Biology and signal transduction pathways of the Lymphotoxin-αβ/LTβR system

This review focuses on the biological functions and signalling pathways activated by Lymphotoxin α (LTα)/Lymphotoxin β (LTβ) and their receptor LTβR. Genetic mouse models shed light on crucial roles for LT/LTβR to build and to maintain the architecture of lymphoid organs and to ensure an adapted immune response against invading pathogens. However, chronic inflammation, autoimmunity, cell death or cancer development are disorders that occur when the LT/LTβR system is twisted. Biological inhibitors, such as antagonist antibodies or decoy receptors, have been developed and used in clinical trials for diseases associated to the LT/LTβR system. Recent progress in the understanding of cellular trafficking and NF-κB signalling pathways downstream of LTα/LTβ may bring new opportunities to develop therapeutics that target the pathological functions of these cytokines.     

Signaling pathways bridging microbial-triggered inflammation and cancer

Microbial-triggered inflammation protects against pathogens and yet can paradoxically cause considerable secondary damage to host tissues that can result in tissue fibrosis and carcinogenesis, if persistent. In addition to classical pathogens, gut microbiota bacteria, i.e. a group of mutualistic microorganisms permanently inhabiting the gastrointestinal tract and which plays a key role in digestion, immunity, and cancer prevention, can induce inflammation-associated cancer following the alterations of their microenvironment. Emerging experimental evidence indicates that microbiota members like Escherichia coli and several other genotoxic and mutagenic pathogens can cause DNA damage in various cell types. In addition, the inflammatory response induced by chronic infections with pathogens like the microbiota members Helicobacter spp., which have been associated with liver, colorectal, cervical cancers and lymphoma, for instance, can also trigger carcinogenic processes. A microenvironment including active immune cells releasing high amounts of inflammatory signaling molecules can favor the carcinogenic transformation of host cells. Pivotal molecules released during immune response such as the macrophage migration inhibitory factor (MMIF) and the reactive oxygen and nitrogen species' products superoxide and peroxynitrite, can further damage DNA and cause the accumulation of oncogenic mutations, whereas pro-inflammatory cytokines, adhesion molecules, and growth factors may create a microenvironment promoting neoplastic cell survival and proliferation. Recent findings on the implication of inflammatory signaling pathways in microbial-triggered carcinogenesis as well as the possible role of microbiota modulation in cancer prevention are herein summarized and discussed.     

Regulation of human neutrophil oxidative burst by pro- and anti-inflammatory cytokines

Human polymorphonuclear neutrophils play a key role in host defenses against invading microorganisms. In response to a variety of stimuli, neutrophils release large quantities of superoxide anion (O2.-) in a phenomenon known as the respiratory burst. O2.- is the precursor of potent oxidants, which are essential for bacterial killing and also potentiate inflammatory reactions. Regulation of this production is therefore critical to kill pathogens without inducing tissue injury. Neutrophil production of O2.- is dependent on the respiratory burst oxidase, or NADPH oxidase, a multicomponent enzyme system that catalyzes NADPH-dependent reduction of oxygen to O2.-. NADPH oxidase is activated and regulated by various neutrophil stimuli at infectious or inflammatory sites. Proinflammatory cytokines such as GM-CSF, TNF and IL-8 modulate NADPH oxidase activity through a priming phenomenon. These cytokines induce a very weak oxidative response by PMN but strongly enhance neutrophil release of reactive oxygen species on exposure to a secondary applied stimulus such as bacterial N-formyl peptides. Priming phenomena are involved in normal innate immune defense and in some inflammatory diseases. The mechanisms underlying the priming process are poorly understood, although some studies have suggested that priming with various agonists is regulated at the receptor and post-receptor levels. Resolution of inflammation involves desensitization phenomena and cytokines are involved in this process by various mechanisms. A better understanding of phenomena involved in the regulation of NADPH oxidase could help to develop novel therapeutic agents for inflammatory diseases involving abnormal neutrophil superoxide production.     

Interaction of dendritic cells with mycobacteria: where the action starts

Dendritic cells (DC) are the major antigen-presenting cells in the induction of cellular responses to intracellular pathogens, such as mycobacteria. Recent studies have shown that they also play a critical role in the regulation of immune responses. The interaction of DC with microbial antigens may be the controlling factor in the development of a Th1-orientated protective immunity. Analysis of the innate response of DC to mycobacteria and the involvement of the DC receptors in antigen recognition have highlighted the pivotal role of these cells in T-cell activation. Mycobacteria-infected DC have an enhanced capacity to release pro-inflammatory cytokines and chemokines and are potent inducers of interferon-gamma-producing cells in vivo. Therefore, DC manipulation for maximal antigen presentation and Th1 cytokine production may form the basis of a new generation of vaccines, with improved efficacy against mycobacterial infections.     

Caspase-1-processed IL-1 family cytokines play a vital role in driving innate IL-17

The interleukin (IL)-1 cyokine family plays a vital role in inflammatory responses during infection and in autoimmune diseases. The pro-inflammatory cytokines, IL-1β and IL-18 are members of the IL-1 family that require cleavage by caspase-1 in the inflammasome to generate the mature active cytokines. Cells of the innate immune system, including γδ T cells and invariant natural killer T (iNKT) cells respond rapidly to invading pathogens by producing inflammatory cytokines, such as IFN-γ and IL-17. IL-1β or IL-18 in combination with IL-23 can induce IL-17 production by γδ T cells without T cell receptor (TCR) engagement. IL-1β and IL-23 can also synergize to induce IL-17 production by iNKT cells. Furthermore, CD4+ αβ effector memory T cells secrete IL-17 in response to IL-23 in combination with either IL-1β or IL-18, in the absence of any TCR stimulation. The early IL-17 produced by innate cells induces recruitment of neutrophils to the site of infection, stimulates local epithelial cells to secrete anti-microbial proteins, such as lipocalins and calgranulins, induces production of structural proteins important in tight junction stability, and promotes production of matrix metalloproteinases. Caspase-1 processed IL-1 family cytokines therefore play a vital role in the innate immune response and induction of IL-17 from innate immune cells which functions to fight infections and promote autoimmunity.     

Inactivation of inflammasomes by pathogens regulates inflammation

Inflammatory response is initiated and sustained by the action of quintessential pro-inflammatory cytokines of immune system namely IL-1β and IL-18. The maturation process of those cytokines is ensured by caspase-1 enzymatic activity, that is in turn is tightly controlled by multiprotein complexes called inflammasomes. Inflammasomes are activated in cells of innate immune system in response to recognition of conservative parts of microbes (pathogen-associated molecular patterns) or by sensing molecular signs of tissue damage (damage-associated molecular patterns). Inflammasome activation apart of cytokines secretion leads to pro-inflammatory cell death, so-called pyroptosis. That culminates in release of cytoplasmatic content of cells including cytokines and alarmins that boost immune response against pathogens, as well as pyroptosis destroys replicative niches of intracellular pathogens. During co-evolution with the host, bacterial and viral pathogens developed a range of molecular inhibitors targeting each step of inflammasome activation. In current review, we will discuss the latest knowledge of inflammasomes’ signaling pathways and tricks that pathogens use to avoid immune recognition and clearance. Our better understanding of inflammasome inhibition by pathogens can lead to better therapeutic approaches for the treatment of infectious diseases.     

Chemokines and chemokine receptors in infectious diseases

Today, 10 years after the discovery of IL-8, chemokines (chemotactic cytokines) are seen as the stimuli that largely control leucocyte migration. Chemokines are low molecular weight chemoattractant cytokines secreted by a variety of cells, including leucocytes, epithelial cells, endothelial cells, fibroblasts and numerous other cell types. They are produced in response to exogenous stimuli, such as viruses and bacterial LPS, and endogenous stimuli, such as IL-1, TNF and IFN. These factors mediate chemotaxis and leucocyte activation. They also regulate leucocyte extravasation from the blood and/or lymph vessel luminal surface to the tissue space, the site of inflammation. There is no doubt that chemokines and chemokine receptors are critical for defence against infectious pathogens. It is also clear that these pathogens have evolved to accommodate the workings of the host immune system. Survival of these infectious agents appears dependent upon strategies that can evade, suppress, counteract or otherwise confound the constellation of host responses to invading pathogens. In this regard, the chemokines and their receptors are a major target. Reviewed in the present paper are several examples in which microbial pathogens have usurped the mammalian chemokine system to subvert the host immune response.     

Bioactive dietary peptides and amino acids in inflammatory bowel disease

Inflammatory bowel disease (IBD), most commonly ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic inflammation of the gastrointestinal tract. Patients affected with IBD experience symptoms including abdominal pain, persistent diarrhea, rectal bleeding, and weight loss. There is no cure for IBD; thus treatments typically focus on preventing complications, inducing and maintaining remission, and improving quality of life. During IBD, dysregulation of the intestinal immune system leads to increased production of pro-inflammatory cytokines, such as TNF-α and IL-6, and recruitment of activated immune cells to the intestine, causing tissue damage and perpetuating the inflammatory response. Recent biological therapies targeting specific inflammatory cytokines or pathways, in particular TNF-α, have shown promise, but not all patients respond to treatment, and some individuals become intolerant to treatment over time. Dietary peptides and amino acids (AAs) have been shown to modulate intestinal immune functions and influence inflammatory responses, and may be useful as alternative or ancillary treatments in IBD. This review focuses on dietary interventions for IBD treatment, in particular the role of dietary peptides and AAs in reducing inflammation, oxidative stress, and apoptosis in the gut, as well as recent advances in the cellular mechanisms responsible for their anti-inflammatory activity.     

病原体与宿主炎症小体相互作用

炎症小体(Inflammasome)是细胞质中多种蛋白组装成的复合物,炎症小体的激活能活化半胱天冬酶-1(caspase-1),进而引起系列促炎细胞因子的成熟与分泌和诱导细胞焦亡。当病原体感染时,炎症小体的激活在宿主天然免疫应答中起重要作用。大量研究表明,多数情况下炎症小体对宿主起保护作用,仅少数情况下保护作用不明显或表现出有利于病原体生存的一面。在长期进化中,病原体也发展出逃避宿主炎症小体作用的策略。病原体可直接抑制炎症小体的激活或减弱炎症小体的作用。本文从病原体感染宿主中炎症小体的作用及病原体对宿主炎性症小体的逃避机制两方面对二者相互作用的最新研究进展进行综述。     

Potential effects of HMGB1 on viral replication and virus infection-induced inflammatory responses: A promising therapeutic target for virus infection-induced inflammatory diseases

Inflammatory responses, characterized by the overproduction of numerous proinflammatory mediators by immune cells, is essential to protect the host against invading pathogens. Excessive production of proinflammatory cytokines is a key pathogenic factor accounting for severe tissue injury and disease progression during the infection of multiple viruses, which are therefore termed as “cytokine storm”. High mobility group box 1 (HMGB1), a ubiquitous DNA-binding protein released either over virus-infected cells or activated immune cells, may act as a proinflammatory cytokine with a robust capacity to potentiate inflammatory response and disease severity. Moreover, HMGB1 is a host factor that potentially participates in the regulation of viral replication cycles with complicated mechanisms. Currently, HMGB1 is regarded as a promising therapeutic target against virus infection. Here, we provide an overview of the updated studies on how HMGB1 is differentially manipulated by distinct viruses to regulate viral diseases.     

Dual character of Toll-like receptor signaling: Pro-tumorigenic effects and anti-tumor functions

As a major class of pattern-recognition receptors, Toll-like receptors (TLRs) play a critical role in defense against invading pathogens. Increasing evidence demonstrates that, in addition to infection, TLRs are involved in other important pathological processes, such as tumorigenesis. Activation of TLRs results in opposing outcomes, pro-tumorigenic effects and anti-tumor functions. TLR signaling can inhibit apoptosis and promote chronic inflammation-induced tumorigenesis. TLR activation in tumor cells and immune cells can induce production of cytokines, increase tumor cell proliferation and apoptosis resistance, promote invasion and metastasis, and inhibit immune cell activity resulting in tumor immune escape. In contrast, the engagement of other TLRs directly induces growth inhibition and apoptosis of tumor cells and triggers activation of immune cells enhancing anti-tumor immune responses. Thus, the interpretation of the precise function of each TLR in tumors is very important for targeting TLRs and using TLR agonists in tumor therapy. We review the role of TLR signaling in tumors and discuss the factors that affect outcomes of TLR activation.     

Mitochondrial function in immune cells in health and disease

One of the main functions of mitochondria is production of ATP for cellular energy needs, however, it becomes more recognized that mitochondria are involved in differentiation and activation processes of immune cells. Upon activation, immune cells have a high need for energy. Immune cells have different strategies to generate this energy. In pro-inflammatory cells, such as activated monocytes and activated T and B cells, the energy is generated by increasing glycolysis, while in regulatory cells, such as regulatory T cells or M2 macrophages, energy is generated by increasing mitochondrial function and beta-oxidation.Except for being important for energy supply during activation, mitochondria also induce immune responses. During an infection, they release mitochondrial danger associated molecules (DAMPs) that resemble structures of bacterial derived pathogen associated molecular patterns (PAMPs). Such mitochondrial DAMPS are for instance mitochondrial DNA with hypomethylated CpG motifs or a specific lipid that is only present in prokaryotic bacteria and mitochondria, i.e. cardiolipin. Via release of such DAMPs, mitochondria guide the immune response towards an inflammatory response against pathogens. This is an important mechanism in early detection of an infection and in stimulating and sustaining immune responses to fight infections. However, mitochondrial DAMPs may also have a negative impact. If mitochondrial DAMPs are released by damaged cells, without the presence of an infection, such as after a trauma, mitochondrial DAMPs may induce an undesired inflammatory response, resulting in tissue damage and organ dysfunction. Thus, immune cells have developed mechanisms to prevent such undesired immune activation by mitochondrial components.In the present narrative review, we will describe the current view of mitochondria in regulation of immune responses. We will also discuss the current knowledge on disturbed mitochondrial function in immune cells in various immunological diseases.     

Recent advances in the relationship between obesity, inflammation, and insulin resistance

It now appears that, in most obese patients, obesity is associated with a low-grade inflammation of white adipose tissue (WAT) resulting from chronic activation of the innate immune system and which can subsequently lead to insulin resistance, impaired glucose tolerance and even diabetes. WAT is the physiological site of energy storage as lipids. In addition, it has been more recently recognized as an active participant in numerous physiological and pathophysiological processes. In obesity, WAT is characterized by an increased production and secretion of a wide range of inflammatory molecules including TNF-alpha and interleukin-6 (IL-6), which may have local effects on WAT physiology but also systemic effects on other organs. Recent data indicate that obese WAT is infiltrated by macrophages, which may be a major source of locally-produced pro-inflammatory cytokines. Interestingly, weight loss is associated with a reduction in the macrophage infiltration of WAT and an improvement of the inflammatory profile of gene expression. Several factors derived not only from adipocytes but also from infiltrated macrophages probably contribute to the pathogenesis of insulin resistance. Most of them are overproduced during obesity, including leptin, TNF-alpha, IL-6 and resistin. Conversely, expression and plasma levels of adiponectin, an insulin-sensitising effector, are down-regulated during obesity. Leptin could modulate TNF-alpha production and macrophage activation. TNF-alpha is overproduced in adipose tissue of several rodent models of obesity and has an important role in the pathogenesis of insulin resistance in these species. However, its actual involvement in glucose metabolism disorders in humans remains controversial. IL-6 production by human adipose tissue increases during obesity. It may induce hepatic CRP synthesis and may promote the onset of cardiovascular complications. Both TNF-alpha and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signalling pathway. In rodents, resistin can induce insulin resistance, while its implication in the control of insulin sensitivity is still a matter of debate in humans. Adiponectin is highly expressed in WAT, and circulating adiponectin levels are decreased in subjects with obesity-related insulin resistance, type 2 diabetes and coronary heart disease. Adiponectin inhibits liver neoglucogenesis and promotes fatty acid oxidation in skeletal muscle. In addition, adiponectin counteracts the pro-inflammatory effects of TNF-alpha on the arterial wall and probably protects against the development of arteriosclerosis. In obesity, the pro-inflammatory effects of cytokines through intracellular signalling pathways involve the NF-kappaB and JNK systems. Genetic or pharmacological manipulations of these effectors of the inflammatory response have been shown to modulate insulin sensitivity in different animal models. In humans, it has been suggested that the improved glucose tolerance observed in the presence of thiazolidinediones or statins is likely related to their anti-inflammatory properties. Thus, it can be considered that obesity corresponds to a sub-clinical inflammatory condition that promotes the production of pro-inflammatory factors involved in the pathogenesis of insulin resistance.     

Regulation of the innate immune system by ubiquitin and ubiquitin-like modifiers

Detection of invading pathogens by pattern recognition receptors (PRRs) is crucial for the activation of the innate immune response. These sensors signal through intertwining signaling cascades which result in the expression of pro-inflammatory cytokines and type I interferons. Conjugation, or binding, of ubiquitin and ubiquitin-like modifiers (UBLs) to a plethora of immune signaling molecules forms a common theme in innate immune regulation. Numerous E3 ligases and deubiquitylating enzymes (DUBs) actively modify signaling components in order to achieve a balanced activation of the innate immune system. This review will discuss how this balance is achieved and which questions remain regarding innate immune regulation by ubiquitin and UBLs.     

Glucocorticoids synergize with IL-1β to induce TLR2 expression via MAP Kinase Phosphatase-1-dependent dual Inhibition of MAPK JNK and p38 in epithelial cells

Background  

Despite the importance of glucocorticoids in suppressing immune and inflammatory responses, their role in enhancing host immune and defense response against invading bacteria is poorly understood. Toll-like receptor 2 (TLR2) has recently gained importance as one of the major host defense receptors. The increased expression of TLR2 in response to bacteria-induced cytokines has been thought to be crucial for the accelerated immune response and resensitization of epithelial cells to invading pathogens.     

Enterovirus-induced production of pro-inflammatory and T-helper cytokines by human leukocytes

Enteroviruses are associated with chronic inflammatory and autoimmune diseases in humans. In these conditions, the cytokine network is supposed to have an important role in inflammation and modulation of the (auto)immune response. In the present study, we demonstrate that coxsackie virus B4 and poliovirus type 1 induce production of pro-inflammatory cytokines IL-1 beta and TNF-alpha in freshly isolated human leucocytes. Furthermore, enteroviruses stimulate the production of cytokines belonging to Th(1)pathways (IFN-gamma, IL-2), and IL-10, which play a role in regulation of the cellular and humoral immune response.