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https://www.readbyqxmd.com/read/28515281/cxcl4-exposure-potentiates-tlr-driven-polarization-of-human-monocyte-derived-dendritic-cells-and-increases-stimulation-of-t-cells
#1
Sandra C Silva-Cardoso, Alsya J Affandi, Lotte Spel, Marta Cossu, Joel A G van Roon, Marianne Boes, Timothy R D J Radstake
Chemokines have been shown to play immune-modulatory functions unrelated to steering cell migration. CXCL4 is a chemokine abundantly produced by activated platelets and immune cells. Increased levels of circulating CXCL4 are associated with immune-mediated conditions, including systemic sclerosis. Considering the central role of dendritic cells (DCs) in immune activation, in this article we addressed the effect of CXCL4 on the phenotype and function of monocyte-derived DCs (moDCs). To this end, we compared innate and adaptive immune responses of moDCs with those that were differentiated in the presence of CXCL4...
May 17, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28508449/satellite-glial-cells-in-human-trigeminal-ganglia-have-a-broad-expression-of-functional-toll-like-receptors
#2
Johanna G Mitterreiter, Werner J D Ouwendijk, Monique van Velzen, Gijsbert P van Nierop, Albert D M E Osterhaus, Georges M G M Verjans
Toll-like receptors (TLRs) orchestrate immune responses to a wide variety of danger- and pathogen-associated molecular patterns. Compared to the central nervous system (CNS), expression profile and function of TLRs in the human peripheral nervous system (PNS) are ill-defined. We analyzed TLR expression of satellite glial cells (SGCs) and microglia, glial cells predominantly involved in local immune responses in ganglia of the human PNS and normal-appearing white matter (NAWM) of the CNS, respectively. Ex vivo flow cytometry analysis of cell suspensions obtained from human cadaveric trigeminal ganglia (TG) and NAWM showed that both SGCs and microglia expressed TLR1-5, TLR7 and TLR9, although expression levels varied between these cell types...
May 15, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28506291/targeting-cd22-with-the-monoclonal-antibody-epratuzumab-modulates-human-b-cell-maturation-and-cytokine-production-in-response-to-toll-like-receptor-7-tlr7-and-b-cell-receptor-bcr-signaling
#3
Natalia V Giltiay, Geraldine L Shu, Anthony Shock, Edward A Clark
BACKGROUND: Abnormal B-cell activation is implicated in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE). The B-cell surface molecule CD22, which regulates activation through the B-cell receptor (BCR), is a potential target for inhibiting pathogenic B cells; however, the regulatory functions of CD22 remain poorly understood. In this study, we determined how targeting of CD22 with epratuzumab (Emab), a humanized anti-CD22 IgG1 monoclonal antibody, affects the activation of human B-cell subsets in response to Toll-like receptor 7 (TLR7) and BCR engagement...
May 15, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28501511/identification-of-quinazoline-based-inhibitors-of-irak4-for-the-treatment-of-inflammation
#4
Graham F Smith, Michael D Altman, Brian Andresen, James Baker, Jason D Brubaker, Hongmin Chen, Yiping Chen, Matthew Childers, Anthony Donofrio, Heidi Ferguson, Christian Fischer, Thierry O Fischmann, Craig Gibeau, Alexander Hicks, Sue Jin, Sam Kattar, Melanie A Kleinschek, Erica Leccese, Charles Lesburg, Chaomin Li, Jongwon Lim, Duan Liu, John K F Maclean, Faruk Mansoor, Lilly Y Moy, Erin F Mulrooney, Antoaneta S Necheva, Jeremy Presland, Larissa Rakhilina, Ruojing Yang, Luis Torres, Jie Zhang-Hoover, Alan Northrup
Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity...
April 18, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28495399/evaluation-of-toll-like-receptor-gene-family-variants-as-prognostic-biomarkers-in-rheumatoid-arthritis
#5
Silvia Torices, Lorena Alvarez-Rodríguez, Ignacio Varela, Pedro Muñoz, Alejandro Balsa, M López-Hoyos, Víctor Martinez-Taboada, Jose L Fernández-Luna
Rheumatoid arthritis (RA) is a systemic autoimmune disease whose main feature is persistent joint inflammation. Toll-like receptors (TLRs) play critical roles in the activation of innate and adaptive immune responses, and influence the activity of NFκB, a key player in chronic inflammation. We aimed at investigating the association of TLR allelic variants with susceptibility and severity of RA through a systematic, high-throughput, analysis of TLR genes. All coding exons and flanking regions of nine members of the TLR family (TLR1-9) were analyzed in 66 patients with RA and 30 healthy controls by next generation sequencing...
May 7, 2017: Immunology Letters
https://www.readbyqxmd.com/read/28495370/an-optimized-method-for-enumerating-cns-derived-memory-b-cells-during-viral-induced-inflammation
#6
Krista D DiSano, Stephen A Stohlman, Cornelia C Bergmann
BACKGROUND: CNS inflammation resulting from infection, injury, or neurodegeneration leads to accumulation of diverse B cell subsets. Although antibody secreting cells (ASC) within the inflamed CNS have been extensively examined, memory B cell (Bmem) characterization has been limited as they do not secrete antibody without stimulation. Moreover, unlike human Bmem, reliable surface markers for murine Bmem remain elusive. NEW METHOD: Using a viral encephalomyelitis model we developed a modified limiting dilution in vitro stimulation assay to convert CNS-derived virus specific Bmem into ASC...
May 8, 2017: Journal of Neuroscience Methods
https://www.readbyqxmd.com/read/28492391/hepatitis-c-virus-drives-increased-type-i-interferon-associated-impairments-associated-with-fibrosis-severity-in-antiretroviral-treatment-treated-hiv-1-hepatitis-c-virus-coinfected-individuals
#7
Morgane Griesbeck, Marc-Antoine Valantin, Karine Lacombe, Assia Samri-Hassimi, Julie Bottero, Catherine Blanc, Zineb Sbihi, Rima Zoorob, Christine Katlama, Marguerite Guiguet, Marcus Altfeld, Brigitte Autran
BACKGROUND: Viral coinfections might contribute to the increased immune activation and inflammation that persist in antiretroviral treatment (ART)-treated HIV-1 patients. We investigated whether the hepatitis C virus (HCV) coinfection contributes to such alterations by impairing the plasmacytoid dendritic cell (pDC) IFNα/TLR7 pathway in a highly homogeneous group of ART-treated HIV-1-HCV-coinfected patients. METHODS: Twenty-nine HIV-1-infected patients with fully suppressive ART were included, 15 of whom being HCV-coinfected with mild-to-moderate fibrosis and matched for their HIV-1 disease, and 13 control healthy donors...
June 1, 2017: AIDS
https://www.readbyqxmd.com/read/28469254/immune-checkpoint-protein-vista-critically-regulates-the-il-23-il-17-inflammatory-axis
#8
Na Li, Wenwen Xu, Ying Yuan, Natarajan Ayithan, Yasutomo Imai, Xuesong Wu, Halli Miller, Michael Olson, Yunfeng Feng, Yina H Huang, Mary Jo Turk, Samuel T Hwang, Subramaniam Malarkannan, Li Wang
V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an inhibitory immune-checkpoint molecule that suppresses CD4(+) and CD8(+) T cell activation when expressed on antigen-presenting cells. Vsir (-/-) mice developed loss of peripheral tolerance and multi-organ chronic inflammatory phenotypes. Vsir (-/-) CD4(+) and CD8(+) T cells were hyper-responsive towards self- and foreign antigens. Whether or not VISTA regulates innate immunity is unknown. Using a murine model of psoriasis induced by TLR7 agonist imiquimod (IMQ), we show that VISTA deficiency exacerbated psoriasiform inflammation...
May 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28457482/aging-effects-on-t-bet-expression-in-human-b-cell-subsets
#9
Daniela Frasca, Alain Diaz, Maria Romero, Francesca D'Eramo, Bonnie B Blomberg
In order to compare human and mouse B cell subset markers, we evaluated T-bet expression in human B cell subsets from individuals of different ages. We found T-bet expressed in unstimulated memory more than naïve B cells, and more in young individuals. TLR7 stimulation up-regulated T-bet in all B cell subsets from young and elderly individuals, and more in the elderly. By fold-increase the best effect was seen in subsets of the elderly and especially in those that undergo class switch (naïve and IgM). We also evaluated CD11c expression, as T-bet+CD11c+ B cells are expanded in healthy elderly individuals and also in patients with autoimmunity...
April 24, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28448022/development-of-an-economical-dna-delivery-system-by-acufection-and-its-application-to-skin-research
#10
Yu-Jei Lin, Tsung-Lin Lee, Chia-Chi Ku
Dysregulation of immune response in skin is associated with numerous human skin disorders. Direct transfer of immune-related genes into skin tissue is a fascinating approach to investigate immune modulation of cutaneous inflammation in mouse models of human diseases. Here we present a cost-effective protocol that delivered naked DNA in mouse skin and leads to transgene expression. The method is coined "acufection", denoting acupuncture-mediated DNA transfection. To perform acufection, mouse skin was first infused with DNA in phosphate-buffered saline (PBS) and then pricked lightly with a bundle of acupuncture needles to facilitate the absorption of DNA and transfection into cells...
April 19, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28439271/cross-talk-between-inhibitory-immunoreceptor-tyrosine-based-activation-motif-signaling-and-toll-like-receptor-pathways-in-macrophages-and-dendritic-cells
#11
REVIEW
Ivan Hirsch, Vaclav Janovec, Ruzena Stranska, Nathalie Bendriss-Vermare
The innate immune cells sense microbial infection and self-ligands by pathogen recognition receptors (PRRs), such as toll-like receptors (TLRs) and regulatory receptors (RRs), associated with immunoreceptor tyrosine-based activation motif (ITAM). Rapid activation and concerted action of PRRs signaling and feedback inhibitory mechanisms must be engaged to ensure the host defense functions and to prevent cytotoxicity associated with excessive activation. ITAM-associated RRs can generate stimulatory or, paradoxically, inhibitory signals...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28439064/immunotherapy-of-dual-function-vector-with-both-immunostimulatory-and-b-cell-lymphoma-2-bcl-2-silencing-effects-on-gastric-carcinoma
#12
Lanying Ma, Mei Han, Zumureti Keyoumu, Hua Wang, Saifuding Keyoumu
BACKGROUND Tumorigenesis is a kind of pathology marked by infinite proliferation and restrained apoptosis compared with normal cells. The abnormal expression of some proto-oncogenes and apoptosis inhibition are essential for tumor growth, which has been confirmed by molecular biologic and immunologic studies. The hypofunction of the host immune system also drives the development and metastasis of malignant tumors. Bcl-2, which has a critical role in regulating apoptosis, is overexpressed in several cancers...
April 25, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/28437629/design-and-development-of-benzoxazole-derivatives-with-toll-like-receptor-9-antagonism
#13
Swarnali Roy, Ayan Mukherjee, Barnali Paul, Oindrila Rahaman, Shounak Roy, Gundaram Maithri, Bandaru Ramya, Sourav Pal, Dipyaman Ganguly, Arindam Talukdar
Toll-like receptor 9 (TLR9) is a major therapeutic target for numerous inflammatory disorders. Development of small molecule inhibitors for TLR9 remains largely empirical due to lack of structural understanding of potential TLR9 antagonism by small molecules and due to the unusual topology of the ligand binding surface of the receptor. To develop a structural model for rational design of small molecule TLR9 antagonists, an enhanced homology model of human TLR9 (hTLR9) was constructed. Binding mode analysis of a series of molecules having characteristic molecular geometry, flexibility and basicity was conducted based on crystal structure of the inhibitory DNA (iDNA) bound to horse and bovine TLR9...
April 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28432455/dual-activation-of-toll-like-receptors-7-and-9-impairs-the-efficacy-of-antitumor-vaccines-in-murine-models-of-metastatic-breast-cancer
#14
Mariela A Moreno Ayala, María Florencia Gottardo, María Soledad Gori, Alejandro Javier Nicola Candia, Carla Caruso, Andrea De Laurentiis, Mercedes Imsen, Slobodanka Klein, Elisa Bal de Kier Joffé, Gabriela Salamone, Maria G Castro, Adriana Seilicovich, Marianela Candolfi
PURPOSE: Since combination of Toll-like receptor (TLR) ligands could boost antitumor immunity, we evaluated the efficacy of dendritic cell (DC) vaccines upon dual activation of TLR9 and TLR7 in breast cancer models. METHODS: DCs were generated from mouse bone marrow or peripheral blood from healthy human donors and stimulated with CpG1826 (mouse TLR9 agonist), CpG2006 or IMT504 (human TLR9 agonists) and R848 (TLR7 agonist). Efficacy of antitumor vaccines was evaluated in BALB/c mice bearing metastatic mammary adenocarcinomas...
April 21, 2017: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/28432147/cutting-edge-a-dual-tlr2-and-tlr7-ligand-induces-highly-potent-humoral-and-cell-mediated-immune-responses
#15
Alice Gutjahr, Laura Papagno, Francesco Nicoli, Alain Lamoureux, Fabienne Vernejoul, Thierry Lioux, Emma Gostick, David A Price, Gérard Tiraby, Eric Perouzel, Victor Appay, Bernard Verrier, Stéphane Paul
TLR agonists are currently being developed and tested as adjuvants in various formulations to optimize the immunogenicity and efficacy of vaccines. The aim of this study was to evaluate the immunostimulatory properties of a novel compound incorporating covalently linked moieties designed to stimulate both TLR2 and TLR7. This dual TLR2/TLR7 agonist induced the maturation of dendritic cells and primed substantial populations of cytolytic and highly polyfunctional effector CD8(+) T cells in vitro, and safely potentiated the immunogenic properties of a nanoparticulate Ag in vivo, eliciting humoral responses with a balanced TH1/TH2 profile in mice...
April 21, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28429728/a-formulated-tlr7-8-agonist-is-a-flexible-highly-potent-and-effective-adjuvant-for-pandemic-influenza-vaccines
#16
Neal Van Hoeven, Christopher B Fox, Brian Granger, Tara Evers, Sharvari W Joshi, Ghislain I Nana, Sarah C Evans, Susan Lin, Hong Liang, Li Liang, Rie Nakajima, Philip L Felgner, Richard A Bowen, Nicole Marlenee, Airn Hartwig, Susan L Baldwin, Rhea N Coler, Mark Tomai, James Elvecrog, Steven G Reed, Darrick Carter
Since 1997, highly pathogenic avian influenza viruses of the H5N1 subtype have been transmitted from avian hosts to humans. The severity of H5N1 infection in humans, as well as the sporadic nature of H5N1 outbreaks, both geographically and temporally, make generation of an effective vaccine a global public health priority. An effective H5N1 vaccine must ultimately provide protection against viruses from diverse clades. Toll-like receptor (TLR) agonist adjuvant formulations have a demonstrated ability to broaden H5N1 vaccine responses in pre-clinical models...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28422377/intraperitoneal-gardiquimod-protects-against-hepatotoxicity-through-inhibition-of-oxidative-stress-and-inflammation-in-mice-with-sepsis
#17
Suqian Guo, Yu Zhang, Zhifen Wang, Yonghao Yu, Guolin Wang
Many reports recapitulate the contribution of reactive oxygen species (ROS) over-accumulation to the organ damage; it is of significance to strictly target ROS production. In this study, we evaluated the potential role of TLR7 agonist gardiquimod (GDQ) in oxidative stress (OS) in liver injury induced by sepsis. Here, we observed that intraperitoneal pretreatment with GDQ dramatically elevated the septic survival rate and effectively attenuated the septic liver injury. Interestingly, the increased ROS and inflammatory factor IL-6 levels were reversed after GDQ intervention...
April 19, 2017: Journal of Biochemical and Molecular Toxicology
https://www.readbyqxmd.com/read/28419514/activition-of-tlr7-inhibition-of-mycobacterium-tuberculosis-survival-by-autophagy-in-raw-264-7-macrophages
#18
Meng Bao, Zhengjun Yi, Yurong Fu
The aim of the study was to evaluate the effect of regulation of TLR7 on Mycobacterium tuberculosis (Mtb) survival in macrophages. TLR7 expression in macrophages infected by Mtb was detected by RT-PCR and western blotting. Regulation of TLR7 was achieved by single strand RNA (ssRNA) or siRNA. The effects of TLR7 on Mtb survival and cell viability were detected by acid fast staining and cell counting kit-8, respectively. Cell ultrastructure was observed via transmission electron microscopy (TEM), and autophagy related protein LC3 was analyzed by western blotting...
April 17, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28416650/epigenetic-regulator-cxxc5-recruits-dna-demethylase-tet2-to-regulate-tlr7-9-elicited-ifn-response-in-pdcs
#19
Shixin Ma, Xiaoling Wan, Zihou Deng, Lei Shi, Congfang Hao, Zhenyuan Zhou, Chun Zhou, Yiyuan Fang, Jinghua Liu, Jing Yang, Xia Chen, Tiantian Li, Aiping Zang, Shigang Yin, Bin Li, Joel Plumas, Laurence Chaperot, Xiaoming Zhang, Guoliang Xu, Lubin Jiang, Nan Shen, Sidong Xiong, Xiaoming Gao, Yan Zhang, Hui Xiao
TLR7/9 signals are capable of mounting massive interferon (IFN) response in plasmacytoid dendritic cells (pDCs) immediately after viral infection, yet the involvement of epigenetic regulation in this process has not been documented. Here, we report that zinc finger CXXC family epigenetic regulator CXXC5 is highly expressed in pDCs, where it plays a crucial role in TLR7/9- and virus-induced IFN response. Notably, genetic ablation of CXXC5 resulted in aberrant methylation of the CpG-containing island (CGI) within the Irf7 gene and impaired IRF7 expression in steady-state pDCs...
May 1, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28408069/tlr7-mediated-activation-of-xbp1-correlates-with-the-ifn%C3%AE-production-in-humans
#20
Claudia Beisel, Susanne Ziegler, Glòria Martrus Zapater, Anaïs Chapel, Morgane Griesbeck, Heike Hildebrandt, Ansgar W Lohse, Marcus Altfeld
The transcription factor X-box binding protein 1 (XBP1) represents a key component of the endoplasmatic reticulum (ER) stress response and is required for the production of several pro-inflammatory cytokines. XBP1 is furthermore essential for the development and survival of plasmacytoid dendritic cells (pDCs), and has recently been suggested to be involved in toll-like receptor (TLR) 2/4 signaling. Activation of TLR7 on pDCs results in an upregulation of pro-inflammatory cytokines, such as type I interferons (IFN-I), and has been implicated in several autoimmune and inflammatory diseases, but the role of XBP1 in this process remains unknown...
April 10, 2017: Cytokine
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