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TIRAP

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https://www.readbyqxmd.com/read/27909057/structure-of-the-tir-domain-of-bcap-which-links-phosphoinositide-metabolism-with-the-negative-regulation-of-the-tlr-signalosome
#1
Samer Halabi, Eiki Sekine, Brett Verstack, Nicholas J Gay, Martin C Moncrieffe
Ligand binding to Toll-like receptors (TLRs) results in dimerization of their cytosolic TIR domains and recruitment of post-receptor signal transducers into a complex signalosome. TLR activation leads to the production of transcription factors, pro-inflammatory molecules and the activation of Phosphoinositide 3-kinases (PI3K) in a process that requires the multi-modular B-cell Adaptor for Phosphoinositide 3-kinase (BCAP). BCAP has a sequence previously proposed as a "cryptic" TIR domain. Here, we present the structure of the N-terminal region of human BCAP and show that it possesses a canonical TIR-fold...
December 1, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27902980/gene-expression-profiling-and-functional-characterization-of-macrophages-in-response-to-circulatory-microparticles-produced-during-trypanosoma-cruzi-infection-and-chagas-disease
#2
Imran H Chowdhury, Sue-Jie Koo, Shivali Gupta, Lisa Yi Liang, Bojlul Bahar, Laura Silla, Julio Nuñez-Burgos, Natalia Barrientos, Maria Paola Zago, Nisha Jain Garg
BACKGROUND: Chronic inflammation and oxidative stress are hallmarks of chagasic cardiomyopathy (CCM). In this study, we determined if microparticles (MPs) generated during Trypanosoma cruzi (Tc) infection carry the host's signature of the inflammatory/oxidative state and provide information regarding the progression of clinical disease. METHODS: MPs were harvested from supernatants of human peripheral blood mononuclear cells in vitro incubated with Tc (control: LPS treated), plasma of seropositive humans with a clinically asymptomatic (CA) or symptomatic (CS) disease state (vs...
December 1, 2016: Journal of Innate Immunity
https://www.readbyqxmd.com/read/27811020/impact-of-ctla4-genotype-and-other-immune-response-gene-polymorphisms-on-outcomes-after-single-umbilical-cord-blood-transplantation
#3
Renato Cunha, Marco A Zago, Sergio Querol, Fernanda Volt, Annalisa Ruggeri, Guillermo Sanz, Fabienne Pouthier, Gesine Kogler, José L Vicario, Paola Bergamaschi, Riccardo Saccardi, Carmen H Lamas, Cristina Díaz-de-Heredia, Gerard Michel, Henrique Bittencourt, Marli Tavella, Rodrigo A Panepucci, Francisco Fernandes, Julia Pavan, Eliane Gluckman, Vanderson Rocha
We evaluated the impact of recipient and cord blood unit (CBU) genetic polymorphisms related to immune response on outcomes after unrelated CB transplants (CBT). Pre-transplant DNA samples from 696 CBU with malignant diseases were genotyped for NLRP1, NLRP2, NLRP3, TIRAP/Mal, IL10, REL, TNFRSF1B and CTLA4. HLA compatibility was 6/6 in 10%, 5/6 in 39%, and ≥4/6 in 51% of transplants. Myeloablative conditioning was used in 80% and in vivo T-cell depletion in 81% of cases. The median number of total nucleated cells infused was 3...
November 3, 2016: Blood
https://www.readbyqxmd.com/read/27646001/myd88-adapter-like-mal-tirap-is-required-for-cytokine-production-by-splenic-ly6clotlr2hi-but-not-by-ly6chitlr2hi-monocytes-during-trypanosoma-cruzi-infection
#4
Humberto Doriguêtto Gravina, Alfredo Miranda Goes, Silvane Maria Fonseca Murta, Catherine Ropert
This study continues to explore the plasticity of Toll-like receptor 2 (TLR2) previously described in immune response during Trypanosoma cruzi infection. Here, we have shown that Ly6C(hi)TLR2(hi) monocytes were involved in TNF-α and IL-12 production, whereas Ly6C(lo)TLR2(hi) monocytes were mainly committed to IL-10 and TNF-α production during T. cruzi infection independently of TLR agonist used (i.e. TLR2 or TLR9 agonists). Another difference between the monocyte populations is that the adapter Mal (encoded by TIRAP) has appeared crucial for the cytokine production by Ly6C(lo) but not by Ly6C(hi) monocytes...
November 4, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27457283/association-of-tlr-polymorphisms-with-bronchopulmonary-dysplasia
#5
Amr Hosny Malash, Aliaa Adel Ali, Rania Mohamed Samy, Radwa Ahmed Shamma
Bronchopulmonary dysplasia (BPD) remains a leading cause of morbidity and mortality during infancy. Evidence suggests that the Toll-like receptor (TLR) signaling pathway plays an integral role in lung inflammation and injury. This study aimed to detect single nucleotide polymorphisms (SNPs) in TLR pathway genes [TLR5 and Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP)] among preterm neonates and to determine their association with the development and severity of bronchopulmonary dysplasia...
October 30, 2016: Gene
https://www.readbyqxmd.com/read/27431585/comparative-genomic-evidence-for-duplication-of-tlr1-subfamily-and-miiuy-croaker-tlr1-perceives-lps-stimulation-via-myd88-and-tirap
#6
Tianjun Xu, Yanjin Wang, Jinrui Li, Chang Shu, Jingjing Han, Qing Chu
Being indispensable pattern recognition receptors in innate immune responses in host protection, Toll-like receptors (TLRs) play an important role in pathogen recognition. Fish TLRs exhibit high variety and distinct features, although little is known about their function on ligand recognition and signaling pathway in fish. This paper reports the evolutionary spectrum of the TLR1 subfamily (referred to as TLR1, TLR6, and TLR10) as determined using the comparative genomic approach. We hypothesized that the TLR1 subfamily underwent two rounds of gene duplication events; the first duplication occurred prior to the divergence of amphibians, and the second one occurred prior to the divergence of eutherians...
September 2016: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/27311859/brucella-tir-like-protein-tcpb-btp1-specifically-targets-the-host-adaptor-protein-mal-tirap-to-promote-infection
#7
Wenna Li, Yuehua Ke, Yufei Wang, Mingjuan Yang, Junguang Gao, Shaoxia Zhan, Du Xinying, Liuyu Huang, Wenfeng Li, Zeliang Chen, Juan Li
Brucella spp. are known to avoid host immune recognition and weaken the immune response to infection. Brucella like accomplish this by employing two clever strategies, called the stealth strategy and hijacking strategy. The TIR domain-containing protein (TcpB/Btp1) of Brucella melitensis is thought to be involved in inhibiting host NF-κB activation by binding to adaptors downstream of Toll-like receptors. However, of the five TIR domain-containing adaptors conserved in mammals, whether MyD88 or MAL, even other three adaptors, are specifically targeted by TcpB has not been identified...
August 26, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27256462/defects-in-early-cell-recruitment-contribute-to-the-increased-susceptibility-to-respiratory-klebsiella-pneumoniae-infection-in-diabetic-mice
#8
Nuria Martinez, Natkunam Ketheesan, Gregory W Martens, Kim West, Egil Lien, Hardy Kornfeld
Diabetes is associated with increased susceptibility to Klebsiella pneumoniae and poor prognosis with infection. We demonstrate accelerated mortality in mice with streptozotocin-induced diabetes following tracheal instillation of K. pneumoniae. Diabetic mice recruited fewer granulocytes to the alveolar airspace and had reduced early production of CXCL1, CXCL2, IL-1β and TNF-α following tracheal instillation of K. pneumoniae-lipopolysaccharide. Additionally, TLR2 and TIRAP expression following K. pneumoniae-lipopolysaccharide exposure was decreased in hyperglycemic mice...
May 30, 2016: Microbes and Infection
https://www.readbyqxmd.com/read/27214039/tlr1-variant-h305l-associated-with-protection-from-pulmonary-tuberculosis
#9
Christian G Meyer, Norbert Reiling, Christa Ehmen, Gerd Ruge, Ellis Owusu-Dabo, Rolf D Horstmann, Thorsten Thye
Toll like receptors (TLR) are key elements of the innate immune response and involved in the recognition of pathogens. To test common and rare TLR variants involved in susceptibility or resistance to infection with Mycobacterium tuberculosis we screened the exons of the genes encoding TLR 1, 2, 4, and the adaptor molecule TIRAP in more than 4500 tuberculosis (TB) cases and controls from Ghana. The analysis yielded 109 variants with possible functional impact, including 101 non-synonymous variants, three stop-variants, and five indels...
2016: PloS One
https://www.readbyqxmd.com/read/27166096/heterozygous-mutants-of-tirap-s180l-polymorphism-protect-adult-patients-with-plasmodium-falciparum-infection-against-severe-disease-and-mortality
#10
Aditya K Panda, Bidyut K Das, Abhinash Panda, Rina Tripathy, Sarit S Pattnaik, Harishankar Mahto, Sylviane Pied, Sulabha Pathak, Shobhona Sharma, Balachandran Ravindran
Toll-interleukin-1 receptor domain containing adapter protein (TIRAP) plays a crucial role in TLR2 and TLR4 signaling pathways. Glycosylphospatidylinositol (GPI), considered a toxin molecule of Plasmodium falciparum, interacts with TLR2 and 4 to induce an immune inflammatory response. A single nucleotide polymorphism at coding region of TIRAP (S180L) has been reported to influence TLRs signaling. In the present study, we investigated the association of TIRAP (S180L) polymorphism with susceptibility/resistance to severe P...
September 2016: Infection, Genetics and Evolution
https://www.readbyqxmd.com/read/27150837/differential-adapter-recruitment-by-tlr2-co-receptors
#11
Wenji Piao, Lisa W Ru, Vladimir Y Toshchakov
TLR2 heterodimers with TLR1 or TLR6 recognize distinct pathogen-associated molecules such as tri- and di-acylated lipopeptides. The activated TLR2 heterodimers recruit Toll-IL-1R domain- (TIR-) containing adapter proteins, TIRAP and MyD88, through the receptor TIR domains. Molecular recognition mechanisms responsible for agonist-driven, TIR domain-mediated receptor-adapter interactions as well as the structure of resultant signaling complexes remain unknown. We previously reported that the cell-permeable peptide derived from helix D of TLR2 TIR (2R9) specifically binds TIRAP in vitro and in cells and thereby inhibits TIRAP-dependent TLR signaling...
July 2016: Pathogens and Disease
https://www.readbyqxmd.com/read/27061018/toll-interleukin-1-receptor-domain-containing-adaptor-protein-positively-regulates-bv2-cell-m1-polarization
#12
Leilei Gong, Hanxiang Wang, Xiaolei Sun, Chun Liu, Chengwei Duan, Rixin Cai, Xingxing Gu, Shunxing Zhu
Microglial activation, including classical (M1) and alternative (M2) activation, plays important roles in the development of several central nervous system disorders and promotes tissue reconstruction. Toll-like receptor (TLR)4 is important for microglial polarization. TIR domain-containing adaptor protein (TIRAP) is an intracellular adaptor protein, which is responsible for the early phase of TLR4 activation. The role of TIRAP in BV2 cell M1 polarization is still unknown. In this study, we showed that TIRAP expression is greatly elevated in lipopolysaccharide (LPS)/interferon (IFN)-γ-treated microglia...
June 2016: European Journal of Neuroscience
https://www.readbyqxmd.com/read/27053552/hiv-1-tat-protein-activates-both-the-myd88-and-trif-pathways-to-induce-tumor-necrosis-factor-alpha-and-interleukin-10-in-human-monocytes
#13
Rémi Planès, Nawal Ben Haij, Kaoutar Leghmari, Manutea Serrero, Lbachir BenMohamed, Elmostafa Bahraoui
UNLABELLED: In this study, we show that the HIV-1 Tat protein interacts with rapid kinetics to engage the Toll-like receptor 4 (TLR4) pathway, leading to the production of proinflammatory and anti-inflammatory cytokines. The pretreatment of human monocytes with Tat protein for 10 to 30 min suffices to irreversibly engage the activation of the TLR4 pathway, leading to the production of tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10), two cytokines strongly implicated in the chronic activation and dysregulation of the immune system during HIV-1 infection...
July 1, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27022195/raftlin-controls-lipopolysaccharide-induced-tlr4-internalization-and-ticam-1-signaling-in-a-cell-type-specific-manner
#14
Megumi Tatematsu, Ryuji Yoshida, Yuka Morioka, Noriko Ishii, Kenji Funami, Ayako Watanabe, Kazuko Saeki, Tsukasa Seya, Misako Matsumoto
The clathrin-dependent endocytic pathway is crucial for endosomal TLR3- and TLR4-mediated Toll-IL-1R domain-containing adaptor molecule-1 (TICAM-1) signaling. TLR4 uses a different signaling platform, plasma membrane and endosomes, for activation of TIRAP-MyD88 and TICAM-2-TICAM-1, respectively. LPS-induced endocytosis of TLR4 is mandatory for TICAM-1-mediated signaling including IFN-β production. Several molecules/mechanisms such as CD14, clathrin, and phosphatidylinositol metabolism have been reported to act as inducers of TLR4 translocation...
May 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27015965/novel-phosphatidylethanolamine-derivatives-accumulate-in-circulation-in-hyperlipidemic-apoe-mice-and-activate-platelets-via-tlr2
#15
Sudipta Biswas, Liang Xin, Soumya Panigrahi, Alejandro Zimman, Hua Wang, Valentin P Yakubenko, Tatiana V Byzova, Robert G Salomon, Eugene A Podrez
A prothrombotic state and increased platelet reactivity are common in dyslipidemia and oxidative stress. Lipid peroxidation, a major consequence of oxidative stress, generates highly reactive products, including hydroxy-ω-oxoalkenoic acids that modify autologous proteins generating biologically active derivatives. Phosphatidylethanolamine, the second most abundant eukaryotic phospholipid, can also be modified by hydroxy-ω-oxoalkenoic acids. However, the conditions leading to accumulation of such derivatives in circulation and their biological activities remain poorly understood...
May 26, 2016: Blood
https://www.readbyqxmd.com/read/26983788/glial-cell-elicited-activation-of-brain-microvasculature-in-response-to-brucella-abortus-infection-requires-asc-inflammasome-dependent-il-1%C3%AE-production
#16
M Cruz Miraglia, Miriam M Costa Franco, Ana M Rodriguez, Paula M Q Bellozi, Carina C Ferrari, Maria I Farias, Vida A Dennis, Paula Barrionuevo, Antonio C P de Oliveira, Fernando Pitossi, Kwang Sik Kim, M Victoria Delpino, Sergio Costa Oliveira, Guillermo H Giambartolomei
Blood-brain barrier activation and/or dysfunction are a common feature of human neurobrucellosis, but the underlying pathogenic mechanisms are largely unknown. In this article, we describe an immune mechanism for inflammatory activation of human brain microvascular endothelial cells (HBMEC) in response to infection with Brucella abortus Infection of HBMEC with B. abortus induced the secretion of IL-6, IL-8, and MCP-1, and the upregulation of CD54 (ICAM-1), consistent with a state of activation. Culture supernatants (CS) from glial cells (astrocytes and microglia) infected with B...
May 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/26889229/the-influence-of-genetic-polymorphisms-in-tlr4-and-tirap-and-their-expression-levels-in-peripheral-blood-on-susceptibility-to-sepsis
#17
Jianping Zhang, Jingping Yang, Xiyuan Xu, Liangshen Liang, Haixia Sun, Guohua Liu, Lihong Zhang, Yun Su
The present study aimed to investigate whether genetic polymorphisms in the Toll-like receptor (TLR)-4 and Toll/interleukin-1 receptor (TIR)-associated protein (TIRAP) genes, and/or their expression levels, influence the susceptibility of a patient to sepsis. A total of 106 patients with sepsis were divided into two groups on the basis of their acute physiology and chronic health evaluation (APACHE) II scores: i) Sepsis group A (APACHE II <20) and ii) Sepsis group B (APACHE II >20). In addition, 100 healthy volunteers were enrolled into the control group...
January 2016: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/26888676/particle-induced-osteolysis-is-mediated-by-tirap-mal-in-vitro-and-in-vivo-dependence-on-adherent-pathogen-associated-molecular-patterns
#18
Christopher P Bechtel, Jeremy J Gebhart, Joscelyn M Tatro, Endre Kiss-Toth, J Mark Wilkinson, Edward M Greenfield
BACKGROUND: Proinflammatory signaling by toll-like receptors (TLRs) likely contributes to biologic responses to wear particles causing aseptic loosening. We recently reported associations with aseptic loosening in patients with polymorphisms in the locus encoding an adapter protein specific for TLR-2 and TLR-4 known as toll/interleukin-1 receptor domain-containing adapter protein/MyD88 adapter-like (TIRAP/Mal). To directly examine the contribution of TIRAP/Mal, we tested the hypothesis that TIRAP/Mal deficiency reduces the activity of wear particles...
February 17, 2016: Journal of Bone and Joint Surgery. American Volume
https://www.readbyqxmd.com/read/26885859/a-common-variant-in-the-adaptor-mal-regulates-interferon-gamma-signaling
#19
Clíona Ní Cheallaigh, Frederick J Sheedy, James Harris, Natalia Muñoz-Wolf, Jinhee Lee, Kim West, Eva Palsson McDermott, Alicia Smyth, Laura E Gleeson, Michelle Coleman, Nuria Martinez, Claire H A Hearnden, Graham A Tynan, Elizabeth C Carroll, Sarah A Jones, Sinéad C Corr, Nicholas J Bernard, Mark M Hughes, Sarah E Corcoran, Mary O'Sullivan, Ciara M Fallon, Hardy Kornfeld, Douglas Golenbock, Stephen V Gordon, Luke A J O'Neill, Ed C Lavelle, Joseph Keane
Humans that are heterozygous for the common S180L polymorphism in the Toll-like receptor (TLR) adaptor Mal (encoded by TIRAP) are protected from a number of infectious diseases, including tuberculosis (TB), whereas those homozygous for the allele are at increased risk. The reason for this difference in susceptibility is not clear. We report that Mal has a TLR-independent role in interferon-gamma (IFN-γ) receptor signaling. Mal-dependent IFN-γ receptor (IFNGR) signaling led to mitogen-activated protein kinase (MAPK) p38 phosphorylation and autophagy...
February 16, 2016: Immunity
https://www.readbyqxmd.com/read/26876434/upregulation-of-inflammasome-activity-and-increased-gut-permeability-are-associated-with-obesity-in-children-and-adolescents
#20
V Rainone, L Schneider, I Saulle, C Ricci, M Biasin, N M Al-Daghri, E Giani, G V Zuccotti, M Clerici, D Trabattoni
BACKGROUND: Immune activation contributes to the persistent state of inflammation associated with metabolic dysfunction in obesity. The specific immune receptors that sense metabolic stress signals and trigger inflammation are nevertheless largely unknown, and little is known on inflammatory and immune gene regulation in obesity. METHODS: The study includes a cross-sectional and a longitudinal arm. Forty children and adolescents were enrolled: 22 obese subjects and 18 age-matched normal weight controls...
June 2016: International Journal of Obesity: Journal of the International Association for the Study of Obesity
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