Mediators of Inflammation The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. Stimulation of Alpha7 Nicotinic Acetylcholine Receptor Attenuates Nicotine-Induced Upregulation of MMP, MCP-1, and RANTES through Modulating ERK1/2/AP-1 Signaling Pathway in RAW264.7 and MOVAS Cells Thu, 16 Nov 2017 10:40:37 +0000 Vagus nerve stimulation through alpha7 nicotine acetylcholine receptors (α7-nAChR) signaling had been demonstrated attenuation of inflammation. This study aimed to determine whether PNU-282987, a selective α7-nAChR agonist, affected activities of matrix metalloproteinase (MMP) and inflammatory cytokines in nicotine-treatment RAW264.7 and MOVAS cells and to assess the underlying molecular mechanisms. RAW264.7 and MOVAS cells were treated with nicotine at different concentrations (0, 1, 10, and 100 ng/ml) for 0–120 min. Nicotine markedly stimulated the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) and c-Jun in RAW264.7 cells. Pretreatment with U0126 significantly suppressed phosphorylation of ERK1/2 and further attenuated nicotine-induced activation of c-Jun and upregulation of MMP-2, MMP-9, monocyte chemotactic protein- (MCP-) 1, and regulated upon activation normal T cell expressed and secreted (RANTES). Similarly, nicotine treatment also increased phosphorylation of c-Jun and expressions of MMP-2, MMP-9, MCP-1, and RANTES in MOVAS cells. When cells were pretreated with PNU-282987, nicotine-induced activations of ERK1/2 and c-Jun in RAW264.7 cells and c-Jun in MOVAS cells were effectively inhibited. Furthermore, nicotine-induced secretions of MMP-2, MMP-9, MCP-1, and RANTES were remarkably downregulated. Treatment with α7-nAChR agonist inhibits nicotine-induced upregulation of MMP and inflammatory cytokines through modulating ERK1/2/AP-1 signaling in RAW264.7 cells and AP-1 in MOVAS cells, providing a new therapeutic for abdominal aortic aneurysm. Liping Liu, Hongxian Wu, Qunan Cao, Zhenzhen Guo, Anmin Ren, and Qiuyan Dai Copyright © 2017 Liping Liu et al. All rights reserved. Neutral Sphingomyelinase Behaviour in Hippocampus Neuroinflammation of MPTP-Induced Mouse Model of Parkinson’s Disease and in Embryonic Hippocampal Cells Thu, 16 Nov 2017 00:00:00 +0000 Neutral sphingomyelinase is known to be implicated in growth arrest, differentiation, proliferation, and apoptosis. Although previous studies have reported the involvement of neutral sphingomyelinase in hippocampus physiopathology, its behavior in the hippocampus during Parkinson’s disease remains undetected. In this study, we show an upregulation of inducible nitric oxide synthase and a downregulation of neutral sphingomyelinase in the hippocampus of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) induced mouse model of Parkinson’s disease. Moreover, the stimulation of neutral sphingomyelinase activity with vitamin 1,25-dihydroxyvitamin D3 reduces specifically saturated fatty acid sphingomyelin by making sphingomyelin a less rigid molecule that might influence neurite plasticity. The possible biological relevance of the increase of neutral sphingomyelinase in Parkinson’s disease is discussed. Samuela Cataldi, Cataldo Arcuri, Stéphane Hunot, François-Pierre Légeron, Carmen Mecca, Mercedes Garcia-Gil, Andrea Lazzarini, Michela Codini, Tommaso Beccari, Anna Tasegian, Bernard Fioretti, Giovanna Traina, Francesco Saverio Ambesi-Impiombato, Francesco Curcio, and Elisabetta Albi Copyright © 2017 Samuela Cataldi et al. All rights reserved. The Role of Sphingosine-1-Phosphate and Ceramide-1-Phosphate in Inflammation and Cancer Wed, 15 Nov 2017 00:00:00 +0000 Inflammation is part of our body’s response to tissue injury and pathogens. It helps to recruit various immune cells to the site of inflammation and activates the production of mediators to mobilize systemic protective processes. However, chronic inflammation can increase the risk of diseases like cancer. Apart from cytokines and chemokines, lipid mediators, particularly sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), contribute to inflammation and cancer. S1P is an important player in inflammation-associated colon cancer progression. On the other hand, C1P has been recognized to be involved in cancer cell growth, migration, survival, and inflammation. However, whether C1P is involved in inflammation-associated cancer is not yet established. In contrast, few studies have also suggested that S1P and C1P are involved in anti-inflammatory pathways regulated in certain cell types. Ceramide is the substrate for ceramide kinase (CERK) to yield C1P, and sphingosine is phosphorylated to S1P by sphingosine kinases (SphKs). Biological functions of sphingolipid metabolites have been studied extensively. Ceramide is associated with cell growth inhibition and enhancement of apoptosis while S1P and C1P are associated with enhancement of cell growth and survival. Altogether, S1P and C1P are important regulators of ceramide level and cell fate. This review focuses on S1P and C1P involvement in inflammation and cancer with emphasis on recent progress in the field. Nitai C. Hait and Aparna Maiti Copyright © 2017 Nitai C. Hait and Aparna Maiti. All rights reserved. Molecular Responses of Human Retinal Cells to Infection with Dengue Virus Sun, 12 Nov 2017 00:00:00 +0000 Recent clinical reports indicate that infection with dengue virus (DENV) commonly has ocular manifestations. The most serious threat to vision is dengue retinopathy, including retinal vasculopathy and macular edema. Mechanisms of retinopathy are unstudied, but observations in patients implicate retinal pigment epithelial cells and retinal endothelial cells. Human retinal cells were inoculated with DENV-2 and monitored for up to 72 hours. Epithelial and endothelial cells supported DENV replication and release, but epithelial cells alone demonstrated clear cytopathic effect, and infection was more productive in those cells. Infection induced type I interferon responses from both cells, but this was stronger in epithelial cells. Endothelial cells increased expression of adhesion molecules, with sustained overexpression of vascular adhesion molecule-1. Transcellular impedance decreased for epithelial monolayers, but not endothelial monolayers, coinciding with cytopathic effect. This reduction was accompanied by disorganization of intracellular filamentous-actin and decreased expression of junctional molecules, zonula occludens 1, and catenin-β1. Changes in endothelial expression of adhesion molecules are consistent with the retinal vasculopathy seen in patients infected with DENV; decreases in epithelial junctional protein expression, paralleling loss of integrity of the epithelium, provide a molecular basis for DENV-associated macular edema. These molecular processes present potential therapeutic targets for vision-threatening dengue retinopathy. Jillian M. Carr, Liam M. Ashander, Julie K. Calvert, Yuefang Ma, Amanda Aloia, Gustavo G. Bracho, Soon-Phaik Chee, Binoy Appukuttan, and Justine R. Smith Copyright © 2017 Jillian M. Carr et al. All rights reserved. Short-Term Postoperative Cognitive Dysfunction and Inflammatory Response in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Pilot Study Thu, 09 Nov 2017 04:02:05 +0000 Objectives. To assess the association between short-term postoperative cognitive dysfuction (POCD) and inflammtory response in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Design. A prospective cohort study. Setting. University medical centre. Participants. Fifty-one adult patients who had undergone CRS-HIPEC and twenty control participants. Measurements. The inflammatory marker levels in plasma and cognitive function were measured. Results. Twenty (39.2%, 20/51) patients developed POCD at 1 w after CRS-HIPEC. The patients with POCD had higher serum interleukin 1β (IL-1β), serum amyloid A (SAA), S100 calcium-binding protein β (S-100β), and high mobility group box-1 protein (HMGB-1) levels at 1 and 24 h postoperatively than patients without POCD. There was an association between POCD and the maximum IL-1β and S-100β concentrations in serum, which remained following adjustment for age and FBS. Conclusion. In this pilot study, perioperative inflammatory marker levels increase significantly after CRS-HIPEC in adult patients, and such elevations are associated with the development of short-term cognitive dysfunction after this complex surgery. These results suggested the need for a larger RCT to replicate and confirm these findings. Hui Yu, Rui Dong, Yayuan Lu, Xi Yang, Chang Chen, Zongze Zhang, and Mian Peng Copyright © 2017 Hui Yu et al. All rights reserved. Effects of FTY720 on Lung Injury Induced by Hindlimb Ischemia Reperfusion in Rats Thu, 09 Nov 2017 00:00:00 +0000 Background. Sphingosine-1-phosphate (S1P) is a biologically active lysophospholipid mediator involved in modulating inflammatory process. We investigated the effects of FTY720, a structural analogue of S1P after phosphorylation, on lung injury induced by hindlimb ischemia reperfusion (IR) in rats. Methods. Fifty Sprague-Dawley rats were divided into groups SM, IR, F3, F5, and F10. Group SM received sham operation, and bilateral hindlimb IR was established in group IR. The rats in groups F3, F5, and F10 were pretreated with 3, 5, and 10 mg/kg/d FTY720 for 7 days before IR. S1P lyase (S1PL), sphingosine kinase (SphK) 1, and SphK2 mRNA expressions, wet/dry weight (W/D), and polymorphonuclear/alveolus (P/A) in lung tissues were detected, and the lung injury score was evaluated. Results. W/D, P/A, and mRNA expressions of S1PL, SphK1, and SphK2 were higher in group IR than in group SM, while these were decreased in both groups F5 and F10 as compared to IR (). The lung tissue presented severe lesions in group IR, which were attenuated in groups F5 and F10 with lower lung injury scores than in group IR (). Conclusions. FTY720 pretreatment could attenuate lung injury induced by hindlimb IR by modulating S1P metabolism and decreasing pulmonary neutrophil infiltration. Liangrong Wang, Feifei Chen, Yafei Pan, Lina Lin, and Xiangqing Xiong Copyright © 2017 Liangrong Wang et al. All rights reserved. Contribution of In Vivo and Organotypic 3D Models to Understanding the Role of Macrophages and Neutrophils in the Pathogenesis of Psoriasis Wed, 08 Nov 2017 00:00:00 +0000 Psoriasis, a common chronic immune-mediated skin disease, is histologically characterized by a rapid keratinocyte turnover and differentiation defects. Key insights favor the idea that T cells are not the only key actors involved in the inflammatory process. Innate immune cells, more precisely neutrophils and macrophages, provide specific signals involved in the initiation and the maintenance of the pathogenesis. Current data from animal models and, to a lesser extent, three-dimensional in vitro models have confirmed the interest in leaning towards other immune cell types as a potential new cellular target for the treatment of the disease. Although these models do not mimic the complex phenotype nor all human features of psoriasis, their development is necessary and essential to better understand reciprocal interactions between skin cells and innate immune cells and to emphasize the crucial importance of the local lesional microenvironment. In this review, through the use of in vivo and 3D organotypic models, we aim to shed light on the crosstalk between epithelial and immune components and to discuss the role of secreted inflammatory molecules in the development of this chronic skin disease. Isabelle Lorthois, Daniel Asselineau, Nathalie Seyler, and Roxane Pouliot Copyright © 2017 Isabelle Lorthois et al. All rights reserved. Taenia crassiceps Antigens Control Experimental Type 1 Diabetes by Inducing Alternatively Activated Macrophages Wed, 08 Nov 2017 00:00:00 +0000 Type 1 diabetes (T1D) is an autoimmune disease caused by the selective destruction of the pancreatic β-cells, causing inability to produce insulin. Proinflammatory cytokines such as IL-1β, IL-6, TNF-α, IFN-γ, IL-12, IL-17, and NO can be released by CD4 and CD8+ lymphocytes as well as by classically activated macrophages (CAMϕs), which are important in the development of T1D. Helminth infections have been shown to prevent T1D, mainly through Th2-biased responses and increased recruitment of regulatory cell populations. Previously, we have shown that Taenia crassiceps infection in mice significantly reduces hyperglycemia, insulitis, and the incidence of T1D. In this study, we determined whether T. crassiceps-derived products such as soluble (TcS) or excreted/secreted (TcES) antigens might have a beneficial influence on the development of experimental T1D. Treatment with different doses before or after induction of T1D was analyzed. Mice that were pretreated with TcS were unable to develop T1D, whereas those receiving TcES early after T1D induction displayed significantly reduced insulitis and hyperglycemia along with increased recruitment of alternatively activated macrophages (AAMϕs) and myeloid-derived suppressor cells (MDSCs). Finally, we examined the modulatory role of AAMϕs on T1D by depleting macrophages with clodronate-loaded liposomes, demonstrating that AAMϕs are key cells in T1D regulation. Arlett Espinoza-Jiménez, Roberto De Haro, and Luis I. Terrazas Copyright © 2017 Arlett Espinoza-Jiménez et al. All rights reserved. Inflammation, Immunity, and Cancer Mon, 06 Nov 2017 00:00:00 +0000 Rajesh Singh, Manoj Kumar Mishra, and Himanshu Aggarwal Copyright © 2017 Rajesh Singh et al. All rights reserved. Intracellular Eukaryotic Pathogens’ Virulence Attributes and Their Interplay with Host Immune Defenses Sun, 05 Nov 2017 06:04:20 +0000 Anamélia Lorenzetti Bocca, Célia Maria de Almeida Soares, Joshua D. Nosanchuk, and Ildinete Silva-Pereira Copyright © 2017 Anamélia Lorenzetti Bocca et al. All rights reserved. Recent Advances in ADAM17 Research: A Promising Target for Cancer and Inflammation Thu, 02 Nov 2017 03:32:03 +0000 Since its discovery, ADAM17, also known as TNFα converting enzyme or TACE, is now known to process over 80 different substrates. Many of these substrates are mediators of cancer and inflammation. The field of ADAM metalloproteinases is at a crossroad with many of the new potential therapeutic agents for ADAM17 advancing into the clinic. Researchers have now developed potential drugs for ADAM17 that are selective and do not have the side effects which were seen in earlier chemical entities that targeted this enzyme. ADAM17 inhibitors have broad therapeutic potential, with properties ranging from tumor immunosurveillance and overcoming drug and radiation resistance in cancer, as treatments for cardiac hypertrophy and inflammatory conditions such as inflammatory bowel disease and rheumatoid arthritis. This review focuses on substrates and inhibitors identified more recently for ADAM17 and their role in cancer and inflammation. Marcia L. Moss and Dmitry Minond Copyright © 2017 Marcia L. Moss and Dmitry Minond. All rights reserved. Adiposity Measures and Plasma Adipokines in Females with Rheumatoid and Osteoarthritis Wed, 01 Nov 2017 00:00:00 +0000 The objective of this study was to examine the relationship between adipokines and adiposity in individuals with rheumatoid and osteoarthritis in the Atlantic PATH cohort. Using a nested case-control analysis, participants in the Atlantic PATH cohort with rheumatoid or osteoarthritis were matched for measures of adiposity with participants without a history of arthritis. Both measured and self-reported data were used to examine disease status, adiposity, and lifestyle factors. Immunoassays were used to measure plasma markers. BMI was positively correlated with percentage body fat, fat mass index (FMI), and a change in BMI from 18 years of age in all 3 groups. There were no statistical differences between levels of plasma adipokines; adiponectin levels were 6.6, 7.9, and 8.2 μg/ml, leptin levels were 10.3, 13.7, and 11.5 ng/ml, and resistin levels were 10.0, 12.1, and 10.8 ng/ml in participants without arthritis, with rheumatoid arthritis, and with osteoarthritis, respectively. Those with higher levels of adiponectin were more likely to have osteoarthritis (but not rheumatoid arthritis). No association was found between arthritis types and leptin or resistin. This study demonstrates differences in measures of adiposity and adipokines in specific types of arthritis and highlights the need for more research targeting specific adipokines during arthritic disease progression. Vanessa DeClercq, Yunsong Cui, Cynthia Forbes, Scott A. Grandy, Melanie Keats, Louise Parker, Ellen Sweeney, Zhijie Michael Yu, and Trevor J. B. Dummer Copyright © 2017 Vanessa DeClercq et al. All rights reserved. Advances of Stem Cell Therapeutics in Cutaneous Wound Healing and Regeneration Sun, 29 Oct 2017 00:00:00 +0000 Cutaneous wound healing is a complex multiple phase process, which overlaps each other, where several growth factors, cytokines, chemokines, and various cells interact in a well-orchestrated manner. However, an imbalance in any of these phases and factors may lead to disruption in harmony of normal wound healing process, resulting in transformation towards chronic nonhealing wounds and abnormal scar formation. Although various therapeutic interventions are available to treat chronic wounds, current wound-care has met with limited success. Progenitor stem cells possess potential therapeutic ability to overcome limitations of the present treatments as it offers accelerated wound repair with tissue regeneration. A substantial number of stem cell therapies for cutaneous wounds are currently under development as a result of encouraging preliminary findings in both preclinical and clinical studies. However, the mechanisms by which these stem cells contribute to the healing process have yet to be elucidated. In this review, we emphasize on the major treatment modalities currently available for the treatment of the wound, role of various interstitial stem cells and exogenous adult stem cells in cutaneous wound healing, and possible mechanisms involved in the healing process. Suman Kanji and Hiranmoy Das Copyright © 2017 Suman Kanji and Hiranmoy Das. All rights reserved. Anti-Inflammatory Activity of Crude Venom Isolated from Parasitoid Wasp, Bracon hebetor Say Sun, 29 Oct 2017 00:00:00 +0000 Pest control in the agricultural fields, a major concern globally, is currently achieved through chemical or biological methods. Chemical methods, which leave toxic residue in the produce, are less preferred than biological methods. Venoms injected by stings of various wasps that kill the pest is considered as the examples of the biological method. Although several studies have investigated the biological control of pests through these venoms, very few studies have reported the effects of these venoms on mammalian cells. Bracon hebetor, an ectoparasitoid of the order Hymenoptera, is having a paramount importance in parasitizing various lepidopterous larvae including Plodia interpunctella also called as Indianmeal moth (IMM). Since it is biologically controlled by B. hebetor venom, therefore in our study, herein for the first time, we report the anti-inflammatory activities of the venom from B. hebetor (BHV). We developed a septic shock mice model for in vivo anti-inflammatory studies and RAW 264.7 cells for in vitro studies. Our results clearly demonstrate that BHV can dose dependently abrogate the nitric oxide (NO) production and suppress the levels of proinflammatory mediators and cytokines without posing any cytotoxicity via the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Evelyn Saba, Tahir Shafeeq, Muhammad Irfan, Yuan Yee Lee, Hyuk-Woo Kwon, Myung Gi Seo, Sang-Joon Park, Kyeong-Yeoll Lee, and Man Hee Rhee Copyright © 2017 Evelyn Saba et al. All rights reserved. T-Cell Subsets in Rheumatoid Arthritis Patients on Long-Term Anti-TNF or IL-6 Receptor Blocker Therapy Wed, 25 Oct 2017 03:37:04 +0000 Data on the impact of biological therapies on the T-cell phenotype in rheumatoid arthritis are limited. Here, we prospectively measured the percentages of 15 circulating T-cell subtypes using flow cytometry. We obtained transversal and longitudinal data in 30 anti-TNF responders, 19 secondary anti-TNF nonresponders, and 43 IL-6R antagonist responders, before, 8 weeks and at least 6 months after biological therapy. Untreated RA patients and healthy controls were also included. The important findings are the following: (1) the proportion of regulatory T-cells (Tregs) which are decreased in untreated RA patients becomes normal in all long-term-treated groups; (2) in anti-TNF responders as well as in nonresponders, the frequencies of naïve CD4+ and CD8+ cells are lower, whereas those of proinflammatory Th1, Th2, and Th17 cells and HLA-DR+-activated cells are higher than those in untreated RA or healthy controls; (3) in IL-6R responders, Th1 proportion is decreased, while that of Th2 and Th17 is increased as compared to that in anti-TNF-treated patients and controls; (4) pending confirmation, a CD4CD69 ratio < 2.43 at baseline, could be useful to predict a good therapeutic response to anti-TNF therapy. This study provides comprehensive information regarding the long-term impacts of those biological therapies on the ecotaxis of T-cells in RA. The registration number of our study is NCT03266822. Sonja Dulic, Zsófia Vásárhelyi, Florentina Sava, László Berta, Balázs Szalay, Gergely Toldi, László Kovács, and Attila Balog Copyright © 2017 Sonja Dulic et al. All rights reserved. HIV as a Cause of Immune Activation and Immunosenescence Wed, 25 Oct 2017 00:00:00 +0000 Systemic immune activation has emerged as an essential component of the immunopathogenesis of HIV. It not only leads to faster disease progression, but also to accelerated decline of overall immune competence. HIV-associated immune activation is characterized by an increase in proinflammatory mediators, dysfunctional T regulatory cells, and a pattern of T-cell-senescent phenotypes similar to those seen in the elderly. These changes predispose HIV-infected persons to comorbid conditions that have been linked to immunosenescence and inflamm-ageing, such as atherosclerosis and cardiovascular disease, neurodegeneration, and cancer. In the antiretroviral treatment era, development of such non-AIDS-defining, age-related comorbidities is a major cause of morbidity and mortality. Treatment strategies aimed at curtailing persistent immune activation and inflammation may help prevent the development of these conditions. At present, the most effective strategy appears to be early antiretroviral treatment initiation. No other treatment interventions have been found effective in large-scale clinical trials, and no adjunctive treatment is currently recommended in international HIV treatment guidelines. This article reviews the role of systemic immune activation in the immunopathogenesis of HIV infection, its causes and the clinical implications linked to immunosenescence in adults, and the therapeutic interventions that have been investigated. T. Sokoya, H. C. Steel, M. Nieuwoudt, and T. M. Rossouw Copyright © 2017 T. Sokoya et al. All rights reserved. Effects of NSAIDs on the Release of Calcitonin Gene-Related Peptide and Prostaglandin E2 from Rat Trigeminal Ganglia Wed, 25 Oct 2017 00:00:00 +0000 Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to treat migraine, but the mechanisms of their effects in this pathology are not fully elucidated. The trigeminal ganglia and calcitonin gene-related peptide (CGRP) have been implicated in the pathophysiology of migraine. The release of CGRP and prostaglandin E2 (PGE2) from freshly isolated rat trigeminal ganglia was evaluated after oral administration of nimesulide, etoricoxib, and ketoprofen, NSAIDs with different pharmacological features. Thirty minutes after oral administration, nimesulide, 10 mg/Kg, decreased the GCRP release induced by an inflammatory soup, while the other NSAIDs were ineffective at this point in time. Two hours after oral nimesulide (5 and 10 mg/Kg) and ketoprofen (10 mg/Kg), but not of etoricoxib, a significant decrease in the CGRP release was observed. All drugs reduced PGE2, although with some differences in timing and doses, and the action on CGRP does not seem to be related to PGE2 inhibition. The reduction of CGRP release from rat trigeminal ganglia after nimesulide and ketoprofen may help to explain the mechanism of action of NSAIDs in migraine. Since at 30 minutes only nimesulide was effective in reducing CGRP release, these results suggest that this NSAID may exert a particularly rapid effect in patients with migraine. Vittorio Vellani, Giorgia Moschetti, Silvia Franchi, Chiara Giacomoni, Paola Sacerdote, and Giada Amodeo Copyright © 2017 Vittorio Vellani et al. All rights reserved. Cardiovascular Disease in Ageing: An Overview on Thoracic Aortic Aneurysm as an Emerging Inflammatory Disease Tue, 24 Oct 2017 06:01:47 +0000 Medial degeneration associated with thoracic aortic aneurysm and acute aortic dissection was originally described by Erdheim as a noninflammatory lesion related to the loss of smooth muscle cells and elastic fibre fragmentation in the media. Recent evidences propose the strong role of a chronic immune/inflammatory process in aneurysm evocation and progression. The coexistence of inflammatory cells with markers of apoptotic vascular cell death in the media of ascending aorta with aneurysms and type A dissections raises the possibility that activated T cells and macrophages may contribute to the elimination of smooth muscle cells and degradation of the matrix. On the other hand, several inflammatory pathways (including TGF-β, TLR-4 interferon-γ, chemokines, and interferon-γ) seem to be involved in the medial degeneration related to aged and dilated aorta. This is an overview on thoracic aortic aneurysm as an emerging inflammatory disease. Calogera Pisano, Carmela Rita Balistreri, Alessandro Ricasoli, and Giovanni Ruvolo Copyright © 2017 Calogera Pisano et al. All rights reserved. Expression of the JAK/STAT Signaling Pathway in Bullous Pemphigoid and Dermatitis Herpetiformis Tue, 24 Oct 2017 00:00:00 +0000 A family of eleven proteins comprises the Janus kinases (JAK) and signal transducers and activators of transcription (STAT) signaling pathway, which enables transduction of signal from cytokine receptor to the nucleus and activation of transcription of target genes. Irregular functioning of the cascade may contribute to pathogenesis of autoimmune diseases; however, there are no reports concerning autoimmune bullous diseases yet to be published. The aim of this study was to evaluate the expression of proteins constituting the JAK/STAT signaling pathway in skin lesions and perilesional area in dermatitis herpetiformis (DH) and bullous pemphigoid (BP), as well as in the control group. Skin biopsies were collected from 21 DH patients, from 20 BP patients, and from 10 healthy volunteers. The localization and expression of selected STAT and JAK proteins were examined by immunohistochemistry and immunoblotting. We found significantly higher expression of JAK/STAT proteins in skin lesions in patients with BP and DH, in comparison to perilesional skin and the control group, which may be related to proinflammatory cytokine network and induction of inflammatory infiltrate in tissues. Our findings suggest that differences in the JAK and STAT expression may be related to distinct cytokines activating them and mediating neutrophilic and/or eosinophilic infiltrate. K. Juczynska, A. Wozniacka, E. Waszczykowska, M. Danilewicz, M. Wagrowska-Danilewicz, J. Wieczfinska, R. Pawliczak, and A. Zebrowska Copyright © 2017 K. Juczynska et al. All rights reserved. The Role of High-Mobility Group Box-1 and Its Crosstalk with Microbiome in Rheumatoid Arthritis Mon, 23 Oct 2017 05:51:22 +0000 Rheumatoid arthritis (RA) is a chronic, definitely disabling, and potentially severe autoimmune disease. Although an increasing number of patients are affected, a key treatment for all patients has not been discovered. High-mobility group box-1 (HMGB1) is a nuclear protein passively and actively released by almost all cell types after several stimuli. HMGB1 is involved in RA pathogenesis, but a convincing explanation about its role and possible modulation in RA is still lacking. Microbiome and its homeostasis are altered in patients with RA, and the microbiota restoration has been proposed to patients with RA. The purpose of the present review is to analyze the available evidences regarding HMGB1 and microbiome roles in RA and the possible implications of the crosstalk between the nuclear protein and microbiome in understanding and possibly treating patients affected by this harmful condition. Federico Biscetti, Andrea Flex, Stefano Alivernini, Barbara Tolusso, Elisa Gremese, and Gianfranco Ferraccioli Copyright © 2017 Federico Biscetti et al. All rights reserved. Prevention of Memory Impairment and Neurotrophic Factors Increased by Lithium in Wistar Rats Submitted to Pneumococcal Meningitis Model Sun, 22 Oct 2017 00:00:00 +0000 The aim of this study was to investigate the effects of lithium on brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF) expression in the hippocampus and on memory in experimental pneumococcal meningitis. The mood-stabilizer lithium is known as a neuroprotective agent with many effects on the brain. In this study, animals received either artificial cerebrospinal fluid or Streptococcus pneumoniae suspension at a concentration of 5 × 109 CFU/mL. Eighteen hours after induction, all animals received ceftriaxone. The animals received saline or lithium (47.5 mg/kg) or tamoxifen (1 mg/kg) as adjuvant treatment, and they were separated into six groups: control/saline, control/lithium, control/tamoxifen, meningitis/saline, meningitis/lithium, and meningitis/tamoxifen. Ten days after meningitis induction, animals were subjected to open-field habituation and the step-down inhibitory avoidance tasks. Immediately after these tasks, the animals were killed and their hippocampus was removed to evaluate the expression of BDNF, NGF, and GDNF. In the meningitis group, treatment with lithium and tamoxifen resulted in improvement in memory. Meningitis group showed decreased expression of BDNF and GDNF in the hippocampus while lithium reestablished the neurotrophin expression. Lithium was able to prevent memory impairment and reestablishes hippocampal neurotrophin expression in experimental pneumococcal meningitis. Lutiana R. Simões, Roberta R. E. S. Abreu, Jaqueline S. Generoso, Jéssica A. Goularte, Allan Collodel, Vijayasree Vayalanellore Giridharan, Anitha Christy Sigamani Arumanayagam, Samira S. Valvassori, João Quevedo, and Tatiana Barichello Copyright © 2017 Lutiana R. Simões et al. All rights reserved. Proportions of Proinflammatory Monocytes Are Important Predictors of Mortality Risk in Hemodialysis Patients Sun, 22 Oct 2017 00:00:00 +0000 Despite the continuous progression in dialysis medicine, mortality and the burden of cardiovascular disease (CVD) among hemodialysis patients are still substantial. Substantial evidence suggests that proinflammatory (CD16+) monocytes contribute to the development of atherosclerosis. A cohort of 136 stable hemodialysis patients (follow-up: 6.25 year) was assessed to investigate the association between the proportion of CD16+ monocytes for all-cause and CVD mortalities. The CD16+ monocytes were associated with both mortalities after adjusting for a preexisting CVD history. Compared to the reference group (CD16+ monocytes within [15.6–18.6], the first and second quartile), patients with CD16+ monocytes above the highest quartile level (>21.5) had an adjusted hazard ratio (HR) of 30.85 (95% confidence interval [CI]: 7.12–133.8) for CVD mortality and 5.28 (2.07–13.49) for all-cause mortality, and those with CD16+ monocytes below the lowest quartile ≤15.6), had significantly elevated death risks after 3.5-year follow-up (HR [95% CI]: 10.9 [2.42–48.96] and 4.38 [1.45–13.24] for CV and all-cause mortalities, respectively). The hemodialysis patients with CD16+ monocyte level in a low but mostly covering normal range also portended a poor prognosis. The findings shed some light for nephrologists on future prospects of early recognizing immune dysfunction and improving early intervention outcomes. Yachung Jeng, Paik Seong Lim, Ming Ying Wu, Tien-Yu Tseng, Chang Hsu Chen, Hung Ping Chen, and Tsai-Kun Wu Copyright © 2017 Yachung Jeng et al. All rights reserved. Davallia mariesii Moore Improves FcεRI-Mediated Allergic Responses in the Rat Basophilic Leukemia Mast Cell Line RBL-2H3 and Passive Cutaneous Anaphylaxis in Mice Thu, 19 Oct 2017 00:00:00 +0000 Davallia mariesii Moore (Drynaria rhizome extract (DRE)) is widely known for its efficacy in treating inflammation, arteriosclerosis, and bone injuries. This study evaluated whether treatment with DRE inhibited FcɛRI-mediated allergic responses in the RBL-2H3 mast cells and investigated the early- and late-phase mechanisms by which DRE exerts its antiallergic effects. IgE anti-DNP/DNP-HSA-sensitized RBL-2H3 mast cells were tested for cytotoxicity to DRE, followed by the assessment of β-hexosaminidase release. We measured the amounts of inflammatory mediators (e.g., histamine, PGD2, TNF-α, IL-4, and IL-6) and examined the expression of genes involved in arachidonate and FcεRI signaling pathways. In addition, we confirmed the antiallergic effects of DRE on passive cutaneous anaphylaxis (PCA) in mice. DRE inhibited RBL-2H3 mast cell degranulation and production of allergic mediators in them. In early allergic responses, DRE reduced expression of FcεRI signaling-related genes (e.g., Syk, Lyn, and Fyn) and extracellular signal-regulated kinase phosphorylation in mast cells. In late allergic responses, DRE reduced PGD2 release and COX-2 expression and cPLA2 phosphorylation in FcɛRI-mediated mast cells. Lastly, 250–500 mg/kg DRE significantly attenuated the IgE-induced PCA reaction in mice. These findings provide novel information on the molecular mechanisms underlying the antiallergic effects of DRE in FcɛRI-mediated allergic responses. Hyun Ju Do, Tae Woo Oh, Ju Hye Yang, Kwang Il Park, and Jin Yeul Ma Copyright © 2017 Hyun Ju Do et al. All rights reserved. Triggering Receptor Expressed on Myeloid Cells 2 Overexpression Inhibits Proinflammatory Cytokines in Lipopolysaccharide-Stimulated Microglia Wed, 18 Oct 2017 06:08:03 +0000 Microglia play an important role in mediating inflammatory processes in the central nervous system (CNS). Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor and could decrease neuropathology in Alzheimer’s disease (AD). However, the detailed mechanism remains unclear. This study was designed to elucidate the effect of TREM2 on microglia. We showed that lipopolysaccharide (LPS) stimulation significantly increases proinflammatory cytokines and suppressed TREM2 in microglia. In addition, TREM2 overexpression inhibited LPS-induced microglia activation and elevated M2 phenotype of microglia. Together, our results demonstrate that TREM2 overexpression reduced LPS-induced proinflammatory cytokine release in microglia and increased M2 phenotype of microglia. These findings provide novel insights that the regulation of microglia polarization may be an approach for ameliorating microglia inflammation in neurodegenerative diseases. Xiaobao Zhang, Fang Yan, Jizheng Cui, Yong Wu, Hengfei Luan, Miaomiao Yin, Zhibin Zhao, Jiying Feng, and Jinwei Zhang Copyright © 2017 Xiaobao Zhang et al. All rights reserved. IL-33-ST2 Axis in Liver Disease: Progression and Challenge Wed, 18 Oct 2017 05:11:58 +0000 The new member of the IL-1 family, interleukin-33 (IL-33), participates in the progression of a variety of diseases through binding with its receptor ST2. Recently, much clinical evidence and experimental data have indicated that IL-33 is associated with various liver diseases. This review primarily addresses the relationship between IL-33 and several hepatic diseases. IL-33 can alleviate high-fat diet- (HFD-) induced hepatic steatosis and insulin resistance, and IL-33 acts as an alarmin, which quickly triggers the immune system to respond to virus invasion and toxic damage to the liver. However, when liver injury is chronic, IL-33 promotes Th2 reactions and hepatic stellate cell (HSC) activity, facilitating progression to liver fibrosis. The complicated functions of IL-33 should be considered before its clinical application. Zijian Sun, Binxia Chang, Miaomiao Gao, Jiyuan Zhang, and Zhengsheng Zou Copyright © 2017 Zijian Sun et al. All rights reserved. Skin Immune Landscape: Inside and Outside the Organism Wed, 18 Oct 2017 00:00:00 +0000 The skin is an essential organ to the human body protecting it from external aggressions and pathogens. Over the years, the skin was proven to have a crucial immunological role, not only being a passive protective barrier but a network of effector cells and molecular mediators that constitute a highly sophisticated compound known as the “skin immune system” (SIS). Studies of skin immune sentinels provided essential insights of a complex and dynamic immunity, which was achieved through interaction between the external and internal cutaneous compartments. In fact, the skin surface is cohabited by microorganisms recognized as skin microbiota that live in complete harmony with the immune sentinels and contribute to the epithelial barrier reinforcement. However, under stress, the symbiotic relationship changes into a dysbiotic one resulting in skin disorders. Hence, the skin microbiota may have either positive or negative influence on the immune system. This review aims at providing basic background information on the cutaneous immune system from major cellular and molecular players and the impact of its microbiota on the well-coordinated immune responses in host defense. Florence Abdallah, Lily Mijouin, and Chantal Pichon Copyright © 2017 Florence Abdallah et al. All rights reserved. Toll-Like Receptor 4 Signalling and Its Impact on Platelet Function, Thrombosis, and Haemostasis Tue, 17 Oct 2017 07:32:45 +0000 Platelets are anucleated blood cells that participate in a wide range of physiological and pathological functions. Their major role is mediating haemostasis and thrombosis. In addition to these classic functions, platelets have emerged as important players in the innate immune system. In particular, they interact with leukocytes, secrete pro- and anti-inflammatory factors, and express a wide range of inflammatory receptors including Toll-like receptors (TLRs), for example, Toll-like receptor 4 (TLR4). TLR4, which is the most extensively studied TLR in nucleated cells, recognises lipopolysaccharides (LPS) that are compounds of the outer surface of Gram-negative bacteria. Unlike other TLRs, TLR4 is able to signal through both the MyD88-dependent and MyD88-independent signalling pathways. Notably, despite both pathways culminating in the activation of transcription factors, TLR4 has a prominent functional impact on platelet activity, haemostasis, and thrombosis. In this review, we summarise the current knowledge on TLR4 signalling in platelets, critically discuss its impact on platelet function, and highlight the open questions in this area. Thomas M. Vallance, Marie-Theres Zeuner, Harry F. Williams, Darius Widera, and Sakthivel Vaiyapuri Copyright © 2017 Thomas M. Vallance et al. All rights reserved. Suppressed Programmed Death 1 Expression on CD4+ and CD8+ T Cells in Psoriatic Patients Tue, 17 Oct 2017 00:00:00 +0000 Psoriasis is a chronic inflammatory disease mediated by T cell immunity. Programmed death 1 (PD-1), a coinhibitory receptor, plays an important role in immune regulation and maintaining peripheral tolerance. The aim of the study was to compare the expression of PD-1 on the peripheral T cells between psoriatic patients and healthy controls. The study included 75 psoriatic patients and 52 healthy volunteers. The percentages and absolute numbers of CD3+, CD4+, CD8+, CD4+PD-1+, and CD8+PD-1+ T cells were analyzed using flow cytometry. The absolute numbers and percentages of CD4+PD-1+ and CD8+PD-1+ T cells were significantly decreased in the psoriatic patients in comparison with the control group. No significant correlations were found between the absolute numbers and percentages of CD4+PD-1+ or CD8+PD-1+ T cells and clinical characteristics of psoriasis. Decreased PD-1 expression on the T cells may be responsible for impaired negative regulation of immune response in psoriasis pathogenesis. Joanna Bartosińska, Ewelina Zakrzewska, Dorota Raczkiewicz, Joanna Purkot, Anna Michalak-Stoma, Małgorzata Kowal, Dorota Krasowska, Grażyna Chodorowska, and Krzysztof Giannopoulos Copyright © 2017 Joanna Bartosińska et al. All rights reserved. Corrigendum to “Hydrogen-Rich Saline Attenuates Cardiac and Hepatic Injury in Doxorubicin Rat Model by Inhibiting Inflammation and Apoptosis” Tue, 17 Oct 2017 00:00:00 +0000 Yunan Gao, Hongxiao Yang, Yanbin Fan, Lin Li, Jiahui Fang, and Wei Yang Copyright © 2017 Yunan Gao et al. All rights reserved. Retracted: Treadmill Training Increases SIRT-1 and PGC-1α Protein Levels and AMPK Phosphorylation in Quadriceps of Middle-Aged Rats in an Intensity-Dependent Manner Mon, 16 Oct 2017 00:00:00 +0000 Mediators of Inflammation Copyright © 2017 Mediators of Inflammation. All rights reserved.