Search

The grey matter is a central target of pathological processes in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. The grey matter is often also affected in multiple sclerosis, an autoimmune disease of the central nervous system. The mechanisms that underlie grey matter inflammation and degeneration in multiple sclerosis are not well understood. Here we show that, in Lewis rats, T cells directed against the neuronal protein [beta]-synuclein specifically invade the grey matter and that this is accompanied by the presentation of multifaceted clinical disease. The expression pattern of [beta]-synuclein induces the local activation of these T cells and, therefore, determined inflammatory priming of the tissue and targeted recruitment of immune cells. The resulting inflammation led to significant changes in the grey matter, which ranged from gliosis and neuronal destruction to brain atrophy. In humans, [beta]-synuclein-specific T cells were enriched in patients with chronic-progressive multiple sclerosis. These findings reveal a previously unrecognized role of [beta]-synuclein in provoking T-cell-mediated pathology of the central nervous system. In a rat model of multiple sclerosis, [beta]-synuclein-specific T cells induce inflammation and pathological changes in the grey matter of the central nervous system; these cells were also found in higher numbers in patients with multiple sclerosis, particularly those with a chronic progressive course., Author(s): Dmitri Lodygin [sup.1] , Moritz Hermann [sup.1] , Nils Schweingruber [sup.1] , Cassandra Flügel-Koch [sup.2] , Takashi Watanabe [sup.3] , Corinna Schlosser [sup.1] , Arianna Merlini [sup.1] , Henrike [...]

OTULIN (OTU deubiquitinase with linear linkage specificity) removes linear polyubiquitin from proteins that have been modified by LUBAC (linear ubiquitin chain assembly complex) and is critical for preventing auto-inflammatory disease.sup.1,2 and embryonic lethality during mouse development.sup.3. Here we show that OTULIN promotes rather than counteracts LUBAC activity by preventing its auto-ubiquitination with linear polyubiquitin. Thus, knock-in mice that express catalytically inactive OTULIN, either constitutively or selectively in endothelial cells, resembled LUBAC-deficient mice.sup.4 and died midgestation as a result of cell death mediated by TNFR1 (tumour necrosis factor receptor 1) and the kinase activity of RIPK1 (receptor-interacting protein kinase 1). Inactivation of OTULIN in adult mice also caused pro-inflammatory cell death. Accordingly, embryonic lethality and adult auto-inflammation were prevented by the combined loss of cell death mediators: caspase 8 for apoptosis and RIPK3 for necroptosis. Unexpectedly, OTULIN mutant mice that lacked caspase 8 and RIPK3 died in the perinatal period, exhibiting enhanced production of type I interferon that was dependent on RIPK1. Collectively, our results indicate that OTULIN and LUBAC function in a linear pathway, and highlight a previously unrecognized interaction between linear ubiquitination, regulators of cell death, and induction of type I interferon. OTULIN, which removes ubiquitin chains deposited by LUBAC, promotes LUBAC activity by preventing its auto-ubiquitination, thereby supporting normal mouse embryo development and preventing pro-inflammatory cell death in adult mice., Author(s): Klaus Heger [sup.1] , Katherine E. Wickliffe [sup.1] , Ada Ndoja [sup.1] , Juan Zhang [sup.2] , Aditya Murthy [sup.3] , Debra L. Dugger [sup.1] , Allie Maltzman [sup.1] [...]

Endoplasmic reticulum (ER) stress is a major contributor to inflammatory diseases, such as Crohn disease and type 2 diabetes (1,2). ER stress induces the unfolded protein response, which involves activation [...]

The integrated stress response (ISR) is a homeostatic mechanism by which eukaryotic cells sense and respond to stress-inducing signals, such as amino acid starvation. General controlled non-repressed (GCN2) kinase is a key orchestrator of the ISR, and modulates protein synthesis in response to amino acid starvation. Here we demonstrate in mice that GCN2 controls intestinal inflammation by suppressing inflammasome activation. Enhanced activation of ISR was observed in intestinal antigen presenting cells (APCs) and epithelial cells during amino acid starvation, or intestinal inflammation. Genetic deletion of Gcn2 (also known as Eif2ka4) in [CD11c.sup.+] APCs or intestinal epithelial cells resulted in enhanced intestinal inflammation and T helper 17 cell ([T.sub.H]17) responses, owing to enhanced inflammasome activation and interleukin (IL)-1β production. This was caused by reduced autophagy in [Gcn2.sup.-/-] intestinal APCs and epithelial cells, leading to increased reactive oxygen species (ROS), a potent activator of inflammasomes1. Thus, conditional ablation of Atg5 or Atg7 in intestinal APCs resulted in enhanced ROS and [T.sub.H]17 responses. Furthermore, in vivo blockade of ROS and IL-1β resulted in inhibition of [T.sub.H]17 responses and reduced inflammation in [Gcn2.sup.-/-] mice. Importantly, acute amino acid starvation suppressed intestinal inflammation via a mechanism dependent on GCN2. These results reveal a mechanism that couples amino acid sensing with control of intestinal inflammation via GCN2., The immune system can sense pathogens through pathogen recognition receptors (2), but emerging evidence suggests that it can also sense and respond to environmental changes that cause cellular stress (3). [...]

Inflammation underlies many chronic and degenerative diseases, but it also mitigates infections, clears damaged cells and initiates tissue repair. Many of the mechanisms that link inflammation to damage repair and regeneration in mammals are conserved in lower organisms, indicating that it is an evolutionarily important process. Recent insights have shed light on the cellular and molecular processes through which conventional inflammatory cytokines and Wnt factors control mammalian tissue repair and regeneration. This is particularly important for regeneration in the gastrointestinal system, especially for intestine and liver tissues in which aberrant and deregulated repair results in severe pathologies., The intestinal epithelium is the most rapidly self-renewing tissue in the mammalian body--cells have a life cycle of 3-4 days. Multiple studies have demonstrated that the intestinal stem cells (ISCs) [...]

Singlet molecular oxygen (.sup.1O.sub.2) has well-established roles in photosynthetic plants, bacteria and fungi.sup.1-3, but not in mammals. Chemically generated .sup.1O.sub.2 oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine.sup.4, whereas enzymatic oxidation of tryptophan to N-formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 1.sup.5. Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure.sup.6. However, whether indoleamine 2,3-dioxygenase 1 forms .sup.1O.sub.2 and whether this contributes to blood pressure control have remained unknown. Here we show that arterial indoleamine 2,3-dioxygenase 1 regulates blood pressure via formation of .sup.1O.sub.2. We observed that in the presence of hydrogen peroxide, the enzyme generates .sup.1O.sub.2 and that this is associated with the stereoselective oxidation of l-tryptophan to a tricyclic hydroperoxide via a previously unrecognized oxidative activation of the dioxygenase activity. The tryptophan-derived hydroperoxide acts in vivo as a signalling molecule, inducing arterial relaxation and decreasing blood pressure; this activity is dependent on Cys42 of protein kinase G1[alpha]. Our findings demonstrate a pathophysiological role for .sup.1O.sub.2 in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions. Singlet molecular oxygen, produced by indoleamine 2,3-dioxygenase 1 activity, gives rise to a signalling molecule that regulates arterial relaxation under inflammatory conditions., Author(s): Christopher P. Stanley [sup.1] , Ghassan J. Maghzal [sup.1] [sup.2] , Anita Ayer [sup.1] [sup.2] , Jihan Talib [sup.1] [sup.2] , Andrew M. Giltrap [sup.3] , Sudhir Shengule [sup.1] [...]

Inflammation is a beneficial host response to infection but can contribute to inflammatory disease if unregulated. The TH17 lineage of T helper (Th) cells can cause severe human inflammatory diseases. These cells exhibit both instability (they can cease to express their signature cytokine, IL-17A) (1) and plasticity (they can start expressing cytokines typical of other lineages) (1,2) upon in vitro re-stimulation. However, technical limitations have prevented the transcriptional profiling of pre- and post-conversion TH17 cells ex vivo during immune responses. Thus, it is unknown whether TH17 cell plasticity merely reflects change in expression of a few cytokines, or if TH17 cells physiologically undergo global genetic reprogramming driving their conversion from one T helper cell type to another, a process known as transdifferentiation (3,4). Furthermore, although TH17 cell instability/plasticity has been associated with pathogenicity (1,2,5), it is unknown whether this could present a therapeutic opportunity, whereby formerly pathogenic TH17 cells could adopt an anti-inflammatory fate. Here we used two new fate-mapping mouse models to track TH17 cells during immune responses to show that [CD4.sup.+] T cells that formerly expressed IL-17A go on to acquire an antiinflammatory phenotype. The transdifferentiation of TH17 into regulatory T cells was illustrated by a change in their signature transcriptional profile and the acquisition of potent regulatory capacity. Comparisons of the transcriptional profiles of pre- and post-conversion TH17 cells also revealed a role for canonical TGF-β signalling and consequently for the aryl hydrocarbon receptor (AhR) in conversion. Thus, TH17 cells transdifferentiate into regulatory cells, and contribute to the resolution of inflammation. Our data suggest that TH17 cell instability and plasticity is a therapeutic opportunity for inflammatory diseases., TH17 cells are characterized by secretion of IL-17A, expression of chemokine receptor CCR6 and transcriptional factor RORγt (6). Their pathogenicity is limited by [Foxp3.sup.+] [T.sub.Reg] and T regulatory type 1 [...]

Regulated cell death has essential functions in development and in adult tissue homeostasis. Necroptosis is a newly discovered pathway of regulated necrosis that requires the proteins RIPK3 and MLKL and is induced by death receptors, interferons, toll-like receptors, intracellular RNA and DNA sensors, and probably other mediators. RIPK1 has important kinase-dependent and scaffolding functions that inhibit or trigger necroptosis and apoptosis. Mouse-model studies have revealed important functions for necroptosis in inflammation and suggested that it could be implicated in the pathogenesis of many human inflammatory diseases. We discuss the mechanisms regulating necroptosis and its potential role in inflammation and disease., Cell death is intricately connected with life in multicellular organisms. The balance between cell death, proliferation and differentiation is crucial for the maintenance of tissue homeostasis throughout life. Programmed cell [...]

The incidences of chronic inflammatory disorders have increased considerably over the past three decades (1). Recent shifts in dietary consumption may have contributed importantly to this surge, but how dietary consumption modulates inflammatory disease is poorly defined. [Pstpip2.sup.cmo] mice, which express a homozygous Leu98Pro missense mutation in the PombeCdc15 homology family protein PSTPIP2 (prolineserine-threonine phosphatase interacting protein 2), spontaneously develop osteomyelitis that resembles chronic recurrent multifocal osteomyelitis in humans (2-4). Recent reports demonstrated a crucial role for interleukin-1β (IL-1β) in osteomyelitis, but deletion of the inflammasome components caspase-1 and NLRP3 failed to rescue [Pstpip2.sup.cmo] mice from inflammatory bone disease (5,6). Thus, the upstream mechanisms controlling IL-1β production in [Pstpip2.sup.cmo] mice remain to be identified. In addition, the environmental factors driving IL-1β-dependent inflammatory bone erosion are unknown. Here we show that the intestinal microbiota of diseased [Pstpip2.sup.cmo] mice was characterized by an outgrowth of Prevotella. Notably, Pstpip2mo mice that were fed a diet rich in fat and cholesterol maintained a normal body weight, but were markedly protected against inflammatory bone disease and bone erosion. Diet-induced protection against osteomyelitis was accompanied by marked reductions in intestinal Prevotella levels and significantly reduced pro-IL-1β expression in distant neutrophils. Furthermore, pro-IL-1β expression was also decreased in [Pstpip2.sup.cmo] mice treated with antibiotics, and in wild-type mice that were kept under germ-free conditions. We further demonstrate that combined deletion of caspases 1 and 8 was required for protection against IL-1β-dependent inflammatory bone disease, whereas the deletion of either caspase alone or of elastase or neutrophil proteinase 3 failed to prevent inflammatory disease. Collectively, this work reveals diet-associated changes in the intestinal microbiome as a crucial factor regulating inflammasome- and caspase-8-mediated maturation of IL-1β and osteomyelitis in [Pstpip2.sup.cmo] mice., Changes in diet are known to determine susceptibility to common autoimmune diseases such as atherosclerosis, coronary heart disease and type II diabetes (7). To address whether dietary intake affects osteomyelitis [...]

Necroptosis has emerged as an important pathway of programmed cell death in embryonic development, tissue homeostasis, immunity and inflammation (1-8). RIPK1 is implicated in inflammatory and cell death signalling (9-13) and its kinase activity is believed to drive RIPK3-mediated necroptosis (14,15). Here we show that kinase-independent scaffolding RIPK1 functions regulate homeostasis and prevent inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis. Intestinal epithelial cell (IEC)-specific RIPK1 knockout caused IEC apoptosis, villus atrophy, loss of goblet and Paneth cells and premature death in mice. This pathology developed independently of the microbiota and of MyD88 signalling but was partly rescued by TNFR1 (also known as TNFRSF1A) deficiency. Epithelial FADD ablation inhibited IEC apoptosis and prevented the premature death of mice with IEC-specific RIPK1 knockout. However, mice lacking both RIPK1 and FADD in IECs displayed RIPK3-dependent IEC necroptosis, Paneth cell loss and focal erosive inflammatory lesions in the colon. Moreover, a RIPK1 kinase inactive knock-in delayed but did not prevent inflammation caused by FADD deficiency in IECs or keratinocytes, showing that RIPK3-dependent necroptosis of FADD-deficient epithelial cells only partly requires RIPK1 kinase activity. Epidermis-specific RIPK1 knockout triggered keratinocyte apoptosis and necroptosis and caused severe skin inflammation that was prevented by RIPK3 but not FADD deficiency. These findings revealed that RIPK1 inhibits RIPK3-mediated necroptosis in keratinocytes in vivoand identified necroptosis as a more potent trigger of inflammation compared with apoptosis. Therefore, RIPK1 is a master regulator of epithelial cell survival, homeostasis and inflammation in the intestine and the skin., Mice lacking RIPK1 die perinatally, exhibiting apoptosis in multiple tissues including the intestine (9) (Extended Data Fig. 1a). We generated mice with IEC-specific knockout of RIPK1 (RIPK1IEC'KO) (Fig. 1a and [...]

Author(s): Qicong Shen [1]; Qian Zhang [1, 2]; Yang Shi [3]; Qingzhu Shi [3]; Yanyan Jiang [1]; Yan Gu [1]; Zhiqing Li [3]; Xia Li [2]; Kai Zhao [2]; Chunmei [...]

Aspergillus fumigatus is a saprophytic fungus that is ubiquitous in the environment and is commonly associated with allergic sensitization and severe asthma in humans. Although A. fumigatus is recognized by [...]

Lung epithelial cells can influence immune responses to airway allergens (1,2). Airway epithelial cells also undergo apoptosis after encountering environmental allergens (3); yet, relatively little is known about how these [...]

In contrast with many capillary beds, the glomerulus readily supports leukocyte recruitment. However, little is known regarding the actions of leukocytes following their recruitment to glomeruli. We used multiphoton confocal microscopy to examine leukocyte behavior in the glomerular microvasculature. In normal glomeruli, neutrophils and monocytes were retained in capillaries for several minutes, remaining static or migrating intravascularly. Induction of glomerular inflammation resulted in an increase in the duration of retention of static and migratory leukocytes. In response to immune complex deposition, both static and migratory neutrophils generated oxidants in inflamed glomeruli via a Mac-1--dependent mechanism. Our results describe a new paradigm for glomerular inflammation, suggesting that the major effect of acute inflammation is to increase the duration of leukocyte retention in the glomerulus. Moreover, these findings describe a previously unknown form of multicellular intravascular patrolling that involves both monocytes and neutrophils, which may underlie the susceptibility of the glomerulus to inflammation., Glomerulonephritis is a leading cause of end-stage renal failure. Evidence suggests that leukocytes are recruited to the glomerulus as part of this inflammatory response, where they are involved in glomerular [...]

BACKGROUND/OBJECTIVES: It has been recognized that certain long-chain polyunsaturated fatty acids (LC-PUFAs) are involved in inflammation and its resolution. It has also been shown that ethnicity may be a factor in affecting systemic inflammation, and limited evidence suggests it may influence plasma LC-PUFA composition. Given the links among these three factors, we aim to determine ethnicity-based differences in plasma LC-PUFA composition among White, Black, Hispanic and Chinese participants, and whether such differences contribute to variations in markers of inflammation and endothelial activation in a sub-cohort of the Multi-Ethnic Study of Atherosclerosis (MESA). SUBJECTS/METHODS: Plasma phospholipid LC-PUFAs levels (%) were determined in 2848 MESA participants using gas chromatography-flame ionization detection. Enzyme immunoassays determined inflammatory markers levels for high-sensitivity C-reactive protein (n = 2848), interleukin-6 (n = 2796), soluble tumor necrosis factor-α receptor type 1 (n = 998), and endothelial activation markers soluble intercellular adhesion molecule-1 (n = 1192) and soluble E-selectin (n = 998). The modifying influence of ethnicity was tested by linear regression analysis. RESULTS: Chinese adults were found to have the highest mean levels of plasma eicosapentaenoic acid (EPA, 1.24%) and docosahexaenoic acid (DHA, 4.95%), and the lowest mean levels of γ-linolenic (0.10%), dihomo-γ-linolenic (DGLA, 2.96%) and arachidonic (10.72%) acids compared with the other ethnicities (all P ≤ 0.01). In contrast, Hispanics had the lowest mean levels of plasma EPA (0.70%) and DHA (3.49%), and the highest levels of DGLA (3.59%; all P ≤ 0.01). Significant differences in EPA and DHA among ethnicities were attenuated following adjustment for dietary non-fried fish and fish oil supplementation. Ethnicity did not modify the associations of LC-PUFAs with markers of inflammation or endothelial activation (all [P.sub.interaction] >0.05). CONCLUSIONS: The absence of a modifying effect of ethnicity indicates that the putative benefits of LC-PUFAs with respect to inflammation are pan-ethnic. Future longitudinal studies may elucidate the origin(s) of ethnicity-based differences in LC-PUFA composition and whether certain patterns, that is, high plasma levels of DGLA and low levels of EPA/DHA, contribute to inflammation-associated health outcomes. European Journal of Clinical Nutrition (2012) 66, 600-605. doi: 10.1038/ejcn.2011.215; published online 4 January 2012 Keywords: race; endothelial activation; inflammation; fatty acid; omega-3; omega-6, INTRODUCTION Dietary intake of long-chain polyunsaturated fatty acids (LC-PUFAs) has gained recent media attention, yet their benefits were recognized decades ago in studies of Greenland Inuit. High intakes of the [...]

Autophagy is an essential, homeostatic process by which cells break down their own components. Perhaps the most primordial function of this lysosomal degradation pathway is adaptation to nutrient deprivation. However, in complex multicellular organisms, the core molecular machinery of autophagy--the 'autophagy proteins'--orchestrates diverse aspects of cellular and organismal responses to other dangerous stimuli such as infection. Recent developments reveal a crucial role for the autophagy pathway and proteins in immunity and inflammation. They balance the beneficial and detrimental effects of immunity and inflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases., There is only one known mechanism that eukaryotic cells possess to dispose of intracellular organelles and protein aggregates that are too large to be degraded by the proteasome. It is [...]

Background: C-reactive protein (CRP), a sensitive marker of inflammation, is an independent predictor of future cardiovascular disease (CVD), which is a major cause of death worldwide. In epidemiological trials, high-fibre intakes have consistently been associated with reduction in CVD risk and CRP levels. Objective: The objective of this study was to assess the influence of dietary fibre (DF) on CRP in clinical trials. Data sources: Databases were searched from the earliest record to April 2008 and supplemented by crosschecking reference lists of relevant publications. Study selection: Human adult intervention trials, at least 2 weeks in duration, with an increased and measurable consumption of DF were included and rated for quality. Data synthesis: Seven clinical trials were included, and six of these reported significantly lower CRP concentrations of 25-54% with increased DF consumption with dosages ranging between 3.3-7.8 g/MJ. The seventh trial with psyllium fibre supplementation failed to lower CRP levels significantly in overweight/obese individuals. Weight loss and altered fatty acid intakes were present in most of the studies. Conclusions: In the presence of weight loss and modified saturated, monounsaturated and polyunsaturated fat intakes, significantly lower CRP concentrations ([down arrow] 25-54%) are seen with increased fibre consumption ([greater than or equal to] 3.3 g/MJ). Mechanisms are inconclusive but may involve the effect of DF on weight loss, and/or changes in the secretion, turnover or metabolism of insulin, glucose, adiponectin, interleukin-6, free fatty acids and triglycerides. Clinical studies of high- and low-fibre diets are needed to explore the potential favourable effects as observed epidemiologically, and to understand individual susceptibility to its antiinflammatory effect and long-term cardiovascular reduction. doi:10.1038/ejcn.2009.8; published online 18 February 2009 Keywords: dietary fibre; C-reactive protein; cardiovascular disease; clinical trials; weight loss, Introduction C-reactive protein (CRP), a sensitive marker of inflammation, is an independent predictor of future cardiovascular disease, a major cause of death worldwide (Ridker et al., 1998, 2002; Pearson et [...]

Objectives: The acute phase response (APR) influences indicators of iron status. A recent WHO/CDC consultation recommended concurrent measurement of [alpha]-1-acid-glycoprotein (AGP) in surveys to control for the APR, and aid in interpreting iron status. They proposed further exploratory analyses using AGP. We examined whether the APR (measured by AGP) influences the expected relationships between iron status indicators in an HIV-infected population. Subjects: We measured hemoglobin (Hb), serum ferritin (SF), transferrin receptor (TfR), erythropoietin (EPO) and AGP in a cross-sectional survey of 643 HIV-positive Zimbabwean women. Results: SF was significantly higher in APR-positive (AGP> 1 g/l) women (P Conclusions: AGP captured the influence of the APR on iron indicators and their relationships with each other. The APR influenced SF and its relationship with Hb as expected. TfR behaved unexpectedly. Although TfR has been promoted as an iron indicator that is uninfluenced by the APR, TfR concentrations were depressed among anemic APR-positive women. Because TfR reflects iron deficiency and erythropoietic activity, pro-inflammatory cytokines associated with the APR may be inhibiting erythropoeisis, which is reflected by lower TfR concentrations. We support the WHO/CDC recommendation that AGP is a useful indicator to assess the influence of the APR on iron status indicators. doi:10.1038/ejcn.2008.33; published online 28 May 2008 Keywords: acute phase response; AGP; iron status; SF; TfR; HIV, Introduction Despite considerable national, regional and global efforts targeted at the prevention of iron deficiency (ID), it remains among the most common nutritional problem in the world (WHO, 2001). In [...]

Selectins and their ligands mediate leukocyte rolling, allowing interactions with chemokines that lead to integrin activation and arrest. Here we show that E-selectin is crucial for generating a secondary wave of activating signals, transduced specifically by E-selectin ligand-1, that induces polarized, activated [[alpha].sub.M][[beta].sub.2] integrin clusters at the leading edge of crawling neutrophils, allowing capture of circulating erythrocytes or platelets. In a humanized mouse model of sickle cell disease, the capture of erythrocytes by [[alpha].sub.M][[beta].sub.2] microdomains leads to acute lethal vascular occlusions. In a model of transfusion-related acute lung injury, polarized neutrophils capture circulating platelets, resulting in the generation of oxidative species that produce vascular damage and lung injury. Inactivation of E-selectin or [[alpha].sub.M][[beta].sub.2] prevents tissue injury in both inflammatory models, suggesting broad implications of this paradigm in thromboinflammatory diseases. These results indicate that endothelial selectins can influence neutrophil behavior beyond its canonical rolling step through delayed, organ-damaging, polarized activation., Leukocytes are recruited to inflamed areas by a tightly regulated cascade of adhesive and signaling events that choreograph their migration. Neutrophil (PMN) rolling is mediated by endothelial P- and E-selectins [...]

Host-and pathogen-associated cytoplasmic double-stranded DNA triggers the activation of a NALP3 (also known as cryopyrin and NLRP3)-independent inflammasome (1), which activates caspase-1 leading to maturation of pro-interleukin-1β and inflammation. The nature of the cytoplasmic-DNA-sensing inflammasome is currently unknown. Here we show that AIM2 (absent in melanoma 2), an interferon-inducible HIN-200 family member that contains an amino-terminal pyrin domain and a carboxy-terminal oligonucleotide/oligosaccharide-binding domain (2, 3), senses cytoplasmic DNA by means of its oligonucleotide/oligosaccharide-binding domain and interacts with ASC (apoptosis-associated speck-like protein containing a CARD) through its pyrin domain to activate caspase-1. The interaction of AIM2 with ASC also leads to the formation of the ASC pyroptosome (4), which induces pyroptotic cell death in cells containing caspase-1. Knockdown of AIM2 by short interfering RNA reduced inflammasome/pyroptosome activation by cytoplasmic DNA in human and mouse macrophages, whereas stable expression of AIM2 in the non-responsive human embryonic kidney 293T cell line conferred responsiveness to cytoplasmic DNA. Our results show that cytoplasmic DNA triggers formation of the AIM2 inflammasome by inducing AIM2 oligomerization. This study identifies AIM2 as an important inflammasome component that senses potentially dangerous cytoplasmic DNA, leading to activation of the ASC pyroptosome and caspase-1., A key innate immune response against infection with microbial or viral pathogens and tissue damage is the rapid activation of multi-protein complexes called inflammasomes (5). The inflammasomes activate caspase-1, a [...]

Objective: To evaluate associations between components of the Mediterranean diet and circulating markers of inflammation in a large cohort of asymptomatic subjects at high risk for cardiovascular disease. Subjects/Methods: A [...]

[beta]-catenin is a central molecule in the Wnt pathway. Expression of a stable form of [beta]-catenin on [CD4.sup.+][CD25.sup.+] regulatory T ([T.sub.reg]) cells resulted in a marked enhancement of survival of these cells in vitro. Furthermore, stable [beta]-catenin-expressing [CD4.sup.+][CD25.sup.+] [T.sub.reg] cells outcompeted control [T.sub.reg] cells in vivo, and the number of [T.sub.reg] cells necessary for protection against inflammatory bowel disease could be substantially reduced when stable [beta]-catenin-expressing [CD4.sup.+][CD25.sup.+] [T.sub.reg] cells were used instead of control [T.sub.reg] cells. Expression of stable [beta]-catenin on potentially pathogenic [CD4.sup.+][CD25.sup.+] T cells rendered these cells anergic, and the [beta]-catenin-mediated induction of anergy occurred even in Foxp3-deficient T cells. Thus, through enhanced survival of existing regulatory T cells, and through induction of unresponsiveness in precursors of T effector cells, [beta]-catenin stabilization has a powerful effect on the prevention of inflammatory disease., [beta]-catenin is an essential component of the Wnt signaling pathway, which is evolutionarily conserved and is involved in a large variety of developmental processes including the specification of cell fate [...]

Author(s): Karen J. Mackenzie [1]; Paula Carroll [1]; Carol-Anne Martin [1]; Olga Murina [1]; Adeline Fluteau [1]; Daniel J. Simpson [1]; Nelly Olova [1]; Hannah Sutcliffe [1]; Jacqueline K. Rainger [...]

Caveolin-1, the primary coat protein of caveolae, has been implicated as a regulator of signal transduction through binding of its "scaffolding domain" to key signaling molecules. However, the physiological importance of caveolin-1 in regulating signaling has been difficult to distinguish from its traditional functions in caveolae assembly, transcytosis, and cholesterol transport. To directly address the importance of the caveolin scaffolding domain in vivo, we generated a chimeric peptide with a cellular internalization sequence fused to the caveolin-1 scaffolding domain (amino acids 82-101). The chimeric peptide was efficiently taken up into blood vessels and endothelial cells, resulting in selective inhibition of acetylcholine (Ach)-induced vasodilation and nitric oxide (NO) production, respectively. More importantly, systemic administration of the peptide to mice suppressed acute inflammation and vascular leak to the same extent as a glucocorticoid or an endothelial nitric oxide synthase (eNOS) inhibitor. These data imply that the caveolin-1 scaffolding domain can selectively regulate signal transduction to eNOS in endothelial cells and that small-molecule mimicry of this domain may provide a new therapeutic approach., Author(s): Mariarosaria Bucci [1, 2, 3]; Jean-Philippe Gratton [1, 3]; Radu Daniel Rudic [1]; Lisette Acevedo [1]; Fiorentina Roviezzo [2]; Giuseppe Cirino [2]; William C. Sessa (corresponding author) [1] Caveolins [...]

Background/objectives Conjugated linoleic acid (CLA) is a polyunsaturated fatty acid with attractive biological activities. Numerous studies have been conducted on the inflammation-lowering effects of CLA in in vitro and animal models. However, the effects of CLA treatment on the inflammatory markers in humans are controversial. Therefore, the objective of this study was to perform a systematic review and meta-analysis on controlled clinical trials (RCT) assessing the effects of CLA supplementation on the circulating inflammatory markers, including C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-[alpha] (TNF-[alpha]). Subjects/methods The literature search of RCTs was performed using Pubmed/Medline, Scopus, ScienceDirect, Web of science, Cochrane, and Google Scholar databases from inception to March 2017. Weighted mean differences were estimated and the pooled effect size was calculated by a random effects model. Results Of the 427 identified studies, eleven RCTs, including 420 subjects were included in the statistical analysis. Findings suggested that CLA supplementation increased blood levels of CRP by 0.89 mg/l (95% CI: 0.11, 1.68; P = 0.025) and TNF-[alpha] levels by 0.39 pg/ml (95% CI: 0.23, 0.55; P < 0.0001). However, blood IL-6 levels were marginally decreased by 0.32 pg/ml (95% CI: -0.71, 0.07; P = 0.11) following CLA supplementation. There was a significant heterogeneity for the impact of CLA on CRP and IL-6, but not TNF-[alpha]. Conclusions This meta-analysis showed that CLA supplementation may increase inflammatory markers (CRP and TNF-[alpha]). There are concerns about using CLA supplementation as an anti-obesity agent among the obese population for at least a short duration., Author(s): Fahimeh Haghighatdoost [sup.1] [sup.2] , B. Fatemeh Nobakht M. Gh [sup.3] Author Affiliations: (1) Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran (2) Department of Community [...]

Author(s): Jennifer Martinez (corresponding author) [1, 2]; Larissa D. Cunha [1]; Sunmin Park [3]; Mao Yang [1]; Qun Lu [3]; Robert Orchard [3]; Quan-Zhen Li [4]; Mei Yan [4]; Laura [...]

The structures of unliganded murine cyclooxygenase-1 and -2 (COX-1 and COX-2) and those of complexes with flurbiprofen, indomethacin and SC-558, a selective COX-2 inhibitor, were studied using crystallography and molecular replacement methods. The results indicated that the overall structures of COX-1 and COX-2 are highly conserved although COX-2 was shown to have a much larger non-steroidal anti-inflammatory drug binding site due to the substitution of a valine for isoleucine in the active site. It was also evident that the time-dependent cyclooxygenase inhibition may proceed via more than one mechanism.

The case of mice exhibiting a lack of cyclooxygenase 2 (COX-2) is discussed with relation to inflammation and renal characteristics. The method used in identifying the deficiency was gene targeting. COX-2 is one of two main determinants in the regulation of prostaglandin synthesis. The regulation of the latter is important in the production of anti-inflammatory substances such as drugs.

Inflammation caused by aggregation of neutrophils (a type of white blood cell) occurs in several clinical conditions, including adult respiratory distress (severe breathing difficulty) and the injury that can result when blood flow is restored to a damaged area (reperfusion injury). If neutrophils are prevented from attaching to certain cells, their ability to provoke an inflammatory response should in principle be reduced. A molecule constructed in such a way as to block adhesion between neutrophils and endothelial cells was evaluated in animals. Mice were given this chimera (made by combining an immunoglobulin with a homing receptor) by intravenous injection, and they subsequently showed a greatly reduced response to thioglycollate, a substance that induces neutrophil-mediated inflammation. This was probably the result of the chimera's ability to bind to cells' homing receptors, preventing white blood cells from binding. Additional experiments were performed to learn more about the chimera's appropriate dose levels and time course. A discussion is presented of the therapeutic possibilities of agents that block cell adhesion for treating inflammatory responses. (Consumer Summary produced by Reliance Medical Information, Inc.)

Author(s): Xing Dai (corresponding author) [1]; Ruslan Medzhitov (corresponding author) [2] The paper in brief * Activated epithelial stem cells (EpSCs) give rise to skin-cell lineages that can replace damaged [...]

P- and E-selectins are both essential for the recruitment of T-helper-1 (Th1) but not T-helper-2 (Th2) into a cutaneous inflammation. Experiment results using P- and E-selectin immunoglobulin construct stains show positive reactions for Th1 cells while Th2 cells were unreactive. These demonstrate the specific effector functions and distinct migration behavior of Th1 cells. The recruitment mediation function of endothelial selectins provide an additional level of regulation for both effector function profile and character of local immune response.

The liver secretory protein fetuin-A (FetA) is now shown to act as an adaptor protein between free fatty acids (FFAs) and Toll-like receptor 4 (TLR4), providing the missing link between [...]

The enthesis is the region at the junction between tendon and bone and has been suggested to be a key target in spondyloarthritic diseases. This zone is now shown to [...]

The pro-inflammatory agents trypsin and mast cell tryptase cleave and activate proteinase-activated receptor 2 (PAR2), which is expressed on sensory nerves, explaining a previously unknown mechanism in neurogenic inflammation (151-158)., Author(s): Susan D. Brain [1] The involvement of sensory nerves in the mediation of nociception and pain, as well in neurogenic inflammation, is established. This dual role of sensory nerves [...]

Mouse models have long served as the foundation of biomedical research, providing insights into mechanisms of disease and serving as the test bed for countless experimental therapies prior to human [...]

Macrophage activation, which contributes to vascular inflammation, is a central feature of atherosclerotic plaque initiation and development. Gokhan Hotamisligil and his colleagues now identify a new anti-inflammatory mechanism in macrophages [...]

Zhao, J. et al. Nat. Immunol. doi:10.1038/ni.2341 (3 June). The cytokine IL-33 is important in lung inflammatory conditions such as asthma. The interaction between IL-33 and its receptor ST2L is [...]

During an inflammatory reaction, the body often responds to low levels of oxygen by turning on a key transcription factor called hypoxia inducible factor-1α (HIF-1α). This protein has long been [...]

This year, biologists had to stomach the fact that the immune system shares numerous, previously unidentified connections with the gut. For example, one study in mice found that a sugar [...]

A single bacterial molecule helps keep microbes in the gut in harmony, according to experiments in mice. Without this molecule, polysaccharide A (PSA), inflammatory reactions in the gut can go [...]