Mitochondria-derived damage-associated molecular patterns and inflammation in the ischemic-reperfused heart

Cardiac cell death after myocardial infarction release endogenous structures termed damage-associated molecular patterns (DAMPs) that trigger the innate immune system and initiate a sterile inflammation in the myocardium. Cardiomyocytes are energy demanding cells and 30% of their volume are mitochondria. Mitochondria are evolutionary endosymbionts originating from bacteria containing molecular patterns similar to bacteria, termed mitochondrial DAMPs (mDAMPs). Consequently, mitochondrial debris may be particularly immunogenic and damaging. However, the role of mDAMPs in myocardial infarction is not clarified. Identifying the most harmful mDAMPs and inhibiting their early inflammatory signaling may reduce infarct size and the risk of developing post-infarct heart failure. The focus of this review is the role of mDAMPs in the immediate pro-inflammatory phase after myocardial infarction before arrival of immune cells in the myocardium. We discuss different mDAMPs, their role in physiology and present knowledge regarding their role in the inflammatory response of acute myocardial infarction.     

Sequestering of damage-associated molecular patterns (DAMPs): a possible mechanism affecting the immune-stimulating properties of aluminium adjuvants

Aluminium-based adjuvants (ABAs) have been used in human and veterinary vaccines for decades, and for a long time, the adjuvant properties were believed to be mediated by an antigen depot at the injection site, prolonging antigen exposure to the immune system. The depot hypothesis is today more or less abandoned, and instead replaced by the assumption that ABAs induce an inflammation at the injection site. Induction of an inflammatory response is consistent with immune activation initiated by recognition of molecular patterns associated with danger or damage (DAMPs), and the latter are derived from endogenous molecules that normally reside intracellularly. When extracellularly expressed, because of damage, stress or cell death, a sterile inflammation is induced. In this paper, we report the induction of DAMP release by viable cells after phagocytosis of aluminium-based adjuvants. Two of the most commonly used ABAs in pharmaceutical vaccine formulations, aluminium oxyhydroxide and aluminium hydroxyphosphate, induced a vigorous extracellular expression of the two DAMP molecules calreticulin and HMGB1. Concomitantly, extracellular adjuvant particles adsorbed the DAMP molecules released by the cells whereas IL-1β, a previously reported inflammatory mediator induced by ABAs, was not absorbed by the adjuvants. Induction of extracellular expression of the two DAMP molecules was more prominent using aluminium hydroxyphosphate compared to aluminium oxyhydroxide, whereas the extracellular adsorption of the DAMP molecules was more pronounced with the latter. Furthermore, it is hypothesised how induction of DAMP expression by ABAs and their concomitant adsorption by extracellular adjuvants may affect the inflammatory properties of ABAs.     

The role of selenium in inflammation and immunity: from molecular mechanisms to therapeutic opportunities

Dietary selenium (]Se), mainly through its incorporation into selenoproteins, plays an important role in inflammation and immunity. Adequate levels of Se are important for initiating immunity, but they are also involved in regulating excessive immune responses and chronic inflammation. Evidence has emerged regarding roles for individual selenoproteins in regulating inflammation and immunity, and this has provided important insight into mechanisms by which Se influences these processes. Se deficiency has long been recognized to negatively impact immune cells during activation, differentiation, and proliferation. This is related to increased oxidative stress, but additional functions such as protein folding and calcium flux may also be impaired in immune cells under Se deficient conditions. Supplementing diets with above-adequate levels of Se can also impinge on immune cell function, with some types of inflammation and immunity particularly affected and sexually dimorphic effects of Se levels in some cases. In this comprehensive article, the roles of Se and individual selenoproteins in regulating immune cell signaling and function are discussed. Particular emphasis is given to how Se and selenoproteins are linked to redox signaling, oxidative burst, calcium flux, and the subsequent effector functions of immune cells. Data obtained from cell culture and animal models are reviewed and compared with those involving human physiology and pathophysiology, including the effects of Se levels on inflammatory or immune-related diseases including anti-viral immunity, autoimmunity, sepsis, allergic asthma, and chronic inflammatory disorders. Finally, the benefits and potential adverse effects of intervention with Se supplementation for various inflammatory or immune disorders are discussed.     

Galectins in innate immunity: dual functions of host soluble β-galactoside-binding lectins as damage-associated molecular patterns (DAMPs) and as receptors for pathogen-associated molecular patterns (PAMPs)

Summary:  The glycocalyx is a glycan layer found on the surfaces of host cells as well as microorganisms and enveloped virus. Its thickness may easily exceed 50 nm. The glycocalyx does not only serve as a physical protective barrier but also contains various structurally different glycans, which provide cell- or microorganism-specific 'glycoinformation'. This information is decoded by host glycan-binding proteins, lectins. The roles of lectins in innate immunity are well established, as exemplified by collectins, dectin-1, and dendritic cell (DC)-specific intracellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). These mammalian lectins are synthesized in the secretory pathway and presented on the cell surface to bind to specific glycan 'epitopes'. As they recognize non-self glycans presented by microorganisms, they can be considered as receptors for pathogen-associated molecular patterns (PAMPs), i.e. pattern recognition receptors (PRRs). One notable exception is the galectin family. Galectins are synthesized and stored in the cytoplasm, but upon infection-initiated tissue damage and/or following prolonged infection, cytosolic galectins are either passively released by dying cells or actively secreted by inflammatory activated cells through a non-classical pathway, the 'leaderless' secretory pathway. Once exported, galectins act as PRR, as well as immunomodulators (or cytokine-like modulators) in the innate response to some infectious diseases. As galectins are dominantly found in the lesions where pathogen-initiated tissue damage signals appear, this lectin family is also considered as potential damage-associated molecular pattern (DAMP) candidates that orchestrate innate immune responses alongside the PAMP system.     

Emerging role of microRNAs in regulating macrophage activation and polarization in immune response and inflammation

Diversity and plasticity are hallmarks of macrophages. Classically activated macrophages are considered to promote T helper type 1 responses and have strong microbicidal, pro‐inflammatory activity, whereas alternatively activated macrophages are supposed to be associated with promotion of tissue remodelling and responses to anti‐inflammatory reactions. Transformation of different macrophage phenotypes is reflected in their different, sometimes even opposite, roles in various diseases or inflammatory conditions. MicroRNAs (miRNAs) have emerged as critical regulators of macrophage polarization (MP). Several miRNAs are induced by Toll‐like receptors signalling in macrophages and target the 3′‐untranslated regions of mRNAs encoding key molecules involved in MP. Therefore, identification of miRNAs related to the dynamic changes of MP and understanding their functions in regulating this process are important for discussing the molecular basis of disease progression and developing novel miRNA‐targeted therapeutic strategies. Here, we review the current knowledge of the role of miRNAs in MP with relevance to immune response and inflammation.     

A low molecular weight component derived from the milk of hyperimmunised cows suppresses inflammation by inhibiting neutrophil emigration

An earlier study demonstrated that hyperimmunisation of dairy cows with a polyvalent bacterial vaccine stimulated the secretion of a small molecular weight anti-inflammatory moiety in the milk. This hyperimmune milk factor (HIMF) has been further investigated in the present experiments. HIMF was found to suppress the cellular phase of the response to carrageenin and also the neutrophil-dependent reverse passive Arthus reaction. These results, together with the observation that the administration of HIMF led to an increase in the number of circulating neutrophils, suggested that the agent might inhibit inflammation by interfering with the ability of neutrophils to emigrate from the vasculature.In vivo studies carried out to evaluate this possibility demonstrated that HIMF suppressed neutrophil emigration by up to 75%.In vitro experiments established that the ability of neutrophils to respond to chemotactic stimuli or adhere to endothelial cells was not affected by HIMF. It is possible, therefore, that the agent modulates inflammation by down-regulating the synthesis of inducible pro-inflammatory cytokines or adhesion molecules. Attempts are presently being made to isolate the active moiety to allow the activity of the agent at the molecular level to be studied in more detail.     

S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules

Damage-associated molecular pattern (DAMP) molecules have been introduced as important proinflammatory factors of innate immunity. One example known for many years to be expressed in cells of myeloid origin are phagocytic S100 proteins, which mediate inflammatory responses and recruit inflammatory cells to sites of tissue damage. An emerging concept of pattern recognition involves the multiligand receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs) in sensing not only pathogen-associated molecular patterns (PAMPs) but also endogenous DAMPs, including S100 proteins. S100A8, S100A9, and S100A12 are found at high concentrations in inflamed tissue, where neutrophils and monocytes belong to the most abundant cell types. They exhibit proinflammatory effects in vitro at concentrations found at sites of inflammation in vivo. Although S100A12 binds to RAGE, at least part of the proinflammatory effects of the S100A8/S100A9 complex depend upon interaction with other receptors. Because of the divergent expression patterns, the absence of S100A12 in rodents, the different interaction partners described, and the specific intracellular and extracellular effects reported for these proteins, it is important to differentiate between distinct S100 proteins rather than subsuming them with the term "S100/calgranulins." Analyzing the molecular basis of the specific effects exhibited by these proteins in greater detail bears the potential to elucidate important mechanisms of innate immunity, to establish valid biomarkers of phagocytic inflammation, and eventually to reveal novel targets for innovative anti-inflammatory therapies.     

线粒体与细胞凋亡

线粒体是所有真核细胞内重要的细胞器 ,是ＡＴＰ生成的主要部位 ,对维持细胞能量代谢和正常功能活动起重要作用。新近研究发现 ,线粒体内包含一些与细胞凋亡有密切关系的物质 :如ｐｒｏ ｃａｓｐａｓｅ ,细胞色素Ｃ (ＣｙｔＣ) ,Ｓｍａｃ Ｄｉａｂｌｏ ,ＡＩＦ等。在一定因素的刺激下 ,线粒体膜的通透性增加 ,这些物质可由线粒体释出 ,诱导细胞凋亡。因此线粒体在细胞凋亡的发生中起重要作用 ,被形象地称为细胞凋亡的“燃烧室”。大多数细胞发生凋亡时均伴有 :(1)胞浆酸化 ;(2 )线粒体结构与功能障碍 ;(3)Ｃａｓｐａｓｅ活化。细胞发生凋亡…     

Initial delay in the immune response to Francisella tularensis is followed by hypercytokinemia characteristic of severe sepsis and correlating with upregulation and release of damage-associated molecular patterns

"Francisella tularensis subsp. novicida" intranasal infection causes a rapid pneumonia in mice with mortality at 4 to 6 days with a low dose of bacteria (10(2) bacteria). The short time to death suggests that there is a failure of the innate immune response. As the neutrophil is often the first cell type to infiltrate sites of infection, we focused on the emigration of neutrophils in this infection, as well as cytokines involved in their recruitment. The results indicated that there was a significant delay in the influx of neutrophils into the bronchoalveolar lavage fluid of F. tularensis subsp. novicida-infected mice. The delay in neutrophil recruitment in F. tularensis subsp. novicida-infected mice correlated with a delay in the upregulation of multiple proinflammatory cytokines and chemokines, as well as a delay in caspase-1 activation. Strikingly, the initial delay in the upregulation of cytokines through 1 day postinfection was followed by profound upregulation of multiple cytokines and chemokines to levels consistent with hypercytokinemia described for severe sepsis. This finding was further supported by a bacteremia and the cellular relocalization and release of high-mobility group box-1 and S100A9, both of which are damage-associated molecular pattern molecules and are known to be mediators of severe sepsis.     

Emerging roles of bile acids in mucosal immunity and inflammation

Bile acids are cholesterol-derived surfactants that circulate actively between the liver and ileum and that are classically recognized for emulsifying dietary lipids to facilitate absorption. More recent studies, however, have revealed new functions of bile acids; as pleotropic signaling metabolites that regulate diverse metabolic and inflammatory pathways in multiple cell types and tissues through dynamic interactions with both germline-encoded host receptors and the microbiota. Accordingly, perturbed bile acid circulation and/or metabolism is now implicated in the pathogenesis of cholestatic liver diseases, metabolic syndrome, colon cancer, and inflammatory bowel diseases (IBDs). Here, we discuss the three-dimensional interplay between bile acids, the microbiota, and the mucosal immune system, focusing on the mechanisms that regulate intestinal homeostasis and inflammation. Although the functions of bile acids in mucosal immune regulation are only beginning to be appreciated, targeting bile acids and their cellular receptors has already proven an important area of new drug discovery.     

Circulating platelets as a source of the damage-associated molecular pattern HMGB1 in patients with systemic sclerosis

The link between platelet activation and vascular injury in Systemic Sclerosis (SSc) is poorly characterized. Here we report that platelet activation results in i) the translocation from the cytoplasm to the surface of HMGB1, a prototypical DAMP signal associated with tissue regeneration and ii) the release of platelet derived microparticles (PDμP) expressing HMGB1. Decreased HMGB1 content (334.6 ± 21.2 vs 587.1 ± 11.1 AUF, P < 0.001) and HMGB1 translocation to the outer leaflet of the plasma membrane (17.8 ± 3.5 vs 4.5 ± 0.5%, P < 0.001) characterize circulating platelets of SSc patients (n = 29) when compared with age-matched healthy controls (HC, n = 20). Conversely, a significantly higher fraction of PDμP in the blood of SSc patients, but not of HC, consistently expose (HMGB1 (MFI 62.8 ± 3.95 vs 4.3 ± 0.7). Platelet HMGB1 depletion is significantly associated in SSc patients with degranulation and with expression of P-selectin and of tissue factor as well as with fibrinogen binding to their plasma membrane. These findings indicate that platelets represent a source of HMGB1, an ancestral signal of necrosis, in the vasculature of SSc patients, possible contributing to persistent microvascular injury and endothelial cell activation.     

Emerging role of leptin in rheumatoid arthritis

Numerous studies have suggested the importance of leptin against autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS) and psoriasis. To summarize our current understanding of the role of leptin in inflammatory responses and rheumatoid arthritis (RA), a systematic review was conducted to assess the discrepancy of leptin in RA and its effect on immunity according to different studies. Recently, emerging data have indicated that leptin is involved in the pathological function of RA, which is common in autoimmune disorders. This review discusses the possible consequences of leptin levels in RA. Blocking the key signal pathways of leptin and inhibiting the leptin activity‐like leptin antagonist may be a promising way for potential therapeutic treatment of RA at risk of detrimental effects. However, leptin was increased in patients with RA and may also regulate joint damage. Thus, more understanding of the mechanism of leptin in RA would be advantageous in the future.     

Emerging patterns of regulatory T cell function in tuberculosis

Tuberculosis (TB) is one of the top 10 causes of mortality worldwide from a single infectious agent and has significant implications for global health. A major hurdle in the development of effective TB vaccines and therapies is the absence of defined immune-correlates of protection. In this context, the role of regulatory T cells (T_reg), which are essential for maintaining immune homeostasis, is even less understood. This review aims to address this knowledge gap by providing an overview of the emerging patterns of T_reg function in TB. Increasing evidence from studies, both in animal models of infection and TB patients, points to the fact the role of T_regs in TB is dependent on disease stage. While T_regs might expand and delay the appearance of protective responses in the early stages of infection, their role in the chronic phase perhaps is to counter-regulate excessive inflammation. New data highlight that this important homeostatic role of T_regs in the chronic phase of TB may be compromised by the expansion of activated human leucocyte antigen D-related (HLA-DR)⁺CD4⁺ suppression-resistant effector T cells. This review provides a comprehensive and critical analysis of the key features of T_reg cells in TB; highlights the importance of a balanced immune response as being important in TB and discusses the importance of probing not just T_reg frequency but also qualitative aspects of T_reg function as part of a comprehensive search for novel TB treatments.     

白血病细胞源外泌体的作用研究进展

<正>白血病(leukemia)是一类造血干/祖细胞恶性克隆性疾病。外泌体是活细胞分泌到胞外的一种纳米级的微囊泡,是细胞间对话的信息和物质载体~([1])。外泌体携带亲本细胞来源的蛋白质、核酸(mRNA、microRNA和DNA等)及脂质等生物信息分子,可近距离和/或经体液流动远距离、特异性调控靶细胞的生理和病理活动~([2-3])。靶细胞摄取外泌体的途径主要有网格蛋白介导的内吞途径、小窝蛋白依赖型内     

Protective role of ceruloplasmin in inflammation

Experimental inflammation in copper Cu)-deficient rats is greater than that induced in controls eating normal diet. Cu-supplementation of the Cu-deficient diet results in a reduced swelling, down to normal levels. Injection of the naturally occurring acute phase reactant, ceruloplasmin (Cp) a Cu-bearing serum protein, also results in reduction of experimental inflammation. Since a rise in serum Cp occurs in normal pregnancy this protective anti-inflammatory action in normal pregnancy this protective anti-inflammatory action of Cp is proposed as an explanation for the widely-observed phenomenon of spontaneous control of rheumatoid arthritis in pregnancy.