadipocyte differentiation. TNFα, instead, promotes a partial transdifferentiation of the preadipocytes to assume a macrophage-like phenotype. PPARγ activation promotes adipogenesis but can apparently not overcome the impaired preadipocyte differentiation seen in hypertrophic obesity.     

IL-17 in obesity and adipogenesis

The pro-inflammatory cytokine interleukin (IL)-17 (also known as IL-17) has been associated with induction of tissue inflammation. Obese individuals exhibit many symptoms of chronic low-grade inflammation, suggesting that IL-17 may impact adipose tissue. However, the role of IL-17 in obesity is largely unexplored. Emerging studies indicate that obesity selectively promotes expansion of the Th17 T-cell lineage, exacerbating disease in murine models of autoimmunity such as EAE and colitis. Human studies support this concept, as new clinical studies suggest that IL-17 is expressed at elevated levels in obese individuals. Conversely, however, an anti-adipogenic role for IL-17 is becoming evident, and therefore the interconnections between IL-17 and fat metabolism may be quite complex. Here, we consolidate the potential implications of IL-17 in relation to obesity and describe the emerging data regarding the role of IL-17 in adipose tissue.     

Activation of the Immune System in Acute Inflammatory Disease

Any inflammation, infectious or noninfectious, is characterized by consecutive changes in the parameters of the total blood counts, including subpopulations of lymphocytes. The magnitude of these changes is determined by the intensity and extent of the inflammation. In patients with active inflammation (without a history of immune insufficiency) an active antibacterial therapy by surgical treatment of abscesses and by antibiotics or sulfanilamides results in a normal development and termination of the inflammation. Under intoxication of the body, the inflammation course is decelerated; and detoxification activates the immune system, normalizes the inflammation course, and promotes its termination. In these cases the use of nonspecific immunity modifiers fails to optimize the course of inflammation. On the contrary, the use of nonspecific immunity modifiers in patients with a history of immune insufficiency often activates the inflammation and promotes its effective termination.     

Diverse effects of obesity on antitumor immunity and immunotherapy

Currently, obesity is one of the biggest health burdens facing society because it causes several comorbidities, such as type 2 diabetes, atherosclerosis, and heart disease. Obesity is also linked to multiple types of cancer. Obesity is the second most common preventable cause of cancer after smoking; the rates of obesity are increasing worldwide, as are the rates of obesity-associated cancer. Multiple factors link obesity to cancer, such as increased levels of growth hormones and adipokines, gut dysbiosis, altered tumor metabolism, and chronic low-grade inflammation. More recently, obesity has been shown to also affect the immune response against cancer. In this review we discuss the interplay between obesity, the immune system, and cancer.     

Role of antigen presentation in the production of pro-inflammatory cytokines in obese adipose tissue

Type II diabetes regroups different physiological anomalies that ultimately lead to low-grade chronic inflammation, insulin resistance and loss of pancreatic β-cells. Obesity is one of the best examples of such a condition that can develop into Metabolic Syndrome, causing serious health problems of great socio-economic consequences. The pathological outcome of obesity has a genetic basis and depends on the delicate balance between pro- and anti-inflammatory effectors of the immune system. The causal link between obesity and inflammation is well established. While innate immunity plays a key role in the development of a pro-inflammatory state in obese adipose tissues, it has now become clear that adaptive immune cells are also involved and participate in the cascade of events that lead to metabolic perturbations. The efficacy of some immunotherapeutic protocols in reducing the symptoms of obesity-driven metabolic syndrome in mice implicated all arms of the immune response. Recently, the production of pathogenic immunoglobulins and pro-inflammatory cytokines by B and T lymphocytes suggested an auto-immune basis for the establishment of a non-healthy obese state. Understanding the cellular landscape of obese adipose tissues and how immune cells sustain chronic inflammation holds the key to the development of targeted therapies. In this review, we emphasize the role of antigen-presenting cells and MHC molecules in obese adipose tissue and the general contribution of the adaptive arm of the immune system in inflammation-induced insulin resistance.     

Obesity and inflammation

The prevalence of obesity has recently increased dramatically and has contributed to the increasing prevalence of various pathological conditions, including type 2 diabetes mellitus, nonalcoholic fatty liver disease, asthma, various types of cancer, cardiovascular and neurodegenerative diseases, and others. Accumulating evidence points to localized inflammation in adipose tissue, which, in turn, promotes systemic low-grade inflammation as a primary force contributing to the development of these pathologies. A better understanding of the underlying mechanisms behind obesity-induced adipose tissue inflammation is required to develop effective therapeutic or prophylactic strategies. This review is aimed to present the current knowledge of adipose tissue inflammation associated with obesity.     

Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance

There is increasing evidence showing that inflammation is an important pathogenic mediator of the development of obesity-induced insulin resistance. It is now generally accepted that tissue-resident immune cells play a major role in the regulation of this obesity-induced inflammation. The roles that adipose tissue (AT)-resident immune cells play have been particularly extensively studied. AT contains most types of immune cells and obesity increases their numbers and activation levels, particularly in AT macrophages (ATMs). Other pro-inflammatory cells found in AT include neutrophils, Th1 CD4 T cells, CD8 T cells, B cells, DCs, and mast cells. However, AT also contains anti-inflammatory cells that counter the pro-inflammatory immune cells that are responsible for the obesity-induced inflammation in this tissue. These anti-inflammatory cells include regulatory CD4 T cells (Tregs), Th2 CD4 T cells, and eosinophils. Hence, AT inflammation is shaped by the regulation of pro- and anti-inflammatory immune cell homeostasis, and obesity skews this balance towards a more pro-inflammatory status. Recent genetic studies revealed several molecules that participate in the development of obesity-induced inflammation and insulin resistance. In this review, the cellular and molecular players that participate in the regulation of obesity-induced inflammation and insulin resistance are discussed, with particular attention being placed on the roles of the cellular players in these pathogeneses. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.     

Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity

Overnutrition is associated with chronic inflammation in metabolic tissues. Whether metabolic inflammation compromises the neural regulatory systems and therefore promotes overnutrition-associated diseases remains unexplored. Here we show that a mediator of metabolic inflammation, IKKbeta/NF-kappaB, normally remains inactive although enriched in hypothalamic neurons. Overnutrition atypically activates hypothalamic IKKbeta/NF-kappaB at least in part through elevated endoplasmic reticulum stress in the hypothalamus. While forced activation of hypothalamic IKKbeta/NF-kappaB interrupts central insulin/leptin signaling and actions, site- or cell-specific suppression of IKKbeta either broadly across the brain or locally within the mediobasal hypothalamus, or specifically in hypothalamic AGRP neurons significantly protects against obesity and glucose intolerance. The molecular mechanisms involved include regulation by IKKbeta/NF-kappaB of SOCS3, a core inhibitor of insulin and leptin signaling. Our results show that the hypothalamic IKKbeta/NF-kappaB program is a general neural mechanism for energy imbalance underlying obesity and suggest that suppressing hypothalamic IKKbeta/NF-kappaB may represent a strategy to combat obesity and related diseases.     

The renin–angiotensin system in adipose tissue and its metabolic consequences during obesity

Obesity is a worldwide disease that is accompanied by several metabolic abnormalities such as hypertension, hyperglycemia and dyslipidemia. The accelerated adipose tissue growth and fat cell hypertrophy during the onset of obesity precedes adipocyte dysfunction. One of the features of adipocyte dysfunction is dysregulated adipokine secretion, which leads to an imbalance of pro-inflammatory, pro-atherogenic versus anti-inflammatory, insulin-sensitizing adipokines. The production of renin–angiotensin system (RAS) components by adipocytes is exacerbated during obesity, contributing to the systemic RAS and its consequences. Increased adipose tissue RAS has been described in various models of diet-induced obesity (DIO) including fructose and high-fat feeding. Up-regulation of the adipose RAS by DIO promotes inflammation, lipogenesis and reactive oxygen species generation and impairs insulin signaling, all of which worsen the adipose environment. Consequently, the increase of circulating RAS, for which adipose tissue is partially responsible, represents a link between hypertension, insulin resistance in diabetes and inflammation during obesity. However, other nutrients and food components such as soy protein attenuate adipose RAS, decrease adiposity, and improve adipocyte functionality. Here, we review the molecular mechanisms by which adipose RAS modulates systemic RAS and how it is enhanced in obesity, which will explain the simultaneous development of metabolic syndrome alterations. Finally, dietary interventions that prevent obesity and adipocyte dysfunction will maintain normal RAS concentrations and effects, thus preventing metabolic diseases that are associated with RAS enhancement.     

青蒿素类化合物与肥胖诱导的代谢性炎症

青蒿素类化合物是治疗疟疾的首选药物,具有高效、速效、低毒和安全的特点。近三十年来,大量研究结果证明青蒿素类化合物具有抗炎和免疫调节功能;这些研究主要集中于自身免疫性疾病,如类风湿性关节炎、全身性红斑狼疮、哮喘病和过敏反应等。最新研究表明,青蒿素类化合物可通过促进白色脂肪棕色化和增强棕色脂肪功能,起到预防肥胖的作用。作为肥胖过程中免疫细胞和炎症状况变化显著的脂肪组织,青蒿素类化合物是否参与其中的免疫炎症调节以及在该过程中发挥的潜在作用有待进一步实验的验证。本文对已有的青蒿素类化合物在抗炎和免疫调节方面的报道进行总结,并对青蒿素类化合物在改善肥胖诱导代谢性炎症方面的潜在应用进行展望。     

TLR4信号转导通路在肿瘤中的作用

慢性炎症与恶性肿瘤密切相关,Toll样受体4（TLR4）在肿瘤中的广泛表达提示其在慢性炎症致瘤机制中发挥重要作用。活化肿瘤细胞TLR4不仅促进肿瘤的生成和转移,而且参与肿瘤的免疫逃逸。另一方面,免疫佐剂又通过激活免疫细胞的TLR4信号产生抗肿瘤免疫。因此,TLR4在肿瘤中起着双刃剑的作用。     

Nod1-mediated lipolysis promotes diacylglycerol accumulation and successive inflammation via PKCδ-IRAK axis in adipocytes

Chronic inflammation contributes to obesity mediated metabolic disturbances, including insulin resistance. Obesity is associated with altered microbial load in metabolic tissues that can contribute to metabolic inflammation. Different bacterial components such as, LPS, peptidoglycans have been shown to underpin metabolic disturbances through interaction with host innate immune receptors. Activation of Nucleotide-binding oligomerization domain-containing protein 1 (Nod1) with specific peptidoglycan moieties promotes insulin resistance, inflammation and lipolysis in adipocytes. However, it was not clear how Nod1-mediated lipolysis and inflammation is linked. Here, we tested if Nod1-mediated lipolysis caused accumulation of lipid intermediates and promoted cell autonomous inflammation in adipocytes. We showed that Nod1-mediated lipolysis caused accumulation of diacylglycerol (DAG) and activation of PKCδ in 3T3-L1 adipocytes, which was prevented with a Nod1 inhibitor. Nod1-activated PKCδ caused downstream stimulation of IRAK1/4 and was associated with increased expression of proinflammatory cytokines such as, IL-1β, IL-18, IL-6, TNFα and MCP-1. Pharmacological inhibition or siRNA mediated knockdown of IRAK1/4 attenuated Nod1-mediated activation of NF-κB, JNK, and the expression of proinflammatory cytokines. These results reveal that Nod1-mediated lipolysis promoted accumulation of DAG, which engaged PKCδ and IRAK1/4 to augment inflammation in 3T3-L1 adipocytes.     

Ceramide kinase deficiency improves diet-induced obesity and insulin resistance

Ceramide kinase (CERK) is an enzyme that phosphorylates ceramide to produce ceramide 1-phosphate. Recently, evidence has emerged that CERK has a role in inflammatory signaling of immune cells. Since obesity is accompanied by chronic, low-grade inflammation, we examined whether CERK might be involved using CERK-null mice. We determined that CERK deficiency suppresses diet-induced increases in body weight, and improves glucose intolerance. Furthermore, we demonstrated that CERK deficiency attenuates MCP-1/CCR2 signaling in macrophages infiltrating the adipose tissue, resulting in the suppression of inflammation in adipocytes, which might otherwise lead to obesity and diabetes.     

Roles of lactoferrin on skin wound healing

Skin wound healing is a complex biological process that requires the regulation of different cell types, including immune cells, keratinocytes, fibroblasts, and endothelial cells. It consists of 5 stages: hemostasis, inflammation, granulation tissue formation, re-epithelialization, and wound remodeling. While inflammation is essential for successful wound healing, prolonged or excess inflammation can result in nonhealing chronic wounds. Lactoferrin, an iron-binding glycoprotein secreted from glandular epithelial cells into body fluids, promotes skin wound healing by enhancing the initial inflammatory phase. Lactoferrin also exhibits anti-inflammatory activity that neutralizes overabundant immune response. Accumulating evidence suggests that lactoferrin directly promotes both the formation of granulation tissue and re-epithelialization. Lactoferrin stimulates the proliferation and migration of fibroblasts and keratinocytes and enhances the synthesis of extracellular matrix components, such as collagen and hyaluronan. In an in vitro model of wound contraction, lactoferrin promoted fibroblast-mediated collagen gel contraction. These observations indicate that lactoferrin supports multiple biological processes involved in wound healing.     

Adipose tissues as an ancestral immune organ: site-specific change in obesity

Close relationships have been demonstrated between adipose tissue and the inflammatory/immune system. Furthermore, obesity is increasingly considered as a state of chronic inflammation. Cytofluorometric analysis reveals the presence of significant levels of lymphocytes in the stroma-vascular fraction of white adipose tissues. In epididymal (EPI) fat, lymphocytes display an "ancestral" immune system phenotype (up to 70% of natural killer (NK), gammadelta+ T and NKT cells among all lymphocytes) whereas the inguinal (ING) immune system presents more adaptive characteristics (high levels of alphabeta+ T and B cells). The percentage of NK cells in EPI fat was decreased in obese mice fed with a high-fat diet, whereas gammadelta positive cells were significantly increased in ING fat. These data support the notion that adipose tissue may elaborate immunological mechanisms to regulate its functions which might be altered in obesity.     

Deficiency of the leukotriene B4 receptor, BLT-1, protects against systemic insulin resistance in diet-induced obesity

Chronic inflammation is an underlying factor linking obesity with insulin resistance. Diet-induced obesity promotes an increase in circulating levels of inflammatory monocytes and their infiltration into expanding adipose tissue. Nevertheless, the endogenous pathways that trigger and sustain chronic low-grade inflammation in obesity are incompletely understood. In this study, we report that a high-fat diet selectively increases the circulating levels of CD11b(+) monocytes in wild-type mice that express leukotriene B(4) receptor, BLT-1, and that this increase is abolished in BLT-1-null mice. The accumulation of classically activated (M1) adipose tissue macrophages (ATMs) and the expression of proinflammatory cytokines and chemokines (i.e., IL-6 and Ccl2) was largely blunted in adipose tissue of obese BLT-1(-/-) mice, whereas the ratio of alternatively activated (M2) ATMs to M1 ATMs was increased. Obese BLT-1(-/-) mice were protected from systemic glucose and insulin intolerance and this was associated with a decrease in inflammation in adipose tissue and liver and a decrease in hepatic triglyceride accumulation. Deletion of BLT-1 prevented high fat-induced loss of insulin signaling in liver and skeletal muscle. These observations elucidate a novel role of chemoattractant receptor, BLT-1, in promoting monocyte trafficking to adipose tissue and promoting chronic inflammation in obesity and could lead to the identification of new therapeutic targets for treating insulin resistance in obesity.     

Role of NKG2D in Obesity-Induced Adipose Tissue Inflammation and Insulin Resistance

The early events that initiate inflammation in the adipose tissue during obesity are not well defined. It is unclear whether the recruitment of CD8 T cells to the adipose tissue during onset of obesity occurs through antigen-dependent or -independent processes. We have previously shown that interaction between NKG2D (natural-killer group 2, member D) and its ligand Rae-1ε is sufficient to recruit cytotoxic T lymphocytes to the pancreas and induce insulitis. Here, we tested whether NKG2D–NKG2D ligand interaction is also involved in obesity-induced adipose tissue inflammation and insulin resistance. We observed a significant induction of NKG2D ligand expression in the adipose tissue of obese mice, especially during the early stages of obesity. However, mice lacking NKG2D developed similar levels of insulin resistance and adipose tissue inflammation compared to control mice when placed on a high-fat diet. Moreover, overexpression of Rae-1ε in the adipose tissue did not increase immune cell infiltration to the adipose tissue either in the setting of a normal or high-fat diet. These results indicate that, unlike in the pancreas, NKG2D–NKG2D ligand interaction does not play a critical role in obesity-induced inflammation in the adipose tissue.     

Adipose tissue macrophage in immune regulation of metabolism

The prevalence of obesity and type 2 diabetes is escalating to an epidemic proportion worldwide.Obesity is known to be associated with a state of chronic,low-grade inflammation.Emerging lines of evidence have shown that both innate and adaptive immune responses play crucial roles in the control of metabolic homeostasis.Macrophages in adipose tissues are the essential effector cells in orchestrating metabolic inflammation,which is thought to promote the pathogenic progression of obesity and obesity-related disorders.Here we discuss our current understanding of the distinct modes of activation of adipose tissue macrophages,which can sense the metabolic cues and exert profound effects upon adipose homeostasis.Targeting macrophages in adipose tissues may provide new avenues for developing immunomodulation-based therapeutics against obesity and obesity-associated metabolic diseases.