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Gaetan Barbet, Leif E Sander, Matthew Geswell, Irina Leonardi, Andrea Cerutti, Iliyan Iliev, J Magarian Blander
Live vaccines historically afford superior protection, yet the cellular and molecular mechanisms mediating protective immunity remain unclear. Here we found that vaccination of mice with live, but not dead, Gram-negative bacteria heightened follicular T helper cell (Tfh) differentiation, germinal center formation, and protective antibody production through the signaling adaptor TRIF. Complementing the dead vaccine with an innate signature of bacterial viability, bacterial RNA, recapitulated these responses...
March 9, 2018: Immunity
Pei-Hui Wang, Sin-Yee Fung, Wei-Wei Gao, Jian-Jun Deng, Yun Cheng, Vidyanath Chaudhary, Kit-San Yuen, Ting-Hin Ho, Ching-Ping Chan, Yan Zhang, Kin-Hang Kok, Wanling Yang, Chi-Ping Chan, Dong-Yan Jin
STING is a core adaptor in innate nucleic acid sensing in mammalian cells, on which different sensing pathways converge to induce type I interferon (IFN) production. Particularly, STING is activated by 2'3'-cGAMP, a cyclic dinucleotide containing mixed phosphodiester linkages and produced by cytoplasmic DNA sensor cGAS. Here, we reported on a novel transcript isoform of STING designated STING-β that dominantly inhibits innate nucleic acid sensing. STING-β without transmembrane domains was widely expressed at low levels in various human tissues and viral induction of STING-β correlated inversely with IFN-β production...
March 14, 2018: Nucleic Acids Research
Lorenza Tulli, Francesca Cattaneo, Juliette Vinot, Cosima T Baldari, Ugo D'Oro
Toll-like receptors (TLRs) play a key role in the activation of innate immune cells, in which their engagement leads to production of cytokines and co-stimulatory molecules. TLRs signaling requires recruitment of toll/IL-1R (TIR) domain-containing adaptors, such as MyD88 and/or TRIF, and leads to activation of several transcription factors, such as NF-κB, the AP1 complex, and various members of the interferon regulatory factor (IRF) family, which in turn results in triggering of several cellular functions associated with these receptors...
2018: Frontiers in Immunology
Moritz E Wigand, Fabian U Lang, Annabel S Müller-Stierlin, Lea Reichhardt, Silvana Trif, Thomas G Schulze, Werner Strik, Thomas Becker, Markus Jäger
BACKGROUND: A neurobiologically informed, system-specific psychopathological approach has been suggested for use in schizophrenia. However, to our knowledge, such an approach has not been used to prospectively describe the course of schizophrenia. SAMPLING AND METHODS: We assessed psychopathology in a well-described sample of 100 patients with schizophrenia or schizoaffective disorder with the Bern Psychopathology Scale (BPS) at 6-month intervals for up to 18 months...
March 14, 2018: Psychopathology
Ariadne Androulidaki, Laurens Wachsmuth, Apostolos Polykratis, Manolis Pasparakis
Type 1 diabetes (T1D) is caused by the autoimmune destruction of the insulin-producing pancreatic beta cells. While the role of adaptive immunity has been extensively studied, the role of innate immune responses and particularly of Toll- like Receptor (TLR) signaling in T1D remains poorly understood. Here we show that myeloid cell-specific MyD88 deficiency considerably protected mice from the development of streptozotocin (STZ)-induced diabetes. The protective effect of MyD88 deficiency correlated with increased expression of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in pancreatic lymph nodes from STZ-treated mice and in bone marrow-derived dendritic cells (BMDC) stimulated with apoptotic cells...
2018: PloS One
Ah-Yeon Kim, Hyun-Jin Shim, Hyeon-Myeong Shin, Yoo Jung Lee, Hyeonjeong Nam, Su Yeon Kim, Hyung-Sun Youn
Toll-like receptors (TLRs) play a crucial role in danger recognition and induction of innate immune response against bacterial and viral infections. The TLR adaptor molecule, toll-interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF), facilitates TLR3 and TLR4 signaling, leading to the activation of the transcription factor, NF-κB and interferon regulatory factor 3 (IRF3). Andrographolide, the active component of Andrographis paniculata, exerts anti-inflammatory effects; however, the principal molecular mechanisms remain unclear...
March 1, 2018: International Immunopharmacology
Jun Yang, Chaojun Yang, Jian Yang, Jiawang Ding, Xinxin Li, Qinqin Yu, Xin Guo, Zhixing Fan, Huibo Wang
The Toll-like receptor 4 (TLR4) signal pathway- induced inflammation is considered to be a crucial link to myocardial ischemia reperfusion injury (MIRI). Our previous study proved that radioprotective 105 kDa protein (RP105), a negative regulator of TLR4, performed a protective role in MIRI by anti-apoptosis approach. However, the mechanism of RP105 cardioprotection of anti-inflammation is still unclear. This study aimed to explore the underlying mechanism of RP105 anti-inflammation effect in MIRI. We established a rat model of MIRI induced by ligation of the left anterior descending coronary artery for 30 min followed by 2 h reperfusion...
March 6, 2018: International Journal of Molecular Medicine
Changjun Jia, Chaoliu Dai, Hailiang Wang, Yi Wan, Yunyu Qiao, Feng Xu, Songlin Peng, Yang Zhao, Chuang Zhao, Liang Zhao
Background/Aims: Hepatic ischemia-reperfusion (I/R) injury is a serious concern during hepatic vascular occlusion. The objectives of this study were to assess effects of three techniques for hepatic vascular occlusion on I/R injury and to explore the underlying mechanisms. Methods: Liver cirrhotic rats had undertaken Pringle maneuver (PR), hemihepatic vascular occlusion (HH), or hepatic blood inflow occlusion without hemihepatic artery control (WH). Levels of tumor necrosis factor alpha (TNF- α ), nuclear factor kappa B (NF- κ B), toll-like receptor 4 (TLR4), TIR-domain-containing adapter-inducing interferon- β (TRIF), and hemeoxygenase 1 (HMOX1) were assayed...
2018: Gastroenterology Research and Practice
Louise Ritchie, Rothwell Tate, Luke H Chamberlain, Graham Robertson, Michele Zagnoni, Teresa Sposito, Selina Wray, John A Wright, Clare E Bryant, Nicholas J Gay, Trevor J Bushell
Toll like receptor 3 (TLR3) belongs to a family of pattern recognition receptors that recognise molecules found on pathogens referred to as pathogen associated molecular patterns (PAMPs). Its involvement in innate immunity is well known but despite its presence in the central nervous system (CNS), our knowledge of its function is limited. Here, we have investigated whether TLR3 activation modulates synaptic activity in primary hippocampal cultures and induced pluripotent stem cell (iPSC)-derived neurons. Synaptically driven spontaneous action potential (AP) firing was significantly reduced by the TLR3 specific activator, poly I:C, in a concentration-dependent manner following both short (5 min) and long exposures (1h) in rat hippocampal cultures...
March 2, 2018: Neuropharmacology
Saskia Lehr, Juliane Vier, Georg Häcker, Susanne Kirschnek
The obligate intracellular bacterium Chlamydia trachomatis is the most common bacterial agent of sexually transmitted disease world-wide. Chlamydia trachomatis primarily infects epithelial cells of the genital tract but the infection may be associated with ascending infection. Infection-associated inflammation can cause tissue damage resulting in female infertility and ectopic pregnancy. The precise mechanism of inflammatory tissue damage is unclear but earlier studies implicate the chlamydial cryptic plasmid as well as responding neutrophils...
February 27, 2018: Microbes and Infection
Alla Splichalova, Vera Slavikova, Zdislava Splichalova, Igor Splichal
Preterm infants born with immature organ systems, which can impede normal development, can also be highly sensitive to different biological and/or environmental factors. Animal models could aid in investigating and understanding the effects of different conditions on the health of these immunocompromised infants. The epitheliochorial placentation of the pig prevents the prenatal transfer of protective colostral immunoglobulins. Surgical colostrum-deprived piglets are free of maternal immunoglobulins, and the cells that are normally provided via colostrum...
2018: Frontiers in Immunology
Xiong-Zhe Han, Rui Ma, Qi Chen, Xin Jin, Yuan-Zhe Jin, Ren-Bo An, Xuan-Mei Piao, Mei-Lan Lian, Lin-Hu Quan, Jun Jiang
ETHNOPHARMACOLOGICAL RELEVANCE: The aerial part of Athyrium multidentatum (Doll.) Ching (AM) is widely used in the northeastern region of China as an edible wild herb, but its medicinal value, especially its anti-inflammatory effect, has not been fully explored. AIM OF THE STUDY: To investigate the anti-inflammatory activity of AM and clarify the anti-inflammatory mechanism involving the TLR4 signaling pathway using a lipopolysaccharide (LPS)-induced inflammatory model...
February 21, 2018: Journal of Ethnopharmacology
Yun Chen, Xiang-Qin Yang, Bor-Yuan Tseng, Ya-Hui Tsai, Sheng-Hong Tseng, Cheng-Hung Lee, Chao-Ling Yao
BACKGROUND/PURPOSE: Toll-like receptors (TLRs) are important regulators of innate immunity, and TLR4 pathway can regulate the survival, migration, and differentiation of stem cells, including intestinal stem cells (ISCs). Deferoxamine (DFO), a hypoxia-mimic compound, can activate the proliferation of ISCs. In this study, we investigated the response of TLR4 signaling to DFO-induced hypoxia in cultured ISCs in vitro. METHODS: After DFO treatment, the crypt organoid number was counted, and the expression levels of Lgr5, Hsp70, HMGB1, HIF-1α, TLR4, MyD88, TRIF, and TRAM in ISCs were examined using QPCR and Western blotting...
February 6, 2018: Journal of Pediatric Surgery
Lan Gu, Ran Meng, Yiting Tang, Kai Zhao, Fang Liang, Rui Zhang, Qianqian Xue, Fangping Chen, Xianzhong Xiao, Huadong Wang, Haichao Wang, Timothy R Billiar, Ben Lu
Outer membrane vesicles (OMVs), released by variety of bacteria, are membrane-enclosed entities enriched in microbial components, toxins and virulent factors. OMVs could deliver lipopolysaccharide (LPS) into the cytosol of host cells and subsequently activate caspase-11, which critically orchestrates immune responses and mediates septic shock. Though it is known that caspase-11 is activated by intracellular LPS, how OMVs deliver LPS into the cytosol remains largely unknown. Here we show that the activation of toll like receptor 4 (TLR4), a LPS receptor on the cytoplasmic membrane, licenses macrophages to transport LPS from OMVs into the cytosol through TIR domain-containing adaptor-inducing interferon-β (TRIF)...
February 16, 2018: Shock
José Carlos Santos, Mathias S Dick, Brice Lagrange, Daniel Degrandi, Klaus Pfeffer, Masahiro Yamamoto, Etienne Meunier, Pawel Pelczar, Thomas Henry, Petr Broz
Pathogenic and commensal Gram-negative bacteria produce and release outer membrane vesicles (OMVs), which present several surface antigens and play an important role for bacterial pathogenesis. OMVs also modulate the host immune system, which makes them attractive as vaccine candidates. At the cellular level, OMVs are internalized by macrophages and deliver lipopolysaccharide (LPS) into the host cytosol, thus activating the caspase-11 non-canonical inflammasome. Here, we show that OMV-induced inflammasome activation requires TLR4-TRIF signaling, the production of type I interferons, and the action of guanylate-binding proteins (GBPs), both in macrophages and in vivo Mechanistically, we find that isoprenylated GBPs associate with the surface of OMVs or with transfected LPS, indicating that the key factor that determines GBP recruitment to the Gram-negative bacterial outer membranes is LPS itself...
February 19, 2018: EMBO Journal
Guomu Liu, Xiaoyu Zhai, Hongyue Zhou, Xiaoyu Yang, Nannan Zhang, Guixiang Tai, Weihua Ni
Our previous study demonstrated that maltose-binding protein (MBP) activated Th1 through the TLR2-mediated MyD88-dependent pathway and the TLR4-mediated TRIF-dependent pathway. The combination of MBP and BCG synergistically induced Th1 activation, and the TLR2/9-mediated MyD88-dependent pathway is involved in this process. To further explore this mechanism, we stimulated purified mouse CD4 + T cells with MBP and BCG in vitro. The results demonstrated that MBP combined with BCG synergistically increased IFN-γ production and TLR2/4/9 expression, suggesting the involvement of TLR2/4/9 in the combination-induced Th1 activation...
February 12, 2018: Cellular Immunology
Mark Lötzerich, Pascal S Roulin, Karin Boucke, Robert Witte, Oleg Georgiev, Urs F Greber
Apoptosis and programmed necrosis (necroptosis) determine cell fate, and antagonize infection. Execution of these complementary death pathways involves the formation of receptor-interacting protein kinase 1 (RIPK1) containing complexes. RIPK1 binds to adaptor proteins, such as TRIF (Toll-IL-1 receptor-domain-containing-adaptor-inducing interferon-beta factor), FADD (Fas-associated-protein with death domain), NEMO (NF-κB regulatory subunit IKKγ), SQSTM1 (sequestosome 1/p62), or RIPK3 (receptor-interacting protein kinase 3), which are involved in RNA sensing, NF-κB signaling, autophagosome formation, apoptosis, and necroptosis...
February 15, 2018: Cell Death & Disease
U Saqib, M S Baig
Toll/IL1 receptor (TIR) adaptor proteins continue to be an integral part of Toll-like receptors' (TLR) signalling involved in inflammation. Signalling is likely to be initiated by these TIR adaptors when they are recruited to a TIR-TIR interface formed by TLR dimerization. Among these, myeloid differentiation factor-88 (MyD88), MyD88 adapter-like protein (Mal), TIR domain-containing adaptor protein inducing interferon-β (TRIF) and TRIF-related adaptor molecule (TRAM) play pivotal roles at many steps in the signalling events leading to inflammation...
February 15, 2018: SAR and QSAR in Environmental Research
Sujatha Muralidharan, Arlene Lim, Donna Catalano, Pranoti Mandrekar
Binge/moderate alcohol suppresses TLR4-MyD88 proinflammatory cytokines; however, alcohol's effects on TLR-TRIF signaling, especially after in vivo exposure in humans, are unclear. We performed a comparative analysis of the TLR4-MyD88, TLR4-TRIF, and TLR3-TRIF pathways in human monocytes following binge alcohol exposure. Mechanistic regulation of TLR-TRIF signaling by binge alcohol was evaluated by analyzing IRF3 and TBK1, upstream regulator protein phosphatase 1 (PP1), and immunoregulatory stress proteins HspA1A and XBP-1 in alcohol-treated human and mouse monocytes/macrophages...
February 14, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Maria Yurchenko, Astrid Skjesol, Liv Ryan, Gabriel Mary Richard, Richard Kumaran Kandasamy, Ninghai Wang, Cox Terhorst, Harald Husebye, Terje Espevik
Signaling lymphocytic activation molecule family 1 (SLAMF1) is an Ig-like receptor and a costimulatory molecule that initiates signal transduction networks in a variety of immune cells. In this study, we report that SLAMF1 is required for Toll-like receptor 4 (TLR4)-mediated induction of interferon β (IFNβ) and for killing of Gram-negative bacteria by human macrophages. We found that SLAMF1 controls trafficking of the Toll receptor-associated molecule (TRAM) from the endocytic recycling compartment (ERC) to Escherichia coli phagosomes...
February 12, 2018: Journal of Cell Biology
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