人类心外脂肪组织与肥胖患者心血管疾病的关系

近年来,越来越多的证据支持心外膜脂肪组织在结构及功能方面对心血管有着重要的影响,临床实践及动物实验也发现心外膜脂肪组织在心血管疾病的发生中扮演着一定的角色。早期通过影像学检查方法对心外膜脂肪组织进行评估,对避免后续心血管疾病的发生具有一定的临床实践意义。     

Composition of fatty acids in a high-fat diet affects adipose tissue inflammation by inducing calreticulin on adipocytes and activating group 1 innate lymphoid cells

Obesity-induced adipose tissue inflammation plays a critical role in the development of metabolic diseases. For example, NK1.1⁺ group 1 innate lymphoid cells (G1-ILCs) in adipose tissues are activated in the early stages of inflammation in response to a high-fat diet (HFD). In this study, we examined whether the composition of fatty acids affected adipose inflammatory responses induced by an HFD. Mice were fed a stearic acid (C18:0)-rich HFD (HFD-S) or a linoleic acid (C18:2)-rich HFD (HFD-L). HFD-L-fed mice showed significant obesity compared with HFD-S-fed mice. Visceral and subcutaneous fat pads were enlarged and contained more NK1.1⁺KLRG1⁺ cells, indicating that G1-ILCs were activated in HFD-L-fed mice. We examined early changes in adipose tissues during the first week of HFD intake, and found that mice fed HFD-L showed increased levels of NK1.1⁺CD11b⁺KLRG1⁺ cells in adipose tissues. In adipose tissue culture, addition of 4-hydroxynonenal, the most frequent product of lipid peroxidation derived from unsaturated fatty acids, induced NK1.1⁺CD11b⁺CD27⁻ cells. We found that calreticulin, a ligand for the NK activating receptor, was induced on the surface of adipocytes after exposure to 4-hydroxynonenal or a 1-week feeding with HFD-L. Thus, excess fatty acid intake and the activation of G1-ILCs initiate and/or modify adipose inflammation.     

The Therapeutic Effect of Human Adult Stem Cells Derived from Adipose Tissue in Endotoxemic Rat Model

Excessive systemic inflammation following sepsis, trauma or burn could lead to multi-organ damage and death. Bone marrow stromal cells (BMSCs), commonly referred to as mesenchymal stem cells (MSCs), has been studied in several immune-associated diseases in human and animal by modulating the inflammatory response. Adipose tissue derived mesenchymal stem cells (ATSCs), which can be obtained more easily, compared with BMSCs, has emerged as an attractive alternative MSCs source for cell therapy. We investigated the therapeutic effects of human ATSCs (hATSCs) in endotoxemic rat model and their capacity to modulate the inflammatory response. Endotoxemia was induced with Lipopolysaccaride intravenously injection (LPS, 10mg/kg). Animals were divided into the following three groups: (1) saline + saline (n=5), (2) LPS + saline (n=5) and (3) LPS + hATSCs (2x10⁶) (n=5). The administration of LPS caused a consistent systemic inflammatory responses, increased concentrations of the pro-inflammatory cytokines that have an important role in sepsis. Treatment of endotoxemia with hATSCs decreased the level of inflammatory cytokines both in serum and in the lung, reduced inflammatory changes in the lung, prevented apoptosis in the kidney and improved multi-organ injury. In conclusion, our data demonstrates that hATSCs regulate the immue/inflammatory responses and improve multi-organ injury and they could be attractive candidates for cell therapy to treat endotoxemia.     

The Role of Pancreatic Infiltrating Innate Immune Cells in Acute Pancreatitis

Acute pancreatitis (AP) is a leading cause of gastrointestinal-related hospital admissions with significant morbidity and mortality. Although the underlying pathophysiology of AP is rather complex, which greatly limits the treatment options, more and more studies have revealed that infiltrating immune cells play a critical role in the pathogenesis of AP and determine disease severity. Thus, immunomodulatory therapy targeting immune cells and related inflammatory mediators is expected to be a novel treatment modality for AP which may improve the prognosis of patients. Cells of the innate immune system, including macrophages, neutrophils, dendritic cells, and mast cells, represent the majority of infiltrating cells during AP. In this review, an overview of different populations of innate immune cells and their role during AP will be discussed, with a special focus on neutrophils and macrophages.     

Adipose tissue spexin in physical exercise and age-associated diseases

It is known that a strong association exists between a suboptimal lifestyle (physical inactivity and sedentary behavior and/or high calorie diet) and increased propensity of developing age-associated diseases, such as obesity and T2DM. Physical exercise can alleviate obesity-induced insulin resistance and T2DM, however, the precise mechanism for this outcome is not fully understood. The endocrine disorder of adipose tissue in obesity plays a critical role in the development of insulin resistance. In this regard, spexin has been recently described as an adipokine that plays an important role in the pathophysiology of obesity-induced insulin resistance and T2DM. In obese states, expression of adipose tissue spexin is reduced, inducing the adipose tissue and skeletal muscle more susceptible to insulin resistance. Emerging evidences point out that exercise can increase spexin expression. In return, spexin could exert the exercise-protective roles to ameliorate insulin resistance, suggesting that spexin is a potential mediator for exercise to ameliorate obesity-induced insulin resistance and T2DM, namely, the beneficial effect of exercise on insulin sensitivity is at least partly mediated by spexin. This review summarizes our and others’ recent studies regarding the effects of obesity on adipose tissue spexin induction, along with the potential effect of exercise on this response in obese context, and provides a new insight into the multivariate relationship among exercise, spexin and T2DM. It should be therefore taken into account that a combination of spexin and exercise training is an effective therapeutic strategy for age-associated diseases.     

Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction

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Adipose tissue at the nexus of systemic and cellular immunometabolism

At the simplest interpretation of the word, Immunometabolism describes the intersection of the fields of immunology and metabolism. With rapidly growing interest in this field, the term has expanded, and now encompasses a variety of concepts and definitions shaped by an individual’s scientific area of expertise, cell-type and tissue of interest, and biological approach. One scientist may be interested in investigating the intrinsic metabolic checkpoints that drive a M1 versus M2 macrophage response, while another may be interested in how macrophages affect systemic metabolism during obesity. Although both interests have very different foci, they both reflect the current interests in immunometabolism and studies over the last decade have uncovered new metabolic nodes that dictate the course of effector fate within cells, as well as an unexpected role for the immune system in controlling systemic metabolism. Thus, immunometabolism is at the frontier for many novel therapeutic targets to control both cell intrinsic and whole body metabolism in many diseases including cancer, diabetes, obesity, and sepsis among others. In this review, we hope to break down the word immunometabolism into two main themes: whole-body metabolism and cellular bioenergetics. In each instance we will focus on the adipose tissue and its resident immune cells to illustrate recent advances in both sectors of immunometabolism.     

Mucosal Immune System in Health and Disease

The mucosal immune system is characterized predominantly by the secretory antibody response and gut-associated lymphoid tissue, cellular part of the mucosal immune system. The secretory antibody system depends on local production and selective epithelial transport of secretory IgA and IgM. Furthermore, secretory antibodies and interactions between the intestinal epithelium and T cells are involved in the mucosal down-regulation of the systemic immune system. Neuropeptides play a crucial role in the regulation of mucosal immune responses. It is possible that impairment of the mucosal immune response contribu tes to the pathogenesis of various intestinal diseases, such as inflammatory bowel disease. Until recently, however, mucosal immunity received relatively little attention from both basic and clinical scientists. Further research on mucosal immunity seems to have promise in helping to provide new understanding of the immune mechanisms and pathogenesis of several gastrointestinal and systemic diseases.     

Effects of Ang II Receptor Blocker Irbesartan on Adipose Tissue Function in Mice with Metabolic Disorders

Recent studies indicate that the functional renin-angiotensin system (RAS) exists in the adipose tissue. The adipose tissue RAS is proposed in the pathophysiology of metabolic disorders. In the present study, we examined therapeutic effects of irbesartan, an angiotensin II (Ang II) type 1 receptor (AT1R)-specific blocker, in genetically obese diabetic KKAy mice, a model of human metabolic disorders without any dietary loading, with our focus on the analysis on possible effect of irbesartan on the adipose tissue. The treatment with irbesartan significantly lowered systolic blood pressure with a concomitant decrease in body weight in KKAy mice. In addition, irbesartan significantly decreased the adipose leptin mRNA expression and tended to decrease IL-6 mRNA expression in the adipose tissue of KKAy mice. Furthermore irbesartan preserved the adipose gene expression of AT1R-associated protein (ATRAP), an endogenous inhibitory molecule of tissue AT1R signaling, with a concomitant tendency of up-regulation of adipose tissue ATRAP/AT1R ratio. Collectively, these results suggest that the irbesartan-induced beneficial suppressive effect on the leptin-IL-6 axis in the adipose tissue in KKAy mice is partly mediated by a trend of up-regulation of the adipose ATRAP/AT1R ratio as one of pleiotropic effects of irbesartan.     

New Adipose Tissue Formation by Human Adipose-Derived Stem Cells with Hyaluronic Acid Gel in Immunodeficient Mice

Background: Currently available injectable fillers have demonstrated limited durability. This report proposes the in vitro culture of human adipose-derived stem cells (hASCs) on hyaluronic acid (HA) gel for in vivo growth of de novo adipose tissue.Methods: For in vitro studies, hASCs were isolated from human adipose tissue and were confirmed by multi-lineage differentiation and flow cytometry. hASCs were cultured on HA gel. The effectiveness of cell attachment and proliferation on HA gel was surveyed by inverted light microscopy. For in vivo studies, HA gel containing hASCs, hASCs without HA gel, HA gel alone were allocated and subcutaneously injected into the subcutaneous pocket in the back of nude mice (n=6) in each group. At eight weeks post-injection, the implants were harvested for histological examination by hematoxylin and eosin (H&E) stain, Oil-Red O stain and immunohistochemical staining. The human-specific Alu gene was examined.Results: hASCs were well attachment and proliferation on the HA gel. In vivo grafts showed well-organized new adipose tissue on the HA gel by histologic examination and Oil-Red O stain. Analysis of neo-adipose tissues by PCR revealed the presence of the Alu gene. This study demonstrated not only the successful culture of hASCs on HA gel, but also their full proliferation and differentiation into adipose tissue.Conclusions: The efficacy of injected filler could be permanent since the reduction of the volume of the HA gel after bioabsorption could be replaced by new adipose tissue generated by hASCs. This is a promising approach for developing long lasting soft tissue filler.     

脂肪干细胞在软骨组织工程中的研究进展

近年来脂肪干细胞（ADSC）的成软骨潜能备受瞩目,其作为种子细胞在软骨组织工程应用方面前景广阔,然而目前并没有一种高效的诱导方法被世界公认。外源性生长因子、基因修饰、共培养、生长因子与共培养联合、支架材料等多种手段均可诱导ADSC向软骨细胞方向分化,但各方法的优劣,诱导分化时的信号通路及新生软骨的性状并未见详细的分析和讨论。文中介绍了以上多种诱导方法的研究现状及问题,并讨论了化学因素、供体年龄、组织获取部位等对其的影响,以期为ADSC的临床应用提供一定的理论参考。     

Metabolic mediators determine the association of antinuclear antibody subtypes with specific clinical symptoms in systemic sclerosis

PurposeThe aim of this study was to investigate the possible link between different types of systemic sclerosis-specific antinuclear antibodies, adipokines and endothelial molecules which were recently found to have a pathogenic significance in systemic sclerosis.Materials/methodsSerum concentration of adiponectin, resistin, leptin, endothelin-1, fractalkine and galectin-3 were determined in the sera of patients with systemic sclerosis (n ​= ​100) and healthy controls (n ​= ​20) using ELISA.ResultsThe following associations between antinuclear antibodies and increased serum concentrations were identified: anticentromere antibodies with endothelin-1 (p ​< ​0.0001; mean level in patients 2.21 vs control group 1.31 ​pg/ml), anti-topoisomerase I antibodies with fractalkine (p ​< ​0.0001; 3.68 vs 1.68 ​ng/ml) and galectin-3 (p ​= ​0.0010, 6.39 vs 3.26 ​ng/ml). Anti-RNA polymerase III antibodies were associated with increased resistin (p ​< ​0.0001; 15.13 vs 8.54 ​ng/ml) and decreased adiponectin (p ​< ​0.0001; 2894 vs 8847 ​ng/ml).ConclusionIn systemic sclerosis metabolic and vascular factors may serve as mediators between immunological abnormalities and non-immune driven clinical symptoms.     

人脂肪干细胞与VEGF-PLGA纳米微球缓释系统构建工程化脂肪组织的相关研究

目的 探讨缓释血管内皮生长因子复合支架与脂肪干细胞构建工程化脂肪的可行性。方法 制备VEGF-PLGA纳米微球缓释支架,检测支架释放 VEGF 浓度,体外提取培养 ADSCs,检测复合支架对 ASC 生长增殖的影响。将复合支架和ADSCs植入裸小鼠背部,8 周后切取植入物称重,组织切片HE染色,评估效果。结果 VEGF-PLGA纳米微球缓释复合支架能连续 12 d释放较高浓度的VEGF,对 ADSCs的生长增殖无影响。动物实验结果显示复合支架与ADSCs共移植能显著提高脂肪组织的形成,增加血管的生成（P＜0.01）,减少组织坏死。结论 VEGF-PLGA纳米微球缓释系统具有良好的生物安全性,其与ADSCs共移植构建工程化脂肪组织具有一定的可行性。     

肿瘤微环境中免疫细胞与肿瘤逃逸

肿瘤微环境是肿瘤细胞赖以生存和发展的内环境,肿瘤免疫逃逸机制与肿瘤微环境密切相关。文章综述了肿瘤微环境中的免疫细胞,如调节性T细胞、骨髓来源的抑制性细胞、选择性活化的巨噬细胞及功能受损的树突状细胞对肿瘤免疫逃逸的作用,以及如何逆转这种肿瘤微环境的免疫治疗策略。     

Innate immunity and chronic immune activation in HCV/HIV-1 co-infection

Innate immune responses are critical in the defense against viral infections. NK cells, myeloid and plasmacytoid dendritic cells, and invariant CD1d-restricted NKT cells mediate both effector and regulatory functions in this early immune response. In chronic uncontrolled viral infections such as HCV and HIV-1, these essential immune functions are compromised and can become a double edged sword contributing to the immunopathogenesis of viral disease. In particular, recent findings indicate that innate immune responses play a central role in the chronic immune activation which is a primary driver of HIV-1 disease progression. HCV/HIV-1 co-infection is affecting millions of people and is associated with faster viral disease progression. Here, we review the role of innate immunity and chronic immune activation in HCV and HIV-1 infection, and discuss how mechanisms of innate immunity may influence protection as well as immunopathogenesis in the HCV/HIV-1 co-infected human host.     

肥大细胞在脂肪组织中的生理与病理作用

脂肪组织可分为白色脂肪组织(white adipose tissue,WAT)与棕色脂肪组织(brown adipose tissue, BAT).WAT行使能量储存功能,将人体多余的能量以化学能形式储存,而BAT则具有产热功能,在寒冷等刺激下将化学能转化为热能,以维持体温.脂肪组织同时还具有内分泌功能,可分泌多种激素...     

Innate activation of human neutrophils and neutrophil-like cells by the pro-inflammatory bacterial metabolite ADP-heptose and Helicobacter pylori

Lipopolysaccharide inner core heptose metabolites, including ADP-heptose, play a substantial role in the activation of cell-autonomous innate immune responses in eukaryotic cells, via the ALPK1-TIFA signaling pathway, as demonstrated for various pathogenic bacteria. The important role of LPS heptose metabolites during Helicobacter pylori infection of the human gastric niche has been demonstrated for gastric epithelial cells and macrophages, while the role of heptose metabolites on human neutrophils has not been investigated. In this study, we aimed to gain a better understanding of the activation potential of bacterial heptose metabolites for human neutrophil cells. To do so, we used pure ADP-heptose and, as a bacterial model, H. pylori, which can transport heptose metabolites into the human host cell via the Cag Type 4 Secretion System (CagT4SS). Main questions were how bacterial heptose metabolites impact on the pro-inflammatory activation, alone and in the bacterial context, and how they influence maturation of human neutrophils. Results of the present study demonstrated that neutrophils respond with high sensitivity to pure heptose metabolites, and that global regulation networks and neutrophil maturation are influenced by heptose exposure. Furthermore, activation of human neutrophils by live H. pylori is strongly impacted by the presence of LPS heptose metabolites and the functionality of its CagT4SS. Similar activities were determined in cell culture neutrophils of different maturation states and in human primary neutrophils. In conclusion, we demonstrated that specific heptose metabolites or bacteria producing heptoses exhibit a strong activity on cell-autonomous innate responses of human neutrophils.     

Reduction in CD16/CD56 and CD16/CD3/CD56 Natural Killer Cells in Coronary Artery Disease

Background: Natural killer (NK) cells are the potential modulators of inflammatory reactions that exert several unique biological effects and could lead to future adverse events of coronary artery disease (CAD).

Hypothesis: The purpose of this study was to find out the possible association of modulation in NK cell, TNK cells, T cells, B cells, and tumor necrosis factor alpha (TNF-α) in CAD patients and various forms of myocardial infarction.

Methods: The present study included total 190 subjects (98 confirmed CAD patients both men and women and 92 healthy control individuals). Serum concentration of TNF-α was measured by ELISA method. For the measurement of various immune cells, viz., NK cell, TNK cells, T cells, and B cells, flow-cytometric analysis was performed.

Results: A significant reduction by 15% (P < 0.001) in CD16/CD56 NK cells was observed in CAD patients. Moreover, non-ST segment elevation myocardial infarction (NSTEMI), ST segment elevation myocardial infarction (STEMI), unstable angina (UA), and combined UA + NSTEMI group also showed a significant decline in NK cells compared with control individuals. CD16/CD56/CD3 TNK cells showed a significant reduction in CAD, NSTEMI, STEMI, and UA categories. However, UA + NSTEMI group did not show any significant change in TNK cells. On the other hand, the level of TNF-α was found to be significantly elevated in CAD, STEMI, and UA groups. NSTEMI and combined UA + NSTEMI group did not show any significant change in TNF-α level.

Conclusion: Current study provides an insight toward the association of immune cells and inflammation with CAD.     

mTORC1 inhibition with rapamycin exacerbates adipose tissue inflammation in obese mice and dissociates macrophage phenotype from function

Genetic- and diet-induced obesity and insulin resistance are associated with an increase in mechanistic target of rapamycin complex (mTORC) 1 activity in adipose tissue. We investigated herein the effects of pharmacological mTORC1 inhibition in the development of adipose tissue inflammation induced by high-fat diet (HFD) feeding, as well as in the polarization, metabolism and function of bone marrow-derived macrophages (BMDM). For this, C57BL/6J mice fed with a standard chow diet or a HFD (60% of calories from fat) and treated with either vehicle (0.1% Me₂SO, 0.2% methylcellulose) or rapamycin (2 mg/ kg/ day, gavage) during 30 days were evaluated for body weight, adiposity, glucose tolerance and adipose tissue inflammation. Although rapamycin did not affect the increase in body weight and adiposity, it exacerbated the glucose intolerance and adipose tissue inflammation induced by HFD feeding, as evidenced by the increased adipose tissue percentage of M1 macrophages, naive and activated cytotoxic T lymphocytes, and mRNA levels of proinflammatory molecules, such as TNF-α, IL-6 and MCP-1. In BMDM in vitro, pharmacological mTORC1 inhibition induced phosphorylation of NFκB p65 and spontaneous polarization of macrophages to a proinflammatory M1 profile, while it impaired M2 polarization induced by IL-4 + IL-13, glycolysis and phagocytosis. Altogether, these findings indicate that mTORC1 activity is an important determinant of adipose tissue inflammatory profile and macrophage plasticity, metabolism and function.