scholarly journals Insight into Phosphatidylinositol-Dependent Membrane Localization of the Innate Immune Adaptor Protein Toll/Interleukin 1 Receptor Domain-Containing Adaptor Protein

2018 ◽  
Vol 9 ◽  
Author(s):  
Mahesh Chandra Patra ◽  
Sangdun Choi
Keyword(s):  
Interleukin 1 ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Membrane Localization ◽  
Insight Into ◽  
Receptor Domain

scholarly journals TIRAP drives myelosuppression through an Ifnγ-Hmgb1 axis that disrupts the marrow microenvironment

2020 ◽  
Author(s):  
Rawa Ibrahim ◽  
Aparna Gopal ◽  
Megan Fuller ◽  
Patricia Umlandt ◽  
Linda Chang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Function ◽  
Bone Marrow Failure ◽  
Interleukin 1 ◽  
Constitutive Expression ◽  
Adaptor Protein ◽  
Hematopoietic Stem ◽  
Bone Marrow Failure Syndromes ◽  
Insight Into ◽  
Receptor Domain

AbstractActivation of inflammatory pathways is associated with bone marrow failure syndromes, but how specific molecules impact on the marrow microenvironment is not well elucidated. We report a novel role for the miR-145 target, Toll/Interleukin-1 receptor domain containing adaptor protein (TIRAP), in driving bone marrow failure. We show that TIRAP is overexpressed in various types of myelodysplastic syndromes (MDS), and suppresses all three major hematopoietic lineages.. Constitutive expression of TIRAP in hematopoietic stem/progenitor cells (HSPC) promotes upregulation of Ifnγ, leading to bone marrow failure. Myelopoiesis is suppressed through Ifnγ-Ifnγr-mediated release of the alarmin, Hmgb1, which disrupts the marrow endothelial niche. Deletion of Ifnγ or Ifnγr blocks Hmgb1 release and is sufficient to reverse the endothelial defect and prevent myelosuppression. In contrast, megakaryocyte and erythroid production is repressed independently of the Ifnγ receptor. Contrary to current dogma, TIRAP-activated Ifnγ-driven marrow suppression is independent of T cell function or pyroptosis. In the absence of Ifnγ, TIRAP drives myeloproliferation, implicating Ifnγ in suppressing the transformation of bone marrow failure syndromes to myeloid malignancy. These findings reveal novel, non-canonical roles of TIRAP, Hmgb1 and Ifnγ function in the marrow microenvironment,and provide insight into the pathophysiology of preleukemic syndromes.Graphical Abstract: Model of proposed mechanism of TIRAP-induced BMFConstitutive TIRAP expression in marrow cells releases Ifnγ, which directly impacts on megakaryocyte and erythroid production, but indirectly suppresses myelopoiesis through the release of the alarmin, Hmgb1, which disrupts the marrow endothelial compartment.

scholarly journals MyD88 Innate Immune Function in a Zebrafish Embryo Infection Model

2006 ◽  
Vol 74 (4) ◽  
pp. 2436-2441 ◽  
Author(s):  
Astrid M. van der Sar ◽  
Oliver W. Stockhammer ◽  
Carina van der Laan ◽  
Herman P. Spaink ◽  
Wilbert Bitter ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Zebrafish Embryo ◽  
Interleukin 1 ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Infection Model ◽  
Morpholino Knockdown ◽  
Signaling Function ◽  
Serovar Typhimurium ◽  
Myeloid Differentiation Factor

ABSTRACT Innate immunity signaling mechanisms during vertebrate embryogenesis are largely unknown. To study Toll-like receptor (TLR) signaling function in the zebrafish embryo model, we designed an experimental setup for antisense morpholino knockdown under conditions of bacterial infection. Clearance of Salmonella enterica serovar Typhimurium Ra bacteria was significantly impaired after knockdown of myeloid differentiation factor 88 (MyD88), a common adaptor protein in TLR and interleukin-1 receptor signaling. Thereby, we demonstrate for the first time that the innate immune response of the developing embryo involves MyD88-dependent signaling, which further establishes the zebrafish embryo as a model for the study of vertebrate innate immunity.

scholarly journals ZCCHC3 modulates TLR3-mediated signaling by promoting recruitment of TRIF to TLR3

2020 ◽  
Vol 12 (4) ◽  
pp. 251-262
Author(s):  
Ru Zang ◽  
Huan Lian ◽  
Xuan Zhong ◽  
Qing Yang ◽  
Hong-Bing Shu
Keyword(s):  
Rna Virus ◽  
Interleukin 1 ◽  
Innate Immune ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Antiviral Genes ◽  
Ligand Stimulation ◽  
Tlr3 Ligand Poly ◽  
Receptor Domain

Abstract Toll-like receptor 3 (TLR3)-mediated signaling is important for host defense against RNA virus. Upon viral RNA stimulation, toll and interleukin-1 receptor domain-containing adaptor inducing IFN-β (TRIF) is recruited to TLR3 and then undergoes oligomerization, which is required for the recruitment of downstream molecules to transmit signals. Here, we identified zinc finger CCHC-type containing 3 (ZCCHC3) as a positive regulator of TLR3-mediated signaling. Overexpression of ZCCHC3 promoted transcription of downstream antiviral genes stimulated by the synthetic TLR3 ligand poly(I:C). ZCCHC3-deficiency markedly inhibited TLR3- but not TLR4-mediated induction of type I interferons (IFNs) and proinflammatory cytokines. Zcchc3−/− mice were more resistant to poly(I:C)- but not lipopolysaccharide-induced inflammatory death. Mechanistically, ZCCHC3 promoted recruitment of TRIF to TLR3 after poly(I:C) stimulation. Our findings reveal that ZCCHC3 plays an important role in TLR3-mediated innate immune response by promoting the recruitment of TRIF to TLR3 after ligand stimulation.

scholarly journals A Polymorphism in Toll‐Interleukin 1 Receptor Domain Containing Adaptor Protein Is Associated with Susceptibility to Meningeal Tuberculosis

2006 ◽  
Vol 194 (8) ◽  
pp. 1127-1134 ◽  
Author(s):  
Thomas R. Hawn ◽  
Sarah J. Dunstan ◽  
Guy E. Thwaites ◽  
Cameron P. Simmons ◽  
Nguyen Thuong Thuong ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Adaptor Protein ◽  
Receptor Domain ◽  
Meningeal Tuberculosis

scholarly journals Angiotensin II-induced hypertension and cardiac hypertrophy are differentially mediated by TLR3- and TLR4-dependent pathways

2019 ◽  
Vol 316 (5) ◽  
pp. H1027-H1038 ◽  
Author(s):  
Madhu V. Singh ◽  
Michael Z. Cicha ◽  
Sarah Nunez ◽  
David K. Meyerholz ◽  
Mark W. Chapleau ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Innate Immune System ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Ang Ii ◽  
Interferon Β ◽  
Induced Hypertension ◽  
Deficient Mice ◽  
Receptor Domain

Toll-like receptors (TLR) are key components of the innate immune system that elicit inflammatory responses through the adaptor proteins myeloid differentiation protein 88 (MyD88) and Toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β (TRIF). Previously, we demonstrated that TRIF mediates the signaling of angiotensin II (ANG II)- induced hypertension and cardiac hypertrophy. Since TRIF is activated selectively by TLR3 and TLR4, our goals in this study were to determine the roles of TLR3 and TLR4 in mediating ANG II-induced hypertension and cardiac hypertrophy, and associated changes in proinflammatory gene expression in heart and kidney. In wild-type (WT) mice, ANG II infusion (1,000 ng·kg−1·min−1 for 3 wk) increased systolic blood pressure and caused cardiac hypertrophy. In ANG II-infused TLR4-deficient mice ( Tlr4del), hypertrophy was significantly attenuated despite a preserved or enhanced hypertensive response. In contrast, in TLR3-deficient mice ( Tlr3−/−), both ANG II-induced hypertension and hypertrophy were abrogated. In WT mice, ANG II increased the expression of several proinflammatory genes in hearts and kidneys that were attenuated in both TLR4- and TLR3-deficient mice compared with WT. We conclude that ANG II activates both TLR4-TRIF and TLR3-TRIF pathways in a nonredundant manner whereby hypertension is dependent on activation of the TLR3-TRIF pathway and cardiac hypertrophy is dependent on both TLR3-TRIF and TLR4-TRIF pathways. NEW & NOTEWORTHY Angiotensin II (ANG II)-induced hypertension is dependent on the endosomal Toll-like receptor 3 (TLR3)-Toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β (TRIF) pathway of the innate immune system but not on cell membrane localized TLR4. However, ANG II-induced cardiac hypertrophy is regulated by both TLR4-TRIF and TLR3-TRIF pathways. Thus, ANG II-induced rise in systolic blood pressure is independent of TLR4-TRIF effect on cardiac hypertrophy. The TLR3-TRIF pathway may be a potential target of therapeutic intervention.

Toll-Interleukin 1 Receptor domain-containing adaptor protein positively regulates BV2 cell M1 polarization

2016 ◽  
Vol 43 (12) ◽  
pp. 1674-1682 ◽  
Author(s):  
Leilei Gong ◽  
Hanxiang Wang ◽  
Xiaolei Sun ◽  
Chun Liu ◽  
Chengwei Duan ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Adaptor Protein ◽  
M1 Polarization ◽  
Receptor Domain
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