Mediators of Inflammation The latest articles from Hindawi © 2018 , Hindawi Limited . All rights reserved. Critical Role of HAX-1 in Promoting Avian Influenza Virus Replication in Lung Epithelial Cells Tue, 16 Jan 2018 00:00:00 +0000 The PB1-F2 protein of influenza A virus has been considered a virulence factor, but its function in inducing apoptosis may be of disadvantage to viral replication. Host mechanisms to regulate PB1-F2-induced apoptosis remain unknown. We generated a PB1-F2-deficient avian influenza virus (AIV) H9N2 and found that the mutant virus replicated less efficiently in human lung epithelial cells. The PB1-F2-deficient virus produced less apoptotic cells, indicating that PB1-F2 of the H9N2 virus promotes apoptosis, occurring at the early stage of infection, in the lung epithelial cells. To understand how host cells regulate PB1-F2-induced apoptosis, we explored to identify cellular proteins interacting with PB1-F2 and found that HCLS1-associated protein X-1 (HAX-1), located mainly in the mitochondria as an apoptotic inhibitor, interacted with PB1-F2. Increased procaspase-9 activations, induced by PB1-F2, could be suppressed by HAX-1. In HAX-1 knockdown A549 cells, the replication of AIV H9N2 was suppressed in parallel to the activation of caspase-3 activation, which increased at the early stage of infection. We hypothesize that HAX-1 promotes AIV replication by interacting with PB1-F2, resulting in the suppression of apoptosis, prolonged cell survival, and enhancement of viral replication. Our data suggest that HAX-1 may be a promoting factor for AIV H9N2 replication through desensitizing PB1-F2 from its apoptotic induction in human lung epithelial cells. Xue Li, Bingqian Qu, Ganlin He, Carol J. Cardona, Yongchun Song, and Zheng Xing Copyright © 2018 Xue Li et al. All rights reserved. Increase of Vascular Endothelial Growth Factor and Decrease of MCP-1 and Some Updated Epidemiology Aspects of Cystic Echinococcosis Human Cases in Calabria Region Sun, 14 Jan 2018 00:00:00 +0000 We aim to investigate some of the pathogenetic mediators of the human echinococcosis and to obtain updated epidemiological findings on cases of echinococcosis in Calabria, Southern Italy. Echinococcosis diagnosis was based on imaging, serological investigations, and molecular assay. Indeed, real-time PCR indicated the presence of G2/G3 genotypes of Echinococcus granulosus complex. Regarding pathogenesis, a relevant novel tool of immune depression should be deemed the reduced level of serum MCP-1. Also, we found a previously unreported VEGF, possibly associated with neovascularization requested by the parasite cyst metabolism. Cytokine profiles suggest a bias of the immunity toward Th2 and Treg responses. Nitric oxide levels exhibited a significant decrease one week after therapy versus basal level measured before surgery and/or chemotherapy. An increase of serum total IgE class and IgG4 subclass was found in Echinococcus-positive patients versus controls. Our data demonstrated an endemic spreading, at least in the province of Catanzaro and neighboring Calabria territories, for such parasitosis with the novel issue of the number of female overcoming male cases. In conclusion, the novel findings of this study were the increased VEGF and the reduced serum MCP-1 in the studied cases, as well as the number of Echinococcus-infected females overcoming the infected males. Giovanni Matera, Maria Teresa Loria, Cinzia Peronace, Tatiana Catanzariti, Pio Settembre, Aida Giancotti, Angelo G. Lamberti, Giorgio S. Barreca, Luisa Galati, Gessica Dodaro, Maria Mazzitelli, Alessio Strazzulla, Carlo Torti, Angela Quirino, Maria Carla Liberto, and Alfredo Focà Copyright © 2018 Giovanni Matera et al. All rights reserved. Corrigendum to “Chemokines and Heart Disease: A Network Connecting Cardiovascular Biology to Immune and Autonomic Nervous Systems” Wed, 10 Jan 2018 09:09:47 +0000 Veronica Dusi, Alice Ghidoni, Alice Ravera, Gaetano M. De Ferrari, and Laura Calvillo Copyright © 2018 Veronica Dusi et al. All rights reserved. The EGFR-ADAM17 Axis in Chronic Obstructive Pulmonary Disease and Cystic Fibrosis Lung Pathology Tue, 09 Jan 2018 00:00:00 +0000 Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) share molecular mechanisms that cause the pathological symptoms they have in common. Here, we review evidence suggesting that hyperactivity of the EGFR/ADAM17 axis plays a role in the development of chronic lung disease in both CF and COPD. The ubiquitous transmembrane protease A disintegrin and metalloprotease 17 (ADAM17) forms a functional unit with the EGF receptor (EGFR), in a feedback loop interaction labeled the ADAM17/EGFR axis. In airway epithelial cells, ADAM17 sheds multiple soluble signaling proteins by proteolysis, including EGFR ligands such as amphiregulin (AREG), and proinflammatory mediators such as the interleukin 6 coreceptor (IL-6R). This activity can be enhanced by injury, toxins, and receptor-mediated external triggers. In addition to intracellular kinases, the extracellular glutathione-dependent redox potential controls ADAM17 shedding. Thus, the epithelial ADAM17/EGFR axis serves as a receptor of incoming luminal stress signals, relaying these to neighboring and underlying cells, which plays an important role in the resolution of lung injury and inflammation. We review evidence that congenital CFTR deficiency in CF and reduced CFTR activity in chronic COPD may cause enhanced ADAM17/EGFR signaling through a defect in glutathione secretion. In future studies, these complex interactions and the options for pharmaceutical interventions will be further investigated. Marta Stolarczyk and Bob J. Scholte Copyright © 2018 Marta Stolarczyk and Bob J. Scholte. All rights reserved. Formononetin Administration Ameliorates Dextran Sulfate Sodium-Induced Acute Colitis by Inhibiting NLRP3 Inflammasome Signaling Pathway Mon, 08 Jan 2018 00:00:00 +0000 Formononetin is a kind of isoflavone compound and has been reported to possess anti-inflammatory properties. In this present study, we aimed to explore the protective effects of formononetin on dextran sulfate sodium- (DSS-) induced acute colitis. By intraperitoneal injection of formononetin in mice, the disease severity of colitis was attenuated in a dose-dependent manner, mainly manifesting as relieved clinical symptoms of colitis, mitigated colonic epithelial cell injury, and upregulations of colonic tight junction proteins levels (ZO-1, claudin-1, and occludin). Meanwhile, our study found that formononetin significantly prevented acute injury of colonic cells induced by TNF-α in vitro, specifically manifesting as the increased expressions of colonic tight junction proteins (ZO-1, claudin-1, and occludin). In addition, the result showed that formononetin could reduce the NLRP3 pathway protein levels (NLRP3, ASC, IL-1β) in vivo and vitro, and MCC950, the NLRP3 specific inhibitor, could alleviate the DSS-induced mice acute colitis. Furthermore, in the foundation of administrating MCC950 to inhibit activation of NLRP3 inflammasome, we failed to observe the protective effects of formononetin on acute colitis in mice. Collectively, our study for the first time confirmed the protective effects of formononetin on DSS-induced acute colitis via inhibiting the NLRP3 inflammasome pathway activation. Dacheng Wu, Keyan Wu, Qingtian Zhu, Weiming Xiao, Qing Shan, Zhigang Yan, Jian Wu, Bin Deng, Yan Xue, Weijuan Gong, Guotao Lu, and Yanbing Ding Copyright © 2018 Dacheng Wu et al. All rights reserved. Targeted Delivery of the HLA-B27-Binding Peptide into the Endoplasmic Reticulum Suppresses the IL-23/IL-17 Axis of Immune Cells in Spondylarthritis Sun, 31 Dec 2017 00:00:00 +0000 Ankylosing spondylitis (AS) is highly associated with the expression of human leukocyte antigen-B27 (HLA-B27). HLA-B27 heavy chain (B27-HC) has an intrinsic propensity to fold slowly, leading to the accumulation of the misfolded B27-HC in the endoplasmic reticulum (ER) and formation of the HLA-B27 HC homodimer, (B27-HC)2, by a disulfide linkage at Cys-67. (B27-HC)2 displayed on the cell surface can act as a ligand of the killer-cell Ig-like receptor (KIR3DL2). (B27-HC)2 binds to KIR3DL2 of NK and Th17 cells and activates both cells, resulting in the activation of the IL-23/IL-17 axis to launch the inflammatory reaction in AS patients. However, activation of the IL-23/IL-17 axis originally derived from the HLA-B27 misfolding in the ER needs to be characterized. In this study, we delivered two HLA-B27-binding peptides, KRGILTLKY and SRYWAIRTR, into the ER by using a tat-derived peptide (GRKKRRQRRR)-His6-ubiquitin (THU) vehicle. Both peptides are derived from the human actin and nucleoprotein of influenza virus, respectively. Our results demonstrated that targeted delivery of both HLA-B27-binding peptides into the ER can promote the HLA-B27 folding, decrease the levels of (B27-HC)2, and suppress the activation of the IL-23/IL-17 axis in response to lipopolysaccharide. Our findings can provide a new therapeutic strategy in AS. Hui-Chun Yu, Kuang-Yung Huang, Ming-Chi Lu, Hsien-Lu Huang, Su-Qin Liu, Ning-Sheng Lai, and Hsien-Bin Huang Copyright © 2017 Hui-Chun Yu et al. All rights reserved. Phenotypic and Functional Properties of Tumor-Infiltrating Regulatory T Cells Sun, 31 Dec 2017 00:00:00 +0000 Regulatory T (Treg) cells maintain immune homeostasis by suppressing excessive immune responses. Treg cells induce tolerance against self- and foreign antigens, thus preventing autoimmunity, allergy, graft rejection, and fetus rejection during pregnancy. However, Treg cells also infiltrate into tumors and inhibit antitumor immune responses, thus inhibiting anticancer therapy. Depleting whole Treg cell populations in the body to enhance anticancer treatments will produce deleterious autoimmune diseases. Therefore, understanding the precise nature of tumor-infiltrating Treg cells is essential for effectively targeting Treg cells in tumors. This review summarizes recent results relating to Treg cells in the tumor microenvironment, with particular emphasis on their accumulation, phenotypic, and functional properties, and targeting to enhance the efficacy of anticancer treatment. Gap Ryol Lee Copyright © 2017 Gap Ryol Lee. All rights reserved. Cigarette Smoke Exposure Inhibits Bacterial Killing via TFEB-Mediated Autophagy Impairment and Resulting Phagocytosis Defect Thu, 28 Dec 2017 08:41:32 +0000 Introduction. Cigarette smoke (CS) exposure is the leading risk factor for COPD-emphysema pathogenesis. A common characteristic of COPD is impaired phagocytosis that causes frequent exacerbations in patients leading to increased morbidity. However, the underlying mechanism is unclear. Hence, we investigated if CS exposure causes autophagy impairment as a mechanism for diminished bacterial clearance via phagocytosis by utilizing murine macrophages (RAW264.7 cells) and Pseudomonas aeruginosa (PA01-GFP) as an experimental model. Methods. Briefly, RAW cells were treated with cigarette smoke extract (CSE), chloroquine (autophagy inhibitor), TFEB-shRNA, CFTR(inh)-172, and/or fisetin prior to bacterial infection for functional analysis. Results. Bacterial clearance of PA01-GFP was significantly impaired while its survival was promoted by CSE (), autophagy inhibition (; ), TFEB knockdown (; ), and inhibition of CFTR function (; ) in comparison to the control group(s) that was significantly recovered by autophagy-inducing antioxidant drug, fisetin, treatment (; ; and ). Moreover, investigations into other pharmacological properties of fisetin show that it has significant mucolytic and bactericidal activities (; ), which warrants further investigation. Conclusions. Our data suggests that CS-mediated autophagy impairment as a critical mechanism involved in the resulting phagocytic defect, as well as the therapeutic potential of autophagy-inducing drugs in restoring is CS-impaired phagocytosis. Garrett Pehote, Manish Bodas, Kathryn Brucia, and Neeraj Vij Copyright © 2017 Garrett Pehote et al. All rights reserved. Inflammatory and Immune-Mediated Cutaneous Diseases Wed, 27 Dec 2017 00:14:30 +0000 Juarez A. S. Quaresma, Mirian N. Sotto, and Anna Balato Copyright © 2017 Juarez A. S. Quaresma et al. All rights reserved. Mitochondrial (Dys) Function in Inflammaging: Do MitomiRs Influence the Energetic, Oxidative, and Inflammatory Status of Senescent Cells? Wed, 27 Dec 2017 00:10:32 +0000 A relevant feature of aging is chronic low-grade inflammation, termed inflammaging, a key process promoting the development of all major age-related diseases. Senescent cells can acquire the senescence-associated (SA) secretory phenotype (SASP), characterized by the secretion of proinflammatory factors fuelling inflammaging. Cellular senescence is also accompanied by a deep reshaping of microRNA expression and by the modulation of mitochondria activity, both master regulators of the SASP. Here, we synthesize novel findings regarding the role of mitochondria in the SASP and in the inflammaging process and propose a network linking nuclear-encoded SA-miRNAs to mitochondrial gene regulation and function in aging cells. In this conceptual structure, SA-miRNAs can translocate to mitochondria (SA-mitomiRs) and may affect the energetic, oxidative, and inflammatory status of senescent cells. We discuss the potential role of several of SA-mitomiRs (i.e., let-7b, miR-1, miR-130a-3p, miR-133a, miR-146a-5p, miR-181c-5p, and miR-378-5p), using miR-146a as a proof-of-principle model. Finally, we propose a comprehensive, metabolic, and epigenetic view of the senescence process, in order to amplify the range of possible approaches to target inflammaging, with the ultimate goal of decelerating the aging rate, postponing or blunting the development of age-related diseases. Angelica Giuliani, Francesco Prattichizzo, Luigina Micolucci, Antonio Ceriello, Antonio Domenico Procopio, and Maria Rita Rippo Copyright © 2017 Angelica Giuliani et al. All rights reserved. Cigarette Smoking and Adipose Tissue: The Emerging Role in Progression of Atherosclerosis Wed, 27 Dec 2017 00:00:00 +0000 Smoking is an established risk factor for atherosclerosis through several underlying pathways. Moreover, in the development of atherosclerotic plaque formation, obesity, defined as excess fat mass accumulation, also plays a vital role in dyslipidemia and insulin resistance. Substantial evidence shows that cigarette smoking induces multiple pathological effects in adipose tissue, such as differentiation of adipocytes, lipolysis, and secretion properties in adipose tissue. Therefore, there is an emerging speculation in which adipose tissue abnormality induced by smoking or nicotine is likely to accelerate the progression of atherosclerosis. Herein, this review aims to investigate the possible interplay between smoking and adipose tissue dysfunction in the development of atherosclerosis. Zhiyan Wang, Di Wang, and Yi Wang Copyright © 2017 Zhiyan Wang et al. All rights reserved. Distinct Signature of Oxylipid Mediators of Inflammation during Infection and Asymptomatic Colonization by E. coli in the Urinary Bladder Wed, 27 Dec 2017 00:00:00 +0000 Urinary tract infection (UTI) is an extremely common infectious disease. Uropathogenic Escherichia coli (UPEC) is the predominant etiological agent of UTI. Asymptomatic bacteriuric E. coli (ABEC) strains successfully colonize the urinary tract resulting in asymptomatic bacteriuria (ABU) and do not induce symptoms associated with UTI. Oxylipids are key signaling molecules involved in inflammation. Based on the distinct clinical outcomes of E. coli colonization, we hypothesized that UPEC triggers the production of predominantly proinflammatory oxylipids and ABEC leads to production of primarily anti-inflammatory or proresolving oxylipids in the urinary tract. We performed quantitative detection of 39 oxylipid mediators with proinflammatory, anti-inflammatory, and proresolving properties, during UTI and ABU caused by genetically distinct E. coli strains in the murine urinary bladder. Our results reveal that infection with UPEC causes an increased accumulation of proinflammatory oxylipids as early as 6 h postinoculation, compared to controls. To the contrary, ABEC colonization leads to decreased accumulation of proinflammatory oxylipids at the early time point compared to UPEC infection but does not affect the level of proresolving oxylipids. This report represents the first comprehensive investigation on the oxylipidome during benign ABEC colonization observed in ABU and acute inflammation triggered by UPEC leading to UTI. Nandakumar Packiriswamy, Jeff Gandy, Sara N. Smith, Harry L. T. Mobley, Lorraine M. Sordillo, and Sargurunathan Subashchandrabose Copyright © 2017 Nandakumar Packiriswamy et al. All rights reserved. Comparison of Oropharyngeal Microbiota from Children with Asthma and Cystic Fibrosis Wed, 27 Dec 2017 00:00:00 +0000 A genuine microbiota resides in the lungs which emanates from the colonization by the oropharyngeal microbiota. Changes in the oropharyngeal microbiota might be the source of dysbiosis observed in the lower airways in patients suffering from asthma or cystic fibrosis (CF). To examine this hypothesis, we compared the throat microbiota from healthy children () and that from children with asthma () and CF () aged 6 to 12 years using 16S rRNA amplicon sequencing. Our results show high levels of similarities between healthy controls and children with asthma and CF revealing the existence of a core microbiome represented by Prevotella, Streptococcus, Neisseria, Veillonella, and Haemophilus. However, in CF, the global diversity, the bacterial load, and abundances of 53 OTUs were significantly reduced, whereas abundances of 6 OTUs representing opportunistic pathogens such as Pseudomonas, Staphylococcus, and Streptococcus were increased compared to those in healthy controls controls and asthmatics. Our data reveal a core microbiome in the throat of healthy children that persists in asthma and CF indicating shared host regulation favoring growth of commensals. Furthermore, we provide evidence for dysbiosis with a decrease in diversity and biomass associated with the presence of known pathogens consistent with impaired host defense in children with CF. Sébastien Boutin, Martin Depner, Mirjam Stahl, Simon Y. Graeber, Susanne A. Dittrich, Antje Legatzki, Erika von Mutius, Marcus Mall, and Alexander H. Dalpke Copyright © 2017 Sébastien Boutin et al. All rights reserved. Significant Cytokine mRNA Expression Changes Immediately after Initiation of Cardiopulmonary Resuscitation Wed, 27 Dec 2017 00:00:00 +0000 Introduction. The purpose of this study was to evaluate immediate immunological changes following cardiopulmonary resuscitation (CPR). mRNA expression levels of selected immunomodulatory cytokines in out-of-hospital cardiac arrest (OHCA) survivors were detected and correlated to clinical parameter. Methods. OHCA survivors with sustained unconsciousness after return of spontaneous circulation (ROSC) were included. PAXgene whole blood samples were drawn immediately after initiation of CPR and subsequently after 6 h, 12 h, 24 h, 48 h, and 72 h. TNF-alpha, IL-8, IL-10, and IL-1ra mRNA levels were quantified by RT-qPCR and compared to multiple organ failure, 30-day survival, and the induction of therapeutic hypothermia (TH). Results. 25 patients (63 ± 15 years) were enrolled presenting a characteristic time-dependent cytokine profile in the early postresuscitation period. High initial TNF-alpha and IL-8 mRNA levels were followed by a significant decrease. IL-1ra mRNA levels significantly increased beginning after 6 h. Nonsurvivors showed significantly higher IL-8 mRNA levels immediately after CPR. TH induced significantly higher IL-1ra mRNA levels compared to normothermia. Conclusion. Significant mRNA cytokine expression changes are already detectable immediately after initiation of CPR. These expressional changes are significantly different depending on 30-day survival. TH seems to attenuate proinflammatory immune reaction by a significant increase of IL-1ra mRNA levels. This trial is registered with DRKS00012940. Mareen Braunstein, Martina Williamson, Thomas Kusmenkov, Jürgen Landes, Peter Biberthaler, Karl-Georg Kanz, Wolfgang Böcker, and Viktoria Bogner Copyright © 2017 Mareen Braunstein et al. All rights reserved. Saquinavir Ameliorates Liver Warm Ischemia-Reperfusion-Induced Lung Injury via HMGB-1- and P38/JNK-Mediated TLR-4-Dependent Signaling Pathways Tue, 26 Dec 2017 00:00:00 +0000 Liver ischemia and reperfusion (I/R) induce local and distant tissue injuries, contributing to morbidity and mortality in a wider range of pathologies. This is especially seen under uncontrolled aseptic inflammatory conditions, leading to injury of remote organs, such as lung injury, and even failure. Saquinavir (SQV) is a kind of HIV protease inhibitor that possesses an anti-inflammatory property. In this study, we investigated whether SQV suppresses Toll-like receptor 4- (TLR4-) dependent signaling pathways of high-mobility group box 1 (HMGB1) and P38/JNK, conferring protection against murine liver I/R-induced lung injury. To investigate our hypothesis, C57BL/6 mice and TLR4 knockout mice (TLR4−/−) were used to perform the study. SQV administration markedly attenuated remote lung tissue injury after 1-hour ischemia and 6-hour reperfusion of the liver. To our expectation, SQV attenuated I/R-induced lung edema, hyperpermeability, and pathological injury. The beneficial effects of SQV were associated with decreased levels of circulating and lung tissue inflammatory cytokines, such as IL-6, IL-1β, TNF-α, and iNOS. The protective effect of SQV was also associated with decreased lung tissue expression of HMGB1, TLR-4, and p-P38/JNK, but not p-ERK in wild-type liver I/R mice. Overall, this study demonstrated a new role of SQV, facilitating negative regulation of HMGB1- and P38/JNK-mediated TLR-4-dependent signaling pathways, conferring protection against liver I/R-induced lung injury. Zhuang Yu, Yao Tong, Renlingzi Zhang, Xibing Ding, and Quan Li Copyright © 2017 Zhuang Yu et al. All rights reserved. MicroRNA-146a Alleviates Experimental Autoimmune Anterior Uveitis in the Eyes of Lewis Rats Sun, 24 Dec 2017 00:00:00 +0000 Purpose. This study aimed to determine the effect and roles of microRNA (miRNA, miR) treatment in experimental autoimmune anterior uveitis (EAAU). Materials and Methods. Uveitis was induced in Lewis rats by simultaneous injections of bovine melanin-associated antigen into the hind footpad and the intraperitoneal cavity. The animals were injected intravitreally with low-dose (0.5 μg) or high-dose (1.5 μg) miR-146a. The clinical scores, leukocyte count in the aqueous humor, and histology were assessed. Cytokine changes were evaluated by relative mRNA expression and enzyme-linked immunosorbent assay (ELISA). The expression of nuclear factor kappa B (NF-κB) was assessed by immunofluorescence and Western blotting. Evaluation of the DNA-binding activity of NF-κB was performed by electrophoretic mobility shift assay (EMSA). Results. Treatment with miR-146a significantly attenuated clinical scores and leukocyte infiltration in a dose-dependent manner, a result that was compatible with histological findings. Following miR-146a injections, downregulation of interleukin- (IL-) 1β, IL-6, and IL-12 and interferon- (IFN-) γ and upregulation of IL-10 and IL-17 were noted. The decreased NF-κB expression on immunofluorescence and Western blotting and reduced DNA-binding activity on EMSA were demonstrated following miR-146a treatment. Conclusions. miR-146a effectively reduced intraocular inflammation in EAAU through the inhibition of NF-κB. miR-146a might be a new treatment choice for uveitis. Yung-Ray Hsu, Shu-Wen Chang, Yu-Cheng Lin, and Chang-Hao Yang Copyright © 2017 Yung-Ray Hsu et al. All rights reserved. Protective Effects of Methotrexate against Proatherosclerotic Cytokines: A Review of the Evidence Thu, 21 Dec 2017 00:00:00 +0000 There is good epidemiological evidence that patients with autoimmune rheumatic disease states, particularly rheumatoid arthritis, have an increased risk of cardiovascular morbidity and mortality when compared to the general population. The presence of a chronic systemic proinflammatory state in this patient group disrupts the structural and functional integrity of the endothelium and the arterial wall, favouring the onset and progression of atherosclerosis. A significant role in the detrimental effects of inflammation on endothelial function and vascular homeostasis is played by specific proatherosclerotic cytokines such as tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). Recent systematic reviews and meta-analyses have shown that treatment with methotrexate, a first-line disease-modifying antirheumatic drug (DMARD), is associated with a significant reduction in atherosclerosis-mediated cardiovascular events, such as myocardial infarction and stroke, and mortality, when compared to other DMARDs. This suggests that methotrexate might exert specific protective effects against vascular inflammation and atherosclerosis in the context of autoimmune rheumatic disease. This review discusses the available evidence regarding the potential antiatherosclerotic effects of methotrexate through the inhibition of TNF-α, IL-1, and IL-6 and provides suggestions for future experimental and human studies addressing this issue. Arduino A. Mangoni, Angelo Zinellu, Salvatore Sotgia, Ciriaco Carru, Matteo Piga, and Gian Luca Erre Copyright © 2017 Arduino A. Mangoni et al. All rights reserved. Corrigendum to “Metabolic Syndrome, Inflammation, and Cancer” Thu, 21 Dec 2017 00:00:00 +0000 Yong Wu, Yunzhou Dong, Shengzhong Duan, Donghui Zhu, and Lin Deng Copyright © 2017 Yong Wu et al. All rights reserved. Autotaxin-Lysophosphatidic Acid: From Inflammation to Cancer Development Thu, 21 Dec 2017 00:00:00 +0000 Lysophosphatidic acid (LPA) is a ubiquitous lysophospholipid and one of the main membrane-derived lipid signaling molecules. LPA acts as an autocrine/paracrine messenger through at least six G protein-coupled receptors (GPCRs), known as LPA1–6, to induce various cellular processes including wound healing, differentiation, proliferation, migration, and survival. LPA receptors and autotaxin (ATX), a secreted phosphodiesterase that produces this phospholipid, are overexpressed in many cancers and impact several features of the disease, including cancer-related inflammation, development, and progression. Many ongoing studies aim to understand ATX-LPA axis signaling in cancer and its potential as a therapeutic target. In this review, we discuss the evidence linking LPA signaling to cancer-related inflammation and its impact on cancer progression. Silvia Anahi Valdés-Rives and Aliesha González-Arenas Copyright © 2017 Silvia Anahi Valdés-Rives and Aliesha González-Arenas. All rights reserved. Serum Interleukin-23 in Polish Patients with Systemic Lupus Erythematosus: Association with Lupus Nephritis, Obesity, and Peripheral Vascular Disease Thu, 21 Dec 2017 00:00:00 +0000 Objectives. To analyze the correlation between the serum concentration of interleukin- (IL-) 23 and atherosclerotic changes, traditional atherosclerotic risk factors, the autoantibody profile, and involvement of selected organs in systemic lupus erythematosus (SLE) patients. Patients and Methods. We studied 94 SLE patients and 27 controls. We analyzed the IL-23 serum concentration, autoantibodies, carotid intima-media thickness and atherosclerotic plaque, the ankle-brachial index, atherosclerotic risk factors, and organ manifestations. Results. Concentrations of IL-23 significantly differed between SLE patients and the controls (). On the basis of multivariate stepwise analysis, we revealed that high levels of IL-23 were associated with atherosclerotic plaque in common femoral arteries (OR = 12.67; 95% CI: 1.41–113.84), lupus nephritis (OR = 3.69; 95% CI: 1.16–12.22), and obesity (OR = 4.21; 95% CI: 1.40–12.67). Autoantibodies related to IL-23 were anti-phosphatidylethanolamine antibodies (OR = 11.06; 95% CI: 1.24–98.65) and anti-SS-B/La antibodies (OR = 15.43; 95% CI: 1.73–137.25). Conclusions. IL-23 may be involved in lupus nephritis pathogenesis. Through its association with obesity and selected antiphospholipid antibodies, IL-23 might promote a hypercoagulable state contributing to atherothrombosis development in SLE patients. Katarzyna Fischer, Hanna Przepiera-Będzak, Marcin Sawicki, Anna Walecka, Iwona Brzosko, and Marek Brzosko Copyright © 2017 Katarzyna Fischer et al. All rights reserved. Administration of FTY720 during Tourniquet-Induced Limb Ischemia Reperfusion Injury Attenuates Systemic Inflammation Tue, 19 Dec 2017 09:17:02 +0000 Acute ischemia-reperfusion injury (IRI) of the extremities leads to local and systemic inflammatory changes which can hinder limb function and can be life threatening. This study examined whether the administration of the T-cell sequestration agent, FTY720, following hind limb tourniquet-induced skeletal muscle IRI in a rat model would attenuate systemic inflammation and multiple end organ injury. Sprague-Dawley rats were subjected to 1 hr of ischemia via application of a rubber band tourniquet. Animals were randomized to receive an intravenous bolus of either vehicle control or FTY720 15 min after band placement. Rats (/time point) were euthanized at 6, 24, and 72 hr post-IRI. Peripheral blood as well as lung, liver, kidney, and ischemic muscle tissue was analyzed and compared between groups. FTY720 treatment markedly decreased the number of peripheral blood T cells () resulting in a decreased systemic inflammatory response and lower serum creatinine levels and had a modest but significant effect in decreasing the transcription of injury-associated target genes in multiple end organs. These findings suggest that early intervention with FTY720 may benefit the treatment of IRI of the limb. Further preclinical studies are necessary to characterize the short-term and long-term beneficial effects of FTY720 following tourniquet-induced IRI. Anthony D. Foster, Diego Vicente, Jonathan J. Sexton, Luke Johnston, Nick Clark, Crystal Leonhardt, Eric A. Elster, Thomas A. Davis, and Matthew J. Bradley Copyright © 2017 Anthony D. Foster et al. All rights reserved. Increased Abundance of Plasmacytoid Dendritic Cells and Interferon-Alpha Induces Plasma Cell Differentiation in Patients of IgA Nephropathy Mon, 18 Dec 2017 06:46:57 +0000 The roles of pDC and IFN-α have not been well defined in IgA nephropathy (IgAN). In this study, we investigated the abundance of pDCs and IFN-α in IgAN patients and the response of peripheral blood mononuclear cells (PBMCs) after stimulation of the pDC-preferred TLR9 ligand CpG2216. The effects of IFN-α on plasma cell differentiation and leukocyte migration were also investigated. Here, we found that the percentages of pDCs were increased in PBMCs of IgAN patients, than in those of healthy controls. Plasma levels of IFN-α proteins and abundance of plasma cells were higher in IgAN patients than in healthy donors. Plasma IFN-α levels were positively associated with proteinuria, renal IgM deposition, and renal tubular atrophy/interstitial fibrosis grade in IgAN patients. Ex vivo activation of TLR9 on pDCs resulted in increased IFN-α production and enhanced plasma cell differentiation in IgAN patients as compared with healthy donors. IFN-α treatment led to increased plasma cell differentiation in vitro. IFN-α also significantly promoted expression of chemokines IP-10 and MCP-1 in human mesangial cells, which subsequently facilitated the transendothelial migration of human CD4+ and CD14+ cells. In conclusion, pDC and its secreted cytokine IFN-α may play important roles in pathological changes of IgA nephropathy. Nuoyan Zheng, Bing Wang, Jinjin Fan, Ning Luo, Qingyu Kong, Hongjian Ye, Jiqin Zhang, Hongyan Ming, and Xueqing Yu Copyright © 2017 Nuoyan Zheng et al. All rights reserved. Inhibiting Interleukin 17 Can Ameliorate the Demyelination Caused by A. cantonensis via iNOS Inhibition Mon, 18 Dec 2017 00:00:00 +0000 Angiostrongylus cantonensis (A. cantonensis) is an important food-borne parasitic disease. Previous study showed that A. cantonensis infection can cause demyelination in the central nerve system, but the mechanism of action has not been understood. To explore the mechanism and to look for effective therapeutic methods, interleukin 17A (IL-17A) and iNOS expressions were detected during A. cantonensis infection. In addition, IL-17A-neutralizing antibody was applied to treat A. cantonensis-infected mice. In our results, we found that IL-17A and iNOS RNA expressions increased gradually in the process of A. cantonensis infection. When infected mice were treated with IL-17A-neutralizing antibody, the pathologic changes of demyelination alleviated obviously, followed with the elevation of myelin basic protein (MBP) in the brain. In addition, the iNOS expression of the brain in infected animals also showed a decrease in astrocytes. Our study provided evidence that IL-17A may take part in the demyelination caused by A. cantonensis and inhibiting IL-17A expression can ameliorate the pathologic changes of demyelination. Moreover, the decreasing of iNOS expression may be the key reason for the effect of IL-17A inhibition on demyelination caused by A. cantonensis. Feng Ying, Zheng Cunjing, Feng Feng, Wan Shuo, Zeng Xin, Xie Fukang, and Wu Zhongdao Copyright © 2017 Feng Ying et al. All rights reserved. HaCaT Cells as a Reliable In Vitro Differentiation Model to Dissect the Inflammatory/Repair Response of Human Keratinocytes Sun, 17 Dec 2017 00:00:00 +0000 Cultured primary human keratinocytes are frequently employed for studies of immunological and inflammatory responses; however, interpretation of experimental data may be complicated by donor to donor variability, the relatively short culture lifetime, and variations between passages. To standardize the in vitro studies on keratinocytes, we investigated the use of HaCaT cells, a long-lived, spontaneously immortalized human keratinocyte line which is able to differentiate in vitro, as a suitable model to follow the release of inflammatory and repair mediators in response to TNFα or IL-1β. Different treatment conditions (presence or absence of serum) and differentiation stimuli (increase in cell density as a function of time in culture and elevation of extracellular calcium) were considered. ELISA and Multiplex measurement technologies were used to monitor the production of cytokines and chemokines. Taken together, the results highlight that Ca2+ concentration in the medium, cell density, and presence of serum influences at different levels the release of proinflammatory mediators by HaCaT cells. Moreover, HaCaT cells maintained in low Ca2+ medium and 80% confluent are similar to normal keratinocytes in terms of cytokine production suggesting that HaCaT cells may be a useful model to investigate anti-inflammatory interventions/therapies on skin diseases. Irma Colombo, Enrico Sangiovanni, Roberta Maggio, Carlo Mattozzi, Stefania Zava, Yolanda Corbett, Marco Fumagalli, Claudia Carlino, Paola Antonia Corsetto, Diletta Scaccabarozzi, Stefano Calvieri, Angela Gismondi, Donatella Taramelli, and Mario Dell’Agli Copyright © 2017 Irma Colombo et al. All rights reserved. The Role of Lower Airway Dysbiosis in Asthma: Dysbiosis and Asthma Wed, 13 Dec 2017 06:39:26 +0000 With the development of culture-independent techniques, numerous studies have demonstrated that the lower airway is not sterile in health and harbors diverse microbial communities. Furthermore, new evidence suggests that there is a distinct lower airway microbiome in those with chronic respiratory disease. To understand the role of lower airway dysbiosis in the pathogenesis of asthma, in this article, we review the published reports about the lung microbiome of healthy controls, provide an outlook on the contribution of lower airway dysbiosis to asthma, especially steroid-resistant asthma, and discuss the potential therapies targeted for lower airway dysbiosis. Junying Lu, Lingxin Xiong, Xiaohao Zhang, Zhongmin Liu, Shiji Wang, Chao Zhang, Jingtong Zheng, Guoqiang Wang, Ruipeng Zheng, Jodie L. Simpson, and Fang Wang Copyright © 2017 Junying Lu et al. All rights reserved. Different Dietary Proportions of Fish Oil Regulate Inflammatory Factors but Do Not Change Intestinal Tight Junction ZO-1 Expression in Ethanol-Fed Rats Wed, 13 Dec 2017 00:00:00 +0000 Sixty male Wistar rats were fed a control or an ethanol-containing diet in groups C or E. The fat compositions were adjusted with 25% or 57% fish oil substituted for olive oil in groups CF25, CF57, EF25, and EF57. Hepatic thiobarbituric acid-reactive substance (TBARS) levels, cytochrome P450 2E1 protein expression, and tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, and IL-10 levels, as well as intracellular adhesion molecule (ICAM)-1 levels were significantly elevated, whereas plasma adiponectin level was significantly reduced in group E (). Hepatic histopathological scores of fatty change and inflammation, in group E were significantly higher than those of group C (). Hepatic TBARS, plasma ICAM-1, and hepatic TNF-α, IL-1β, and IL-10 levels were significantly lower, and plasma adiponectin levels were significantly higher in groups EF25 and EF57 than those in group E (). The immunoreactive area of the intestinal tight junction protein, ZO-1, showed no change between groups C and E. Only group CF57 displayed a significantly higher ZO-1 immunoreactive area compared to group C (). 25% or 57% fish oil substituted for dietary olive oil could prevent ethanol-induced liver damage in rats, but the mechanism might not be related to intestinal tight junction ZO-1 expression. Yi-Wen Chien, Hsiang-Chi Peng, Ya-Ling Chen, Man-Hui Pai, Hsiao-Yun Wang, Hsiao-Li Chuang, and Suh-Ching Yang Copyright © 2017 Yi-Wen Chien et al. All rights reserved. HIF1α-Induced Glycolysis Metabolism Is Essential to the Activation of Inflammatory Macrophages Wed, 13 Dec 2017 00:00:00 +0000 Hypoxia-inducible factor (HIF) 1α is a metabolic regulator that plays an important role in immunologic responses. Previous studies have demonstrated that HIF1α participates in the M1 polarization of macrophages. To clarify the mechanism of HIF1α-induced polarization of M1 macrophage, myeloid-specific HIF1α overexpression (Lysm HIF1α lsl) mice were employed and the bone marrow-derived and peritoneal macrophages were isolated. RT-PCR results revealed that HIF1α overexpression macrophage had a hyperinflammatory state characterized by the upregulation of M1 markers. Cellular bioenergetics analysis showed lower cellular oxygen consumption rates in the Lysm HIF1α lsl mice. Metabolomics studies showed that HIF1α overexpression led to increased glycolysis and pentose phosphate pathway intermediates. Further results revealed that macrophage M1 polarization, induced by HIF1α overexpression, was via upregulating the mRNA expression of the genes related to the glycolysis metabolism. Our results indicate that HIF1α promoted macrophage glycolysis metabolism, which induced M1 polarization in mice. Ting Wang, Huiying Liu, Guan Lian, Song-Yang Zhang, Xian Wang, and Changtao Jiang Copyright © 2017 Ting Wang et al. All rights reserved. Gene Expression, Oxidative Stress, and Senescence of Primary Coronary Endothelial Cells Exposed to Postprandial Serum of Healthy Adult and Elderly Volunteers after Oven-Cooked Meat Meals Tue, 12 Dec 2017 05:06:19 +0000 Epidemiological studies have linked high consumption of meat with major age-related diseases including cardiovascular diseases. Abnormal postprandial increases in plasma lipids after a meat meal have been hypothesized among the pathogenetic mechanisms. However, it is still unknown if the postprandial serum derived after a normal meat meal is able to affect endothelial function, and if the type of meat and the age of the donors are critical factors. Here, we show the effects of postprandial sera derived from healthy adults and elderly volunteers who consumed meat meals on human coronary artery endothelial cell (HCAEC) oxidative stress, gene expression, DNA damage, and cellular senescence. We observed that a single exposure to postprandial serum induces a slight increase in ROS that is associated with modulation of gene expression pathways related to oxidative stress response and metabolism. The postprandial-induced increase in ROS is not associated with a measurable DNA oxidative damage. However, repeated exposure to postprandial serum induces an acceleration of cellular senescence. Taking into account the deleterious role of cellular senescence in age-related vascular diseases, the results suggest a new mechanism by which excessive meat consumption and time spent in postprandial state may affect health status during aging. Costarelli Laura, Giacconi Robertina, Francesco Piacenza, Andrea Basso, Deborah Pacetti, Michele Balzano, Riccardo Gagliardi, Natale Giuseppe Frega, Eugenio Mocchegiani, Mauro Provinciali, and Marco Malavolta Copyright © 2017 Costarelli Laura et al. All rights reserved. Small Intestinal Bacterial Overgrowth Affects the Responsiveness to Colchicine in Familial Mediterranean Fever Tue, 12 Dec 2017 00:00:00 +0000 Objective. Familial Mediterranean fever (FMF) is an autosomal recessive disease due to a MEFV gene mutation. Since Helicobacter pylori infection has been described to increase the severity and frequency of FMF attacks, we evaluate if overgrowth of small intestinal bacterial (SIBO), associated with a release of bacterial products, can affect the response to colchicine in FMF patients poorly responsive to colchicine. Methods. We revised our Periodic Fever Centre database to detect FMF patients who were poorly responsive to colchicine, without a well-defined cause of drug resistance. They were evaluated for SIBO presence, then treated with decontamination therapy. Results. Among 223 FMF patients, 49 subjects show colchicine resistance, and no other known causes of colchicine unresponsiveness has been found in 25 patients. All 25 patients underwent glucose breath test; 20 (80%) of them were positive, thus affected by SIBO. After a successful decontamination treatment, 11 patients (55%) did not show FMF attacks during the following three months (), while 9 of them revealed a significant reduction of the number of attacks compared to three months before (). Conclusion. The SIBO eradication improves laboratory and clinical features of FMF patients. Thus, patients with unresponsiveness to colchicine treatment should be investigated for SIBO. E. Verrecchia, L. L. Sicignano, M. La Regina, G. Nucera, I. Patisso, L. Cerrito, M. Montalto, A. Gasbarrini, and R. Manna Copyright © 2017 E. Verrecchia et al. All rights reserved. Nuclear Translocation of SGPP-1 and Decrease of SGPL-1 Activity Contribute to Sphingolipid Rheostat Regulation of Inflammatory Dendritic Cells Mon, 11 Dec 2017 10:00:09 +0000 A balanced sphingolipid rheostat is indispensable for dendritic cell function and survival and thus initiation of an immune response. Sphingolipid levels are dynamically maintained by the action of sphingolipid enzymes of which sphingosine kinases, S1P phosphatases (SGPP-1/2) and S1P lyase (SGPL-1), are pivotal in the balance of S1P and sphingosine levels. In this study, we present that SGPP-1 and SGPL-1 are regulated in inflammatory dendritic cells and contribute to S1P fate. TLR-dependent activation caused SGPL-1 protein downregulation with subsequent decrease of enzymatic activity by two-thirds. In parallel, confocal fluorescence microscopy revealed that endogenous SGPP-1 was expressed in nuclei of naive dendritic cells and was translocated into the cytoplasmatic compartment upon inflammatory stimulation resulting in dephosphorylation of S1P. Mass spectrometric determination showed that a part of the resulting sphingosine was released from the cell, increasing extracellular levels. Another route of diminishing intracellular S1P was possibly taken by its export via ATP-binding cassette transporter C1 which was upregulated in array analysis, while the S1P transporter, spinster homolog 2, was not relevant in dendritic cells. These investigations newly describe the sequential expression and localization of the endogenous S1P regulators SGPP-1 and SGPL-1 and highlight their contribution to the sphingolipid rheostat in inflammation. Anja Schwiebs, Dominique Thomas, Burkhard Kleuser, Josef M. Pfeilschifter, and Heinfried H. Radeke Copyright © 2017 Anja Schwiebs et al. All rights reserved.