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https://www.readbyqxmd.com/read/27931982/jak-inhibitor-tofacitinib-suppresses-interferon-alfa-production-by-plasmacytoid-dendritic-cells-and-inhibits-arthrogenic-and-antiviral-effects-of-interferon-alfa
#1
Patrick P C Boor, Petra E de Ruiter, Patrick S Asmawidjaja, Erik Lubberts, Luc J W van der Laan, Jaap Kwekkeboom
Tofacitinib is an oral Janus kinase inhibitor that is effective for the treatment of rheumatoid arthritis and shows encouraging therapeutic effects in several other autoimmune diseases. A prominent adverse effect of tofacitinib therapy is the increased risk of viral infections. Despite its advanced stage of clinical development, the modes of action that mediate the beneficial and adverse effects of tofacitinib in autoimmune diseases remain unclear. Interferon alfa (IFNα) produced by plasmacytoid dendritic cells (PDCs) is critically involved in the pathogenesis of many systemic autoimmune diseases and in immunity to viral infections...
November 20, 2016: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/27916941/autoimmune-regulator-expression-in-dc2-4-cells-regulates-the-nf-%C3%AE%C2%BAb-signaling-and-cytokine-expression-of-the-toll-like-receptor-3-pathway
#2
Jitong Sun, Kunwei Niu, Haiying Fu, Haijun Li, Yi Li, Wei Yang
Autoimmune regulator (Aire) mutations result in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), which manifests as multi-organ autoimmunity and chronic mucocutaneous candidiasis (CMC). Indendritic cells (DCs), pattern recognition receptors (PRR), such as Toll-like receptors (TLRs), are closely involved in the recognition of various pathogens, activating the intercellular signaling pathway, followed by the activation of transcription factors and the expression of downstream genes, which take part in mediating the immune response and maintaining immune tolerance...
December 1, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27911948/tlr3-induced-maturation-of-murine-dendritic-cells-regulates-ctl-responses-by-modulating-pd-l1-trafficking
#3
Aditi Varthaman, Hélène D Moreau, Mathieu Maurin, Philippe Benaroch
Targeting TLR3 through formulations of polyI:C is widely studied as an adjuvant in cancer immunotherapy. The efficacy of such targeting has been shown to increase in combination with anti-PD-L1 treatment. Nevertheless, the mechanistic details of the effect of polyI:C on DC maturation and the impact on T-DC interactions upon PD-L1 blockade is largely unknown. Here we found that although DC treatment with polyI:C induced a potent inflammatory response including the production of type I interferon, polyI:C treatment of DCs impaired activation of peptide specific CD8+ T cells mainly due to PD-L1...
2016: PloS One
https://www.readbyqxmd.com/read/27910914/in-vivo-stepwise-immunomodulation-using-chitosan-nanoparticles-as-a-platform-nanotechnology-for-cancer-immunotherapy
#4
Hee Dong Han, Yeongseon Byeon, Jong-Hwa Jang, Hat Nim Jeon, Ga Hee Kim, Min Gi Kim, Chan-Gi Pack, Tae Heung Kang, In Duk Jung, Yong Taik Lim, Young Joo Lee, Jeong-Won Lee, Byung Cheol Shin, Hyung Jun Ahn, Anil K Sood, Yeong-Min Park
Dentritic cell (DC)-based cancer immunotherapy faces challenges in both efficacy and practicality. However, DC-based vaccination requires multiple injections and elaborates ex vivo manipulation, which substantially limits their use. Therefore, we sought to develop a chitosan nanoparticle (CH-NP)-based platform for the next generation of vaccines to bypass the ex vivo manipulation and induce immune responses via active delivery of polyinosinic-polycytidylic acid sodium salt (poly I:C) to target Toll-like receptor 3 (TLR3) in endosomes...
December 2, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27895399/altered-pattern-of-tumor-necrosis-factor-alpha-production-in-peripheral-blood-monocytes-from-crohn-s-disease
#5
Claudia Loganes, Alessia Pin, Samuele Naviglio, Martina Girardelli, Anna Monica Bianco, Stefano Martelossi, Alberto Tommasini, Elisa Piscianz
AIM: To evaluate the inflammatory state in Crohn's disease (CD) patients and correlate it with genetic background and microbial spreading. METHODS: By means of flow cytometry, production of tumor necrosis factor-alpha (TNF-α) was measured in peripheral blood monocytes from patients suffering from CD, ulcerative colitis (UC) and in healthy subjects after stimulation of the NOD2 and TLR pathways. CD patients were genotyped for the three most common NOD2 variants (R702W, G908R and L1007Pfs*2) and basal production of TNF-α was correlated to NOD2 genotype...
November 7, 2016: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/27891130/molecular-mechanisms-that-underlie-the-dynamic-adaptation-of-innate-monocyte-memory-to-varying-stimulant-strength-of-tlr-ligands
#6
Ruoxi Yuan, Shuo Geng, Liwu Li
In adaptation to rising stimulant strength, innate monocytes can be dynamically programed to preferentially express either pro- or anti-inflammatory mediators. Such dynamic innate adaptation or programing may bear profound relevance in host health and disease. However, molecular mechanisms that govern innate adaptation to varying strength of stimulants are not well understood. Using lipopolysaccharide (LPS), the model stimulant of toll-like-receptor 4 (TLR4), we reported that the expressions of pro-inflammatory mediators are preferentially sustained in monocytes adapted by lower doses of LPS, and suppressed/tolerized in monocytes adapted by higher doses of LPS...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27881733/lysosomal-trafficking-regulator-lyst-links-membrane-trafficking-to-toll-like-receptor-mediated-inflammatory-responses
#7
Andreas Westphal, Weijia Cheng, Jinbo Yu, Guntram Grassl, Martina Krautkrämer, Otto Holst, Niko Föger, Kyeong-Hee Lee
Subcellular compartmentalization of receptor signaling is an emerging principle in innate immunity. However, the functional integration of receptor signaling pathways into membrane trafficking routes and its physiological relevance for immune responses is still largely unclear. In this study, using Lyst-mutant beige mice, we show that lysosomal trafficking regulator Lyst links endolysosomal organization to the selective control of toll-like receptor 3 (TLR3)- and TLR4-mediated proinflammatory responses. Consequently, Lyst-mutant mice showed increased susceptibility to bacterial infection and were largely resistant to endotoxin-induced septic shock...
November 23, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27881328/immunostimulatory-capacity-of-dental-casting-alloys-on-endotoxin-responsiveness
#8
Dessy Rachmawati, B Mary E von Blomberg, Cornelis J Kleverlaan, Rik J Scheper, Ingrid M W van Hoogstraten
STATEMENT OF PROBLEM: Oral metal exposure has been associated with systemic and local adverse reactions, probably due to elemental release from the alloys. Although supraphysiological concentrations of salts from dentally applied metals can activate innate cells through TLR4 (Ni, Co, Pd) and TLR3 (Au), whether direct exposure to solid alloys can also trigger innate immune reactivity is still unknown. PURPOSE: The purpose of this in vitro study was to determine whether dental cast alloy specimens can activate innate cells and influence their responsiveness to bacterial endotoxin...
October 27, 2016: Journal of Prosthetic Dentistry
https://www.readbyqxmd.com/read/27873163/an-update-on-the-use-of-immunomodulators-in-primary-immunodeficiencies
#9
REVIEW
Pandiarajan Vignesh, Amit Rawat, Surjit Singh
The genomic revolution in the past decade fuelled by breathtaking advances in sequencing technologies has defined several new genetic diseases of the immune system. Many of these newly characterized diseases are a result of defects in genes involved in immune regulation. The discovery of these diseases has opened a vista of new therapeutic possibilities. Immunomodulatory agents, a hitherto unexplored therapeutic option in primary immunodeficiency diseases have been tried in a host of these newly described maladies...
November 21, 2016: Clinical Reviews in Allergy & Immunology
https://www.readbyqxmd.com/read/27863662/surface-assembled-poly-i-c-on-pegylated-plga-microspheres-as-vaccine-adjuvant-apc-activation-and-bystander-cell-stimulation
#10
Annina M Hafner, Blaise Corthésy, Marcus Textor, Hans P Merkle
Biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres are potential vehicles to deliver antigens for vaccination. Because they lack the full capacity to activate professional antigen presenting cells (APCs), combination with an immunostimulatory adjuvant may be considered. A candidate is the synthetic TLR3 ligand polyriboinosinic acid-polyribocytidylic acid, poly(I:C), which drives cell-mediated immunity. However, poly(I:C) has also been linked to the pathogenesis of autoimmunity, as affected by widespread stimulation of non-hematopoietic bystander cells...
November 30, 2016: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/27846843/strong-inflammatory-responses-and-apoptosis-in-the-oviducts-of-egg-laying-hens-caused-by-genotype-viid-newcastle-disease-virus
#11
Ruiqiao Li, Kangkang Guo, Caihong Liu, Jing Wang, Dan Tan, Xueying Han, Chao Tang, Yanming Zhang, Jingyu Wang
BACKGROUND: Newcastle disease virus (NDV) can cause serious damage to the reproductive tracts of egg-laying hens and leads to egg production and quality reduction. However, the mechanism of severe pathological damage in the oviducts of egg-laying hens after NDV infection has not been fully elucidated. In this study, the correlation between the primary pathological lesions and viral load in the oviducts of egg-laying hens infected with the velogenic genotype VIId NDV strain was evaluated by pathological observation and virus detection...
November 15, 2016: BMC Veterinary Research
https://www.readbyqxmd.com/read/27845762/recent-progress-in-the-molecular-recognition-and-therapeutic-importance-of-interleukin-1-receptor-associated-kinase-4
#12
REVIEW
Mahesh Chandra Patra, Sangdun Choi
Toll-like receptors (TLRs) are the most upstream pattern recognition receptors in the cell, which detect pathogen associated molecular patterns and initiate signal transduction, culminating in the transcription of pro-inflammatory cytokines and antiviral interferon. Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key mediator in TLR (except for TLR3) and interleukin-1 receptor signaling pathways. The loss of kinase function of IRAK4 is associated with increased susceptibility to various pathogens, while its over-activation causes autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and cancer...
November 13, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27834952/double-stranded-rna-promotes-ctl-independent-tumor-cytolysis-mediated-by-cd11b-ly6g-intratumor-myeloid-cells-through-the-ticam-1-signaling-pathway
#13
Hiroaki Shime, Misako Matsumoto, Tsukasa Seya
PolyI:C, a synthetic double-stranded RNA analog, acts as an immune-enhancing adjuvant that regresses tumors in cytotoxic T lymphocyte (CTL)-dependent and CTL-independent manner, the latter of which remains largely unknown. Tumors contain CD11b(+)Ly6G(+) cells, known as granulocytic myeloid-derived suppressor cells (G-MDSCs) or tumor-associated neutrophils (TANs) that play a critical role in tumor progression and development. Here, we demonstrate that CD11b(+)Ly6G(+) cells respond to polyI:C and exhibit tumoricidal activity in an EL4 tumor implant model...
November 11, 2016: Cell Death and Differentiation
https://www.readbyqxmd.com/read/27830702/hyperglycaemia-inhibits-reg3a-expression-to-exacerbate-tlr3-mediated-skin-inflammation-in-diabetes
#14
Yelin Wu, Yanchun Quan, Yuanqi Liu, Keiwei Liu, Hongquan Li, Ziwei Jiang, Tian Zhang, Hu Lei, Katherine A Radek, Dongqing Li, Zhenhua Wang, Jilong Lu, Wang Wang, Shizhao Ji, Zhaofan Xia, Yuping Lai
Dysregulated inflammatory responses are known to impair wound healing in diabetes, but the underlying mechanisms are poorly understood. Here we show that the antimicrobial protein REG3A controls TLR3-mediated inflammation after skin injury. This control is mediated by REG3A-induced SHP-1 protein, and acts selectively on TLR3-activated JNK2. In diabetic mouse skin, hyperglycaemia inhibits the expression of IL-17-induced IL-33 via glucose glycation. The decrease in cutaneous IL-33 reduces REG3A expression in epidermal keratinocytes...
November 10, 2016: Nature Communications
https://www.readbyqxmd.com/read/27830700/sensing-of-hsv-1-by-the-cgas-sting-pathway-in-microglia-orchestrates-antiviral-defence-in-the-cns
#15
Line S Reinert, Katarína Lopušná, Henriette Winther, Chenglong Sun, Martin K Thomsen, Ramya Nandakumar, Trine H Mogensen, Morten Meyer, Christian Vægter, Jens R Nyengaard, Katherine A Fitzgerald, Søren R Paludan
Herpes simplex encephalitis (HSE) is the most common form of acute viral encephalitis in industrialized countries. Type I interferon (IFN) is important for control of herpes simplex virus (HSV-1) in the central nervous system (CNS). Here we show that microglia are the main source of HSV-induced type I IFN expression in CNS cells and these cytokines are induced in a cGAS-STING-dependent manner. Consistently, mice defective in cGAS or STING are highly susceptible to acute HSE. Although STING is redundant for cell-autonomous antiviral resistance in astrocytes and neurons, viral replication is strongly increased in neurons in STING-deficient mice...
November 10, 2016: Nature Communications
https://www.readbyqxmd.com/read/27825367/involvement-of-the-different-lung-compartments-in-the-pathogenesis-of-ph1n1-influenza-virus-infection-in-ferrets
#16
Beatriz Vidaña, Jorge Martínez, Jaime Martorell, María Montoya, Lorena Córdoba, Mónica Pérez, Natàlia Majó
Severe cases after pH1N1 infection are consequence of interstitial pneumonia triggered by alveolar viral replication and an exacerbated host immune response, characterized by the up-regulation of pro-inflammatory cytokines and the influx of inflammatory leukocytes to the lungs. Different lung cell populations have been suggested as culprits in the unregulated innate immune responses observed in these cases. This study aims to clarify this question by studying the different induction of innate immune molecules by the distinct lung anatomic compartments (vascular, alveolar and bronchiolar) of ferrets intratracheally infected with a human pH1N1 viral isolate, by means of laser microdissection techniques...
November 8, 2016: Veterinary Research
https://www.readbyqxmd.com/read/27818460/different-expression-patterns-of-toll-like-receptor-mrnas-in-blood-mononuclear-cells-of-iga-nephropathy-and-iga-vasculitis-with-nephritis
#17
Ayano Saito, Atsushi Komatsuda, Hajime Kaga, Ryuta Sato, Masaru Togashi, Shin Okuyama, Hideki Wakui, Naoto Takahashi
Mucosal immunity may play a key role in IgA nephropathy (IgAN) and IgA vasculitis with nephritis (IgAVN). IgAVN is characterized by the presence of non-thrombocytopenic palpable purpura, associated with glomerulonephritis with IgA-dominant immune deposits. Recent studies have shown the up-regulation of Toll-like receptors (TLRs) in patients with IgAN or IgAVN. Among TLRs that mediate innate immune reactions, TLR2, TLR4, and TRL5 recognize bacterial components, while TLR3, TLR7, and TLR9 recognize viral components...
2016: Tohoku Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27810922/-lubac-deficiency-perturbs-tlr3-signaling-to-cause-immunodeficiency-and-autoinflammation
#18
Julia Zinngrebe, Eva Rieser, Lucia Taraborrelli, Nieves Peltzer, Torsten Hartwig, Hongwei Ren, Ildikó Kovács, Cornelia Endres, Peter Draber, Maurice Darding, Silvia von Karstedt, Johannes Lemke, Balazs Dome, Michael Bergmann, Brian J Ferguson, Henning Walczak
The linear ubiquitin chain assembly complex (LUBAC), consisting of SHANK-associated RH-domain-interacting protein (SHARPIN), heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1), and HOIL-1-interacting protein (HOIP), is a critical regulator of inflammation and immunity. This is highlighted by the fact that patients with perturbed linear ubiquitination caused by mutations in the Hoip or Hoil-1 genes, resulting in knockouts of these proteins, may simultaneously suffer from immunodeficiency and autoinflammation. TLR3 plays a crucial, albeit controversial, role in viral infection and tissue damage...
November 14, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27805282/toll-like-receptor-3-stimulation-triggers-metabolic-reprogramming-in-pharyngeal-cancer-cell-line-through-myc-mapk-and-hif
#19
Tanja Matijevic Glavan, Ana Cipak Gasparovic, Benjamin Vérillaud, Pierre Busson, Jasminka Pavelic
Toll-like receptor 3 (TLR3) has a dual role in cancer; its activation can trigger apoptosis as well as stimulate cancer cell survival, proliferation, and progression. We have shown here that TLR3 activation can induce metabolic reprogramming in a pharyngeal cancer cell line, leading to increased aerobic glycolysis, cell migration, elevated levels of reactive oxidative species (ROS), and decreased anti-oxidative response. Key proteins in these signaling pathways are heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), pyruvate kinase M2 (PKM2), and CD44 variants, which were over-expressed after TLR3 stimulation...
November 2, 2016: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/27795434/clec5a-mediated-enhancement-of-the-inflammatory-response-in-myeloid-cells-contributes-to-influenza-pathogenicity-in-vivo
#20
Ooiean Teng, Szu-Ting Chen, Tsui-Ling Hsu, Sin Fun Sia, Suzanne Cole, Sophie A Valkenburg, Tzu-Yun Hsu, Jian Teddy Zheng, Wenwei Tu, Roberto Bruzzone, Joseph Sriyal Malik Peiris, Shie-Liang Hsieh, Hui-Ling Yen
: Human infections with influenza viruses exhibit mild to severe clinical outcome as a result of complex virus-host interactions. Induction of inflammatory mediators via pattern recognition receptors may dictate subsequent host responses for pathogen clearance and tissue damage. We identified that human C-type lectin member 5A (CLEC5A) interacts with the hemagglutinin protein of influenza viruses expressed on lentiviral pseudoparticles through lectin screening. Silencing CLEC5A gene expression, blocking influenza-CLEC5A interactions with anti-CLEC5A antibodies, or dampening CLEC5A-mediated signaling using a spleen tyrosine kinase inhibitor consistently reduced the levels of pro-inflammatory cytokines produced by human macrophages without affecting the replication of influenza A viruses of different subtypes...
October 19, 2016: Journal of Virology
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