综述:炎症小体信号通路的负调控

炎症小体(inflammasomes)活化后产生的IL-1β和IL-18等促炎因子对天然免疫和适应性免疫具有重要作用.炎症小体持续活化可引起促炎因子过度表达,导致慢性炎症和自身免疫疾病的发生.正常生理状态下,机体存在多种炎症小体负调机制,以维持免疫反应平衡.病理状态下,感染机体的病原微生物通过多种途径抑制炎症小体信号通路的活化及促炎因子的产生,以利于免疫逃逸.本文综述了机体和病原微生物对炎症小体信号通路的负调控机理.阐明炎症小体信号通路负调控机制将为感染性疾病及其他炎症小体相关炎症性疾病的治疗提供策略.     

炎症小体信号通路的负调控

炎症小体(inflammasomes)活化后产生的IL-1β和IL-18等促炎因子对天然免疫和适应性免疫具有重要作用.炎症小体持续活化可引起促炎因子过度表达,导致慢性炎症和自身免疫疾病的发生.正常生理状态下,机体存在多种炎症小体负调机制,以维持免疫反应平衡.病理状态下,感染机体的病原微生物通过多种途径抑制炎症小体信号通路的活化及促炎因子的产生,以利于免疫逃逸.本文综述了机体和病原微生物对炎症小体信号通路的负调控机理.阐明炎症小体信号通路负调控机制将为感染性疾病及其他炎症小体相关炎症性疾病的治疗提供策略.     

Immunity:肠道表皮细胞稳态调节新机制

正肠道微环境稳态的维持依赖于肠道寄生的微生物与表皮细胞,基质细胞以及免疫细胞的共同作用。肠道表皮细胞在细菌与粘膜层免疫细胞之间建立了物理与生化的"栅栏"。它能够通过分泌抗菌因子以及调节粘膜免疫反应来对肠道的微生物施加影响。肠道免疫稳态的紊乱会伴随许多炎性疾病的出现,包括克罗恩氏病以及溃疡性肠炎。目前引起肠道炎症反应的机制仍不清楚。在肠道炎性反应中,肿瘤坏死因子(TNF)扮演了十分重要的角色、。TNF与受体结合后,会激活转录因子NF-KB的表达,从而促进细胞的存     

NLRP3炎症体与肠道疾病

Nod样受体蛋白3(Nod-like receptor protein 3,NLRP3)炎症体是机体先天免疫的重要感受器,通过诱导炎症反应和细胞焦亡参与宿主免疫防御,并在维持肠道稳态方面发挥重要作用。近年来,NLRP3炎症体在放射性肠炎、炎症性肠病、结直肠癌和其他肠道疾病中的作用引起临床医生与科研人员的广泛关注。本文就NLRP3炎症体的激活机制和其在肠道疾病中的作用机制进行综述,旨在为临床治疗提供新的靶点与思路。     

NF-κB在溃疡性结肠炎中的作用

核因子NF-κB（Nuclear factor kappa-B,NF-κB）是一种多向性的转录因子,它参与多种炎症和免疫应答相关分子基因的表达,同时也参与调控细胞的增殖和分化。它在动脉粥样硬化、关节炎、哮喘、肿瘤等疾病的发展中都起了重要的作用。炎症是多种细胞及细胞因子参与的机体防御性反应,但严重或长期的炎症则会造成机体损伤。溃疡性结肠炎（UC）是一组以慢性、周期性炎症为特征的肠道疾病,长期、反复的肠道炎症不仅影响患者生活质量,而且增加了肠道纤维化及癌变的风险,而核因子NF-κB与炎症反应关系非常密切。本文就NF-κB的作用与UC的联系作一简要综述。     

NF-κB在溃疡性结肠炎中的作用

核因子NF-κB(Nuclear factor kappa-B,NF-κB)是一种多向性的转录因子,它参与多种炎症和免疫应答相关分子基因的表达,同时也参与调控细胞的增殖和分化。它在动脉粥样硬化、关节炎、哮喘、肿瘤等疾病的发展中都起了重要的作用。炎症是多种细胞及细胞因子参与的机体防御性反应,但严重或长期的炎症则会造成机体损伤。溃疡性结肠炎(UC)是一组以慢性、周期性炎症为特征的肠道疾病,长期、反复的肠道炎症不仅影响患者生活质量,而且增加了肠道纤维化及癌变的风险,而核因子NF-κB与炎症反应关系非常密切。本文就NF-κB的作用与UC的联系作一简要综述。     

病毒感染激活和抑制炎症小体的研究进展

促炎细胞因子白细胞介素1β(IL-1β)和白细胞介素18(IL-18)主要由巨噬细胞和树突细胞产生,是宿主针对各种侵入病原体产生先天免疫应答的重要介质。这些促炎细胞因子从病毒感染的细胞中分泌,被称为炎症小体的多蛋白复合物严格调控。根据炎症小体识别蛋白的种类,炎症小体主要分为两类,即核苷酸结合寡聚结构域样受体(NOD-like receptors,NLRs)和黑色素瘤缺乏因子2样受体(Absent in melanoma 2,AIM2)炎症小体。与其他宿主防御机制不同,炎症小体活化后,会诱导促炎细胞因子IL-1β、IL-18的成熟及分泌。适量的促炎细胞因子有利于控制病理性感染,但如果过量,则会对机体造成一定免疫损伤。本文主要对近几年有关病毒感染对炎症小体的激活和抑制机制进行了综述,总结分析了炎症小体在参与天然免疫反应及病毒感染致病过程中具有的重要作用。     

炎症小体在对抗微生物感染中的作用

炎症小体(inflammasomes)是由胞浆内模式识别受体(PRRs)参与组装的多蛋白复合物,是天然免疫系统的重要组成部分。炎症小体能够识别病原相关分子模式(PAMPs)或者宿主来源的危险信号分子(DAMPs),招募和激活促炎症蛋白酶Caspase-1。活化的Caspase-1切割IL-1β和IL-18的前体,产生相应的成熟细胞因子。炎症小体的活化还能够诱导细胞的炎症坏死(pyroptosis)。目前已经确定多种炎症小体参与了针对多种病原体的宿主防御反应,病原体也已经进化出多种相应的机制来抑制炎症小体的活化。该文总结了炎症小体在抗感染免疫研究领域的最新进展,重点讨论了炎症小体对细菌、病毒、真菌和寄生虫的识别,以及炎症小体的活化在宿主抗感染过程中所发挥的作用。     

树突状细胞与Toll受体研究新进展

树突状细胞是最强的抗原提呈细胞,在免疫系统中发挥着着重要作用。Toll样受体是表达在树突状细胞上的一种PRRs,主要功能是通过识别病原体微生物所携带的病原相关分子模式激活DC,使其分泌各种免疫调节细胞因子,从而启动免疫应答。在肠道免疫中TLR信号的激活为肠道提供保护作用。本文简述了树突状细胞的生物特性、不同亚型。重点阐述了Toll样受体在肠道免疫中的作用及益生菌对肠道Toll样受体表达的影响。     

肠道菌群与自身免疫性疾病研究进展

自身免疫性疾病是以机体自身反应性T细胞和B细胞过度活化,大量自身抗体产生为特点,并引起多器官多系统广泛损伤的慢性系统性多关节炎症性疾病。研究证实,特定的肠道菌群可通过特定的分子模式诱导产生多种炎性细胞及炎性因子从而调节肠黏膜屏障的完整性,影响黏膜免疫功能,引起免疫性炎症。深入了解两者之间的关系,对进一步研究自身免疫性疾病的病因及发病机制,优化治疗策略等具有重要的临床应用价值。本文主要对肠道菌群与类风湿性关节炎、系统性红斑狼疮、脊柱关节炎等自身免疫性疾病的关系做一简要综述。     

Mucosal defences against orally acquired protozoan parasites, emphasis on Toxoplasma gondii infections

Protozoan parasites that gain access to the host through the mucosal tissue of the alimentary tract may influence the development of intestinal inflammatory disorders. Despite the diversity of the extracellular and intracellular protozoan pathogens discussed in this review, our current understanding of the mechanisms involved in the immune response indicates that a common exuberant immune response to rid the host of these agents is elicited. This robust inflammatory response is orchestrated both by cells from parenchymatous origin such as intestinal epithelial cells and by cells from the haematopoietic system such as macrophages, dendritic cells and lymphocytes. This inflammatory immune response is controlled by a series of regulatory mechanisms in most species. When this balance is no longer evident, an inflammation of the intestine may occur, leading to acute gastritis and diarrhoea and that would add pathological effects to those because of the pathogen itself.     

斑马鱼食源性肠炎模型及其免疫细胞成像分析方法的建立

为了研究豆粕替代鱼粉对鱼类肠黏膜免疫的影响和建立缓解肠炎药物的筛选及功能性饲料添加剂的平台,研究采用固有免疫或适应性免疫细胞荧光标记的斑马鱼品系,通过50％的豆粕添加量替代鱼粉作为蛋白源,共设计了两组饲料,分别在幼鱼固有免疫或适应性免疫的发育阶段中饲喂荧光标记的斑马鱼,构建了斑马鱼豆粕诱导的肠炎模型,对构建的食源性肠炎...     

The regulation effect of AMPK in immune related diseases

AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a key role in energetic metabolism regulation. Metabolic changes in immune cells, such as dendritic cell (DC), macrophages, neutrophils and lymphocytes that participate in the signal directed programs that promote or inhibit immune mediated diseases, including cancer, atherosclerosis and inflammatory diseases. Multiple pathogenic mechanisms are involved in the initiation and progression of disease, and many pathways have been uncovered. The mechanistic overlap in the metabolic changes and inflammation could indicate that some of the targets they have are in common, whereas AMPK could be useful in treatment of both disorders. The insight into identification of AMPK responsible for specific immune regulation, anti-inflammatory actions and understanding of the underlying molecular mechanism will promote the generation of novel AMPK activators, and provide novel therapy strategy.     

Involvement of adenosine A2A receptors in engulfment-dependent apoptotic cell suppression of inflammation

Efficient execution of apoptotic cell death followed by efficient clearance mediated by professional macrophages is a key mechanism in maintaining tissue homeostasis. Removal of apoptotic cells usually involves three central elements: 1) attraction of phagocytes via soluble "find me" signals, 2) recognition and phagocytosis via cell surface-presenting "eat me" signals, and 3) suppression or initiation of inflammatory responses depending on additional innate immune stimuli. Suppression of inflammation involves both direct inhibition of proinflammatory cytokine production and release of anti-inflammatory factors, which all contribute to the resolution of inflammation. In the current study, using wild-type and adenosine A(2A) receptor (A2AR) null mice, we investigated whether A2ARs, known to mediate anti-inflammatory signals in macrophages, participate in the apoptotic cell-mediated immunosuppression. We found that macrophages engulfing apoptotic cells release adenosine in sufficient amount to trigger A2ARs, and simultaneously increase the expression of A2ARs, as a result of possible activation of liver X receptor and peroxisome proliferators activated receptor δ. In macrophages engulfing apoptotic cells, stimulation of A2ARs suppresses the NO-dependent formation of neutrophil migration factors, such as macrophage inflammatory protein-2, using the adenylate cyclase/protein kinase A pathway. As a result, loss of A2ARs results in elevated chemoattractant secretion. This was evident as pronounced neutrophil migration upon exposure of macrophages to apoptotic cells in an in vivo peritonitis model. Altogether, our data indicate that adenosine is one of the soluble mediators released by macrophages that mediate engulfment-dependent apoptotic cell suppression of inflammation.     

Impact of substance P on cellular immunity

Much evidence suggests a cross-talking between nerve fibers and the immunity system. The immunomodulation by substance P includes cell activation and proliferation of human cells, with cytokine and chemokine generation and release. Substance P was first isolated by Leeman et al. as an undecapeptide with important neurotransmitter-neuromodulator effects. In addition, substance P was shown to induce and mediate inflammation, angiogenesis, infections, intestinal mucosal immunity and stress. Substance P is able to activate several immune cells, such as CD4+ and CD8+ T lymphocytes, mast cells, NK cells and macrophages. In recent studies we have shown that substance P can activate interleukin-8, a CXC chemokine, demonstrating its involvement in immune cell chemoattraction. We believe that substance P is important in understanding the pathophysiology of inflammation.     

The dendritic cell niche in chronic obstructive pulmonary disease

The pulmonary innate immune system is heavily implicated in the perpetual airway inflammation and impaired host defense characterizing Chronic Obstructive Pulmonary Disease (COPD). The airways of patients suffering from COPD are infiltrated by various immune and inflammatory cells including macrophages, neutrophils, T lymphocytes, and dendritic cells. While the role of macrophages, neutrophils and T lymphocytes is well characterized, the contribution of dendritic cells to COPD pathogenesis is still the subject of emerging research. A paper by Botelho and colleagues in the current issue of Respiratory Research investigates the importance of dendritic cell recruitment in cigarette-smoke induced acute and chronic inflammation in mice. Dendritic cells of the healthy lung parenchyma and airways perform an important sentinel function and regulate immune homeostasis. During inflammatory responses the function and migration pattern of these cells is dramatically altered but the underlying mechanisms are incompletely understood. Botelho and colleagues demonstrate here the importance of IL-1R1/IL-1α related mechanisms including CCL20 production in cigarette-smoke induced recruitment of dendritic cells and T cell activation in the mouse lung.     

Natural Helicobacter infection modulates mouse intestinal muscularis macrophage responses

Helicobacter species are common laboratory pathogens which induce intestinal inflammation and disease in susceptible mice. Since in vitro studies indicate that Helicobacter products activate macrophages, we hypothesized that in vivo Helicobacter infection regulates the inflammatory response of intestinal muscularis macrophages from C57Bl/6 mice. Helicobacter hepaticus infection increased surface expression of macrophage markers F4/80, CD11b and MHC-II within whole intestinal muscle mounts. However, constitutive cytokine and chemokine production by macrophages isolated from infected mice significantly decreased compared to macrophages from uninfected mice despite no detectable bacterial products in the cultures. In addition, muscularis macrophages from infected mice up-regulated FIZZ-1 and SK-1 gene expression, suggesting the macrophages had an anti-inflammatory phenotype. Corresponding with increased anti-inflammatory gene expression, macrophages from infected mice were more phagocytic but did not produce cytokines after stimulation with LPS and IFN-γ or immune complexes and IL-4. Therefore, the presence of Helicobacter infection matures intestinal muscularis macrophages, modulating the constitutive macrophage response to become more anti-inflammatory and resistant to secondary stimulation.     

Bone marrow mononuclear cells for joint therapy: The role of macrophages in inflammation resolution and tissue repair

Osteoarthritis (OA) is the most prevalent joint disease causing major disability and medical expenditures. Synovitis is a central feature of OA and is primarily driven by macrophages. Synovial macrophages not only drive inflammation but also its resolution, through a coordinated, simultaneous expression of pro- and anti-inflammatory mechanisms that are essential to counteract damage and recover homeostasis. Current OA therapies are largely based on anti-inflammatory principles and therefore block pro-inflammatory mechanisms such as prostaglandin E₂ and Nuclear factor-kappa B signaling pathways. However, such mechanisms are also innately required for mounting a pro-resolving response, and their blockage often results in chronic low-grade inflammation. Following minor injury, macrophages shield the damaged area and drive tissue repair. If the damage is more extensive, macrophages incite inflammation recruiting more macrophages from the bone marrow to maximize tissue repair and ultimately resolve inflammation. However, sustained damage and inflammation often overwhelms pro-resolving mechanisms of synovial macrophages leading to the chronic inflammation and related tissue degeneration observed in OA. Recently, experimental and clinical studies have shown that joint injection with autologous bone marrow mononuclear cells replenishes inflamed joints with macrophage and hematopoietic progenitors, enhancing mechanisms of inflammation resolution, providing remarkable and long-lasting effects. Besides creating an ideal environment for resolution with high concentrations of interleukin-10 and anabolic growth factors, macrophage progenitors also have a direct role in tissue repair. Macrophages constitute a large part of the early granulation tissue, and further transdifferentiate from myeloid into a mesenchymal phenotype. These cells, characterized as fibrocytes, are essential for repairing osteochondral defects. Ongoing “omics” studies focused on identifying key drivers of macrophage-mediated resolution of joint inflammation and those required for efficient osteochondral repair, have the potential to uncover ways for developing engineered macrophages or off-the-shelf pro-resolving therapies that can benefit patients suffering from many types of arthropaties, not only OA.     

禽沙门菌诱导宿主免疫应答的特性

沙门菌病(Salmonellosis)是全世界最普遍的食源性疾病之一,不仅对养殖业造成经济损失,还对人类安全构成威胁。禽沙门菌感染肠道后,可诱导肠上皮细胞表达多种TLRs和炎症反应的发生,在分泌的趋化因子作用下免疫效应细胞迁移到感染部位。细菌通过肠上皮细胞屏障后被巨噬细胞或树突状细胞吞噬,其中巨噬细胞是沙门菌的主要定殖场所。天然免疫系统将抗原递呈给淋巴细胞后,机体能够在2–3周内通过以Th1为主的免疫应答清除在肠道和深层组织中的沙门菌。而宿主特异性血清型鸡白痢沙门菌从肠道侵入后,在肝脾和其他器官中定殖,进而引发全身感染。早期感染阶段不会引起肠道炎症反应,主要诱导以Th2为主的免疫应答,而Th1型应答相对较弱,有利于鸡白痢沙门菌在机体内的持续存在和感染。本文围绕禽沙门菌的致病机理和免疫应答特性进行阐述,尤其对鸡白痢沙门菌免疫逃逸和持续载菌的特性进行深入分析,为禽沙门菌病的防控提供新靶标和新见解。     

The role of nitric oxide in inflammatory reactions

Nitric oxide (NO) was initially described as a physiological mediator of endothelial cell relaxation, an important role in hypotension. NO is an intercellular messenger that has been recognized as one of the most versatile players in the immune system. Cells of the innate immune system--macrophages, neutrophils and natural killer cells--use pattern recognition receptors to recognize the molecular patterns associated with pathogens. Activated macrophages then inhibit pathogen replication by releasing a variety of effector molecules, including NO. In addition to macrophages, a large number of other immune-system cells produce and respond to NO. Thus, NO is important as a toxic defense molecule against infectious organisms. It also regulates the functional activity, growth and death of many immune and inflammatory cell types including macrophages, T lymphocytes, antigen-presenting cells, mast cells, neutrophils and natural killer cells. However, the role of NO in nonspecific and specific immunity in vivo and in immunologically mediated diseases and inflammation is poorly understood. This Minireview will discuss the role of NO in immune response and inflammation, and its mechanisms of action in these processes.