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Erica L Heipertz, Jourdan Harper, Wendy E Walker
IFN regulatory factor (IRF)3 plays a detrimental role in the cecal ligation and puncture (CLP) mouse model of sepsis. However, it is unclear which pathway activates IRF3 in this context. In this report we investigate two pathways that activate IRF3: the Stimulator of Interferon Genes (STING) pathway (which senses cytosolic DNA) and the TIR-domain-containing adapter-inducing interferon-β (TRIF) pathway (which sense dsRNA and LPS via Toll-like receptor (TLR) 3 and 4). Initially, we examine the impact of these pathways using a severe CLP model (∼90% mortality)...
October 17, 2016: Shock
Wei-Shan Hung, Pin Ling, Ju-Chien Cheng, Shy-Shin Chang, Ching-Ping Tseng
Toll-like receptor 4 (TLR4) plays a pivotal role in the host response to lipopolysaccharide (LPS), a major cell wall component of Gram-negative bacteria. Here, we elucidated whether the endocytic adaptor protein Disabled-2 (Dab2), which is abundantly expressed in macrophages, plays a role in LPS-stimulated TLR4 signaling and trafficking. Molecular analysis and transcriptome profiling of RAW264.7 macrophage-like cells expressing short-hairpin RNA of Dab2 revealed that Dab2 regulated the TLR4/TRIF pathway upon LPS stimulation...
October 17, 2016: Scientific Reports
Lance W Peterson, Naomi H Philip, Christopher P Dillon, John Bertin, Peter J Gough, Douglas R Green, Igor E Brodsky
Innate immune responses that are crucial for control of infection are often targeted by microbial pathogens. Blockade of NF-κB and MAPK signaling by the Yersinia virulence factor YopJ inhibits cytokine production by innate immune cells but also triggers cell death. This cell death requires RIPK1 kinase activity and caspase-8, which are engaged by TLR4 and the adaptor protein TRIF. Nevertheless, TLR4- and TRIF-deficient cells undergo significant apoptosis, implicating TLR4/TRIF-independent pathways in the death of Yersinia-infected cells...
October 12, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Xiangyu Yao, Jian Wu, Meng Lin, Wenxiang Sun, Xiao He, Channe Gowda, Silvia Bolland, Carole A Long, Rongfu Wang, Xin-Zhuan Su
Both type I interferon (IFN-I) and CD40 play a significant role in various infectious diseases, including malaria and autoimmune disorders. CD40 is mostly known to function in adaptive immunity, but previous observations of elevated CD40 levels early after malaria infection of mice led us to investigate its roles in innate IFN-I responses and disease control. Using a Plasmodium yoelii nigeriensis N67 and C57BL/6 mouse model, we showed that infected CD40-/- mice had reduced STING and serum IFN-β levels day-2 post infection, higher day-4 parasitemia, and earlier deaths...
October 2016: PLoS Pathogens
Ana T G Guerrero, Larissa G Pinto, Fernando Q Cunha, Sérgio H Ferreira, Jose C Alves-Filho, Waldiceu A Verri, Thiago M Cunha
BACKGROUND: Toll-like receptors (TLRs) including TLR4 and their signal pathways contribute to the pathogenesis of arthritis. Herein, we evaluated the mechanisms underlying the hyperalgesic response caused by TLR4 activation in the tibio-tarsal joint in mice. METHODS: Joint inflammatory hyperalgesia was induced by intra-articular (ia) injection of LPS (lipopolysaccharide- TLR4 agonist) in C57BL/6, TLR4, TLR2, MyD88, TRIF, TNFR1/2 and IL-1R1 knockout ((-/-)) mice...
August 24, 2016: Pharmacological Reports: PR
Qin Yang, Maren J Pröll, Dessie Salilew-Wondim, Rui Zhang, Dawit Tesfaye, Huitao Fan, Mehmet U Cinar, Christine Große-Brinkhaus, Ernst Tholen, Mohammad A Islam, Michael Hölker, Karl Schellander, Muhammad J Uddin, Christiane Neuhoff
Pulmonary alveolar macrophages (AMs) are important in defense against bacterial lung inflammation. Cluster of differentiation 14 (CD14) is involved in recognizing bacterial lipopolysaccharide (LPS) through MyD88-dependent and TRIF pathways of innate immunity. Sulforaphane (SFN) shows anti-inflammatory activity and suppresses DNA methylation. To identify CD14 epigenetic changes by SFN in the LPS-induced TRIF pathway, an AMs model was investigated in vitro CD14 gene expression was induced by 5 µg/ml LPS at the time point of 12 h and suppressed by 5 µM SFN...
September 29, 2016: Innate Immunity
Hongmei Wang, Xusheng Zhang, Xiufen Zheng, Zhu Lan, Jun Shi, Jifu Jiang, Terry Zwiep, Qing Li, Douglas Quan, Zhu-Xu Zhang, Weiping Min
Toll-like receptors (TLRs) act as initiators and conductors responsible for both innate and adaptive immune responses in organ transplantation. The mammalian target of rapamycin (mTOR) is one of the most critical signaling kinases that affects broad aspects of cellular functions including metabolism, growth, and survival. Recipients (BALB/c) were treated with MyD88, TRIF and mTOR siRNA vectors, 3 and 7 days prior to heart transplantation and 7, 14 and 21 days after transplantation. After siRNA treatment, recipients received a fully MHC-mismatched C57BL/6 heart...
2016: Scientific Reports
Xin Wang, Tanmay Majumdar, Patricia Kessler, Evgeny Ozhegov, Ying Zhang, Saurabh Chattopadhyay, Sailen Barik, Ganes C Sen
The intracellular microbial nucleic acid sensors, TLR3 and STING, recognize pathogen molecules and signal to activate the interferon pathway. The TIR-domain containing protein TRIF is the sole adaptor of TLR3. Here, we report an essential role for TRIF in STING signaling: various activators of STING could not induce genes in the absence of TRIF. TRIF and STING interacted directly, through their carboxy-terminal domains, to promote STING dimerization, intermembrane translocation, and signaling. Herpes simplex virus (HSV), which triggers the STING signaling pathway and is controlled by it, replicated more efficiently in the absence of TRIF, and HSV-infected TRIF(-/-) mice displayed pronounced pathology...
September 14, 2016: Cell Host & Microbe
Gil Ju Seo, Younho Choi, Jae U Jung
STING is a crucial component of the mammalian innate immune response to microbial infection. In this issue of Cell Host & Microbe, Wang et al. (2016) report that TRIF, an adaptor of Toll-like receptors (TLRs), is essential for STING-mediated innate antiviral immunity as well as pro-protozoal responses.
September 14, 2016: Cell Host & Microbe
Felipe V Pereira, Amanda C L Melo, Filipe M de Melo, Diego Mourão-Sá, Priscila Silva, Rodrigo Berzaghi, Carolina C A Herbozo, Jordana Coelho-Dos-Reis, Jorge A Scutti, Clarice S T Origassa, Rosana M Pereira, Luis Juliano, Maria Aparecida Juliano, Adriana K Carmona, Niels O S Câmara, Moriya Tsuji, Luiz R Travassos, Elaine G Rodrigues
Despite the recent approval of new agents for metastatic melanoma, its treatment remains challenging. Moreover, few available immunotherapies induce a strong cellular immune response, and selection of the correct immunoadjuvant is crucial for overcoming this obstacle. Here, we studied the immunomodulatory properties of arazyme, a bacterial metalloprotease, which was previously shown to control metastasis in a murine melanoma B16F10-Nex2 model. The antitumor activity of arazyme was independent of its proteolytic activity, since heat-inactivated protease showed comparable properties to the active enzyme; however, the effect was dependent on an intact immune system, as antitumor properties were lost in immunodeficient mice...
July 2016: Oncoimmunology
Siv H Moen, Marita Westhrin, Muhammad Zahoor, Nikolai N Nørgaard, Hanne Hella, Berit Størdal, Anders Sundan, Nadra J Nilsen, Anne-Marit Sponaas, Therese Standal
INTRODUCTION: Mesenchymal stem cells, also called mesenchymal stromal cells, MSCs, have great potential in stem cell therapy partly due to their immunosuppressive properties. How these cells respond to chronic inflammatory stimuli is therefore of importance. Toll-like receptors (TLR)s are innate immune receptors that mediate inflammatory signals in response to infection, stress, and damage. Caspase-8 is involved in activation of NF-kB downstream of TLRs in immune cells. Here we investigated the role of caspase-8 in regulating TLR-induced cytokine production from human bone marrow-derived mesenchymal stromal cells (hBMSCs)...
September 2016: Immunity, Inflammation and Disease
Yin Wu, Dongren Ren, Guo-Yun Chen
TLR4 signaling is critical for providing effective immune protection, but it must be tightly controlled to avoid inflammation-induced pathology. Previously, we reported extensive and direct interactions between TLR and Siglec families of pattern recognition receptors. In this study, we examined the biological significance of this interaction during infection. We show that Siglec-E is required for Escherichia coli-induced endocytosis of TLR4. Siglec-E-deficient dendritic cells infected with E. coli fail to internalize TLR4...
September 12, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Surasak Jittavisutthikul, Watee Seesuay, Jeeraphong Thanongsaksrikul, Kanyarat Thueng-In, Potjanee Srimanote, Rolf G Werner, Wanpen Chaicumpa
A safe and effective direct acting anti-hepatitis C virus (HCV) agent is still needed. In this study, human single chain variable fragments of antibody (scFvs) that bound to HCV NS3/4A protein were produced by phage display technology. The engineered scFvs were linked to nonaarginines (R9) for making them cell penetrable. HCV-RNA-transfected Huh7 cells treated with the transbodies produced from four different transformed E. coli clones had reduced HCV-RNA inside the cells and in the cell spent media, as well as fewer HCV foci in the cell monolayer compared to the transfected cells in culture medium alone...
2016: Frontiers in Immunology
Remzi Onur Eren, Marta Reverte, Matteo Rossi, Mary-Anne Hartley, Patrik Castiglioni, Florence Prevel, Ricardo Martin, Chantal Desponds, Lon-Fye Lye, Stefan K Drexler, Walter Reith, Stephen M Beverley, Catherine Ronet, Nicolas Fasel
Some strains of the protozoan parasite Leishmania guyanensis (L.g) harbor a viral endosymbiont called Leishmania RNA virus 1 (LRV1). LRV1 recognition by TLR-3 increases parasite burden and lesion swelling in vivo. However, the mechanisms by which anti-viral innate immune responses affect parasitic infection are largely unknown. Upon investigating the mammalian host's response to LRV1, we found that miR-155 was singularly and strongly upregulated in macrophages infected with LRV1+ L.g when compared to LRV1- L...
September 14, 2016: Cell Host & Microbe
Anyelo Duran, Nereida Valero, Jesus Mosquera, Lineth Delgado, Melchor Alvarez-Mon, Mariana Torres
AIMS: Dengue disease courses with high viremia titers and high cytokine production suggesting viral replication and active immune response that could be related to viral evasion. One of the main targets of dengue virus (DENV) is monocyte/macrophage cells; however, little information regarding viral evasive mechanisms and pathway activation in monocytes infected by DENV is available. The aim of this study was to determine the role of myeloid differentiation primary response (MyD88), TIR-domain-containing adapter- inducing interferon-β (TRIF) and NF-kB pathways in viral replication and cytokine production in human monocyte cultures infected by DENV2...
October 1, 2016: Life Sciences
Bin Huang, Dae-Weon Park, Suk-Hwan Baek
The activation of toll-like receptor 2 (TLR2) stimulates foam cell formation, which is a key early event in the process of atherosclerosis. In the present study, the role of toll/interleukin-1 receptor-domain-containing adaptor-inducing interferon-β (TRIF) in TLR2-mediated foam cell formation was investigated, and the importance of monocyte chemoattractant protein‑1 (MCP‑1), tissue factor (TF) and lectin‑like oxidized low‑density lipoprotein receptor‑1 (Lox‑1) were examined. Treatment of Raw 264...
October 2016: Molecular Medicine Reports
Yun-Xia Shao, Xin-Xing Xu, Yuan-Yuan Li, Xiang-Ming Qi, Kun Wang, Yong-Gui Wu, Xiao-Ming Meng
ETHNOPHARMACOLOGICAL RELEVANCE: Paeoniflorin(PF), extracted from the root peeled of Paeonia lactiflora Pall(Family: Ranunculaceae), has therapeutic potential in many animal models of inflammatory diseases. AIM OF THE STUDY: Although the anti-inflammatory efficacy of PF has been well illustrated in several animal models, whether it could attenuate diabetic nephropathy and detailed mechanisms are still obscure. Till now, accumulating evidence has proposed the pivotal role of toll-like receptors (TLRs) in renal inflammation in diabetic patients...
August 23, 2016: Journal of Ethnopharmacology
Guan-Lin Lee, Jing-Yiing Wu, Chien-Sung Tsai, Chih-Yuan Lin, Yi-Ting Tsai, Chin-Sheng Lin, Yi-Fu Wang, Shaw-Fang Yet, Yu-Juei Hsu, Cheng-Chin Kuo
Migration of vascular smooth muscle cells (VSMCs) into the intima is considered to be a vital event in the pathophysiology of atherosclerosis. Despite substantial evidence supporting the pathogenic role of Toll-like receptor 4 (TLR4) in the progression of atherogenesis, its function in the regulation of VSMC migration remains unclear. The goal of the present study was to elucidate the mechanism by which TLR4 regulates VSMC migration. Inhibitor experiments revealed that TLR4-induced IL-6 secretion and VSMC migration were mediated via the concerted actions of MyD88 and TRIF on the activation of p38 MAPK and ERK1/2 signaling...
2016: International Journal of Molecular Sciences
Xiaoqin Wei, Wei Qian, Suolang Sizhu, Lijuan Shi, Meilin Jin, Hongbo Zhou
Toll-like receptors (TLRs) trigger the innate immune response by responding to specific components of microorganisms. The TIR domain-containing adaptor inducing IFN-β (TRIF) plays an essential role in mammalian TLR-mediated signaling. The role of TRIF in ducks (duTRIF) remains poorly understood. In this study, we cloned and characterized the full-length coding sequence of duTRIF from duck embryo fibroblasts (DEFs). In healthy ducks, duTRIF transcripts were broadly expressed in different tissues, with higher expression levels in the spleen and liver...
December 2016: Developmental and Comparative Immunology
Md Aminul Islam, Christine Große-Brinkhaus, Maren Julia Pröll, Muhammad Jasim Uddin, Sharmin Aqter Rony, Dawit Tesfaye, Ernst Tholen, Michael Hölker, Karl Schellander, Christiane Neuhoff
BACKGROUND: Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically important viral diseases affecting swine industry worldwide. Despite routine farm vaccination, effective control strategies for PRRS remained elusive which underscores the need for in-depth studies to gain insight into the host immune response to vaccines. The current study aimed to investigate transcriptional responses to PRRS Virus (PRRSV) vaccine in the peripheral blood mononuclear cells (PBMCs) within 3 days following vaccination in German Landrace pigs...
2016: BMC Genomics
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