TIRAP in the Mechanism of Inflammation

The Toll-interleukin-1 Receptor (TIR) domain-containing adaptor protein (TIRAP) represents a key intracellular signalling molecule regulating diverse immune responses. Its capacity to function as an adaptor molecule has been widely investigated in relation to Toll-like Receptor (TLR)-mediated innate immune signalling. Since the discovery of TIRAP in 2001, initial studies were mainly focused on its role as an adaptor protein that couples Myeloid differentiation factor 88 (MyD88) with TLRs, to activate MyD88-dependent TLRs signalling. Subsequent studies delineated TIRAP’s role as a transducer of signalling events through its interaction with non-TLR signalling mediators. Indeed, the ability of TIRAP to interact with an array of intracellular signalling mediators suggests its central role in various immune responses. Therefore, continued studies that elucidate the molecular basis of various TIRAP-protein interactions and how they affect the signalling magnitude, should provide key information on the inflammatory disease mechanisms. This review summarizes the TIRAP recruitment to activated receptors and discusses the mechanism of interactions in relation to the signalling that precede acute and chronic inflammatory diseases. Furthermore, we highlighted the significance of TIRAP-TIR domain containing binding sites for several intracellular inflammatory signalling molecules. Collectively, we discuss the importance of the TIR domain in TIRAP as a key interface involved in protein interactions which could hence serve as a therapeutic target to dampen the extent of acute and chronic inflammatory conditions.

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The TLR signalling adaptor TRIF/TICAM-1 has an N-terminal helical domain with structural similarity to IFIT proteins

Acta Crystallographica Section D Biological Crystallography ◽

10.1107/s0907444913022385 ◽

2013 ◽

Vol 69 (12) ◽

pp. 2420-2430 ◽

Cited By ~ 9

Author(s):

M. Obayed Ullah ◽

Thomas Ve ◽

Matthew Mangan ◽

Mohammed Alaidarous ◽

Matthew J. Sweet ◽

...

Keyword(s):

Interleukin 1 ◽

Functional Characterization ◽

Self Regulation ◽

Adaptor Protein ◽

Structural Similarity ◽

Interferon Β ◽

Tetratricopeptide Repeats ◽

Tir Domain ◽

Signalling Molecules ◽

Selective Targeting

TRIF/TICAM-1 (TIR domain-containing adaptor inducing interferon-β/TIR domain-containing adaptor molecule 1) is the adaptor protein in the Toll-like receptor (TLR) 3 and 4 signalling pathway that leads to the production of type 1 interferons and cytokines. The signalling involves TIR (Toll/interleukin-1 receptor) domain-dependent TRIF oligomerization. A protease-resistant N-terminal region is believed to be involved in self-regulation of TRIF by interacting with its TIR domain. Here, the structural and functional characterization of the N-terminal domain of TRIF (TRIF-NTD) comprising residues 1–153 is reported. The 2.22 Å resolution crystal structure was solved by single-wavelength anomalous diffraction (SAD) using selenomethionine-labelled crystals of TRIF-NTD containing two additional introduced Met residues (TRIF-NTDA66M/L113M). The structure consists of eight antiparallel helices that can be divided into two subdomains, and the overall fold shares similarity to the interferon-induced protein with tetratricopeptide repeats (IFIT) family of proteins, which are involved in both the recognition of viral RNA and modulation of innate immune signalling. Analysis of TRIF-NTD surface features and the mapping of sequence conservation onto the structure suggest several possible binding sites involved in either TRIF auto-regulation or interaction with other signalling molecules or ligands. TRIF-NTD suppresses TRIF-mediated activation of the interferon-β promoter, as well as NF-κB-dependent reporter-gene activity. These findings thus identify opportunities for the selective targeting of TLR3- and TLR4-mediated inflammation.

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Hyperferritinaemia: An Iron Sword of Autoimmunity

Current Pharmaceutical Design ◽

10.2174/1381612825666190709202804 ◽

2019 ◽

Vol 25 (27) ◽

pp. 2909-2918 ◽

Cited By ~ 4

Author(s):

Joanna Giemza-Stokłosa ◽

Md. Asiful Islam ◽

Przemysław J. Kotyla

Keyword(s):

Immune Response ◽

Macrophage Activation ◽

Inflammatory Diseases ◽

Acute Phase Reactant ◽

Catastrophic Antiphospholipid Syndrome ◽

Inflammatory Conditions ◽

Phase Reactant ◽

Signalling Molecule ◽

Cytokine Synthesis

Background:: Ferritin is a molecule that plays many roles being the storage for iron, signalling molecule, and modulator of the immune response. Methods:: Different electronic databases were searched in a non-systematic way to find out the literature of interest. Results:: The level of ferritin rises in many inflammatory conditions including autoimmune disorders. However, in four inflammatory diseases (i.e., adult-onset Still’s diseases, macrophage activation syndrome, catastrophic antiphospholipid syndrome, and sepsis), high levels of ferritin are observed suggesting it as a remarkable biomarker and pathological involvement in these diseases. Acting as an acute phase reactant, ferritin is also involved in the cytokine-associated modulator of the immune response as well as a regulator of cytokine synthesis and release which are responsible for the inflammatory storm. Conclusion:: This review article presents updated information on the role of ferritin in inflammatory and autoimmune diseases with an emphasis on hyperferritinaemic syndrome.

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Pococurante (Poc): An ENU-Induced Missense Mutation of MyD88 with Selective Effects on TLR Signal Transduction.

Blood ◽

10.1182/blood.v104.11.649.649 ◽

2004 ◽

Vol 104 (11) ◽

pp. 649-649

Author(s):

Zhengfan Jiang ◽

Chenglong Li ◽

Louis Shamel ◽

Arthur Olson ◽

Bruce Beutler

Keyword(s):

Signal Transduction ◽

Interleukin 1 ◽

Adaptor Protein ◽

Structural Diversity ◽

Lipoteichoic Acid ◽

Protein Docking ◽

Structural Basis ◽

Cpg Dna ◽

Cpg Dinucleotides ◽

Tir Domain

Abstract Toll-like receptors (TLRs) are key sensors of the innate immune system, and individual TLRs respond to specific molecules derived from microbes. MyD88 is a Toll/Interleukin-1/Resistance (TIR) domain-containing adaptor protein required for signaling by all TLRs except TLR3. While the structural basis of association between MyD88 and TIR-domain receptors is obscure, MyD88-deficient mice show no responses to bacterial flagellin, peptidoglycan (PGN), lipoteichoic acid (LTA), bacterial lipopeptides such as PAM2CSK4, PAM3CSK4 and R- or S-MALP-2, DNA bearing unmethylated CpG dinucleotides (CpG DNA), or Resiquimod (RSQ). Using germline ENU mutagenesis, we have produced a large number of phenotypic variants that have abnormal TLR signaling. We now report the identification of a new mutation called Pococurante (Poc), originally detected in screening because macrophages from this mouse showed no response to the tri-acylated lipopeptide PAM3CSK4, the di-acylated lipopeptide S-MALP-2, LTA, CpG DNA, RSQ, and a markedly reduced response to LPS: the ligands for TLRs 2/1, 2/6, 9, 7 and 4 respectively. They also had no response to interleukin-1, a cytokine that signals by way of a MyD88-dependent TIR domain receptor. However, Poc mice showed a normal response to PGN, as well as R-MALP-2 and PAM2CSK4 lipopeptides. The latter three ligands are sensed in a TLR2-dependent, MyD88-dependent fashion. The Poc phenotype was ascribed to a point mutation of MyD88 affecting a surface residue (I179N). Because the mutation is discriminatory, permitting MyD88 to carry a signal from some TIR domain receptors but not others, we infer that it resides at the receptor:adaptor signaling interface. A new model of TIR receptor:adaptor interaction is proposed on the basis of docking studies that take account of the Poc phenotype, made using the protein-protein docking program SURFDOCK. We note that S-MALP-2 is dependent upon TLR2/6 heterodimers, while PAM3CSK4 sensing depends upon TLR2/1 heterodimers. Since the Poc mutation forbids detection of both these ligands while it allows detection of PAM2CSK4 and R-MALP-2, it may be inferred that TLR2 signal transduction entails greater structural diversity than was previously supposed. The involvement of TLR2 homodimers, or the incorporation of subunits yet unknown into the receptor complex, cannot be excluded.

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Signalling networks, inflammation and innate immunity

Biochemical Society Transactions ◽

10.1042/bst0311462 ◽

2003 ◽

Vol 31 (6) ◽

pp. 1462-1471 ◽

Cited By ~ 9

Author(s):

S.K. Dower ◽

E.E. Qwarnstrom

Keyword(s):

Real Time ◽

Fluorescent Protein ◽

Inflammatory Diseases ◽

Interleukin 1 ◽

Biological Significance ◽

Nuclear Factor Κb ◽

Mitogen Activated Protein Kinase ◽

Screening Methods ◽

Expression Screening ◽

Tir Domain

We have been analysing the signalling systems that couple to receptors of the TIR (Toll/interleukin-1 receptor) family, which signal through a common cytoplasm region; the TIR domain. These systems are of both practical and fundamental biological significance, being central to the pathogenesis of chronic inflammatory diseases such as atherosclerosis, to host defence throughout the biological world, and are ancient in the context of life on earth, having originated more than 1 billion years ago: prior to the divergence of plants and animals. TIR domain receptors couple to at least two sets of well-characterized pathways: those leading to the activation of inhibitory κB kinase complexes/nuclear factor κB, and those leading to the activation of mitogen-activated protein kinase/AP-1/ATF-2 etc. We have been investigating these systems using a combination of expression screening methods to identify new components, and real-time green fluorescent protein-based techniques to observe execution of signalling programmes in real time. Our data reveal that there is a very large level of cell-to-cell variation in signal programme execution even in clonal populations and that at least one mechanism for dealing with this heterogeneity is the assembly of signal transduction components into large multiprotein complexes.

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The SARM1 TIR NADase: Mechanistic Similarities to Bacterial Phage Defense and Toxin-Antitoxin Systems

Frontiers in Immunology ◽

10.3389/fimmu.2021.752898 ◽

2021 ◽

Vol 12 ◽

Author(s):

Aaron DiAntonio ◽

Jeffrey Milbrandt ◽

Matthew D. Figley

Keyword(s):

Defense Mechanisms ◽

Interleukin 1 ◽

Innate Immune ◽

Activation Mechanism ◽

Bacterial Toxin ◽

Axon Degeneration ◽

Tir Domain ◽

Immune Mechanisms ◽

Signalling Molecules ◽

Tir Domains

The Toll/interleukin-1 receptor (TIR) domain is the signature signalling motif of innate immunity, with essential roles in innate immune signalling in bacteria, plants, and animals. TIR domains canonically function as scaffolds, with stimulus-dependent multimerization generating binding sites for signalling molecules such as kinases and ligases that activate downstream immune mechanisms. Recent studies have dramatically expanded our understanding of the TIR domain, demonstrating that the primordial function of the TIR domain is to metabolize NAD+. Mammalian SARM1, the central executioner of pathological axon degeneration, is the founding member of the TIR-domain class of NAD+ hydrolases. This unexpected NADase activity of TIR domains is evolutionarily conserved, with archaeal, bacterial, and plant TIR domains all sharing this catalytic function. Moreover, this enzymatic activity is essential for the innate immune function of these proteins. These evolutionary relationships suggest a link between SARM1 and ancient self-defense mechanisms that has only been strengthened by the recent discovery of the SARM1 activation mechanism which, we will argue, is strikingly similar to bacterial toxin-antitoxin systems. In this brief review we will describe the regulation and function of SARM1 in programmed axon self-destruction, and highlight the parallels between the SARM1 axon degeneration pathway and bacterial innate immune mechanisms.

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Differences of plasma IL-1 and TNF-α in healthy Chinese Population

Open Medicine ◽

10.1515/med-2015-0044 ◽

2015 ◽

Vol 10 (1) ◽

Author(s):

Jintao Yuan ◽

Lan Wang ◽

Yijin Lin ◽

Jianhong Chen ◽

Jianghong Hu

Keyword(s):

Immune Responses ◽

Opportunistic Infections ◽

Inflammatory Diseases ◽

Interleukin 1 ◽

Predictive Biomarkers ◽

Enzyme Linked Immunosorbent Assay ◽

Tnf Α ◽

Inflammatory Processes ◽

Factor Α ◽

Necrosis Factor

AbstractPle iotropic proinflammatory cytokines, interleukin- 1 (IL-1) and tumor necrosis factor-α (TNF-α), involved in the regulations of various immune responses, inflammatory processes and hematopoiesis. In the present study, the expression levels of IL-1 and TNF-α were detected by enzyme-linked immunosorbent assay (ELISA). Following the cytokine blockade as a successful clinical therapy for autoimm une diseases such as rheumatoid arthritis, the patients are more susceptible to a variety of opportunistic infections. IL-1 and TNF-α may be useful predictive biomarkers of diseases and offer potential targets for therapeutic intervention of inflammatory diseases. However, our results showed that the plasma IL-1 level was significantly higher in women compared to men (69.5 ± 19.8 pg/ ml in men and 80.1 ± 19.5 pg/ml in women, respectively); the plasma levels of TNF-α were higher in men than women (20.8 ± 4.9 pg/ml and 18.7 ± 7.1 pg/ml, respectively). The significant gender difference of plasma interleukin-1 (IL-1) and TNF-α levels present in healthy adults in Jiangsu Province, China (P=0.002 and P=0.015, respectively), and may be as a hint for sex differences of susceptibility to many diseases and elementary immune response.

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Common and distinct features of TIR domain function

Acta Crystallographica Section A Foundations and Advances ◽

10.1107/s2053273314097575 ◽

2014 ◽

Vol 70 (a1) ◽

pp. C242-C242

Author(s):

Simon Williams ◽

Mohammed Alaidarous ◽

Thomas Ve ◽

Xiaoxiao Zhang ◽

Eugene Valkov ◽

...

Keyword(s):

Fungal Pathogens ◽

Paracoccus Denitrificans ◽

Brucella Melitensis ◽

Interleukin 1 ◽

Adaptor Protein ◽

Site Directed Mutagenesis ◽

Tir Domain ◽

Common Features ◽

Self Association ◽

Tir Domains

TIR (Toll/interleukin-1 receptor, resistance protein) domains feature in diverse proteins with functions in the immune system, such as animal TLRs (Toll-like receptors), plant NLRs (nucleotide binding, leucine-rich repeat) and bacterial virulence factors. It has been well established, especially through the work on TLRs, that signalling depends on regulated self-association of TIR domains. However, every single TIR domain structure has revealed a different association mode [1]. In the search for common features, we have targeted a number of TIR domains from mammals, plants and bacteria to characterize structurally. We have determined the crystal structures of the TIR domains from the human TLR adaptor protein MAL [1], the bacterial protein TcpB from Brucella melitensis [2] and the plant immune proteins L6 from flax [3] and SNC1, RPS4 and RRS1 from Arabidopsis (unpublished). In the case of the proteins RPS4 and RRS1, which work together as a protein complex to confer resistance to three different bacterial and fungal pathogens, we have determined, using linker-assisted crystallization, the first structure of a hetero-dimeric complex of TIR domains (Fig. 1). The association interface in this complex is conserved in the crystals of the TIR domains of RPS4 and RRS1 on their own, as well as in those of SNC1 and another Arabidopsis protein AT1G72930. Similarly, the dimerization interface observed in the structure of TcpB is conserved in the structure of the TIR domain-containing protein from Paracoccus denitrificans. We validated the association interfaces by site-directed mutagenesis coupled with a variety of cellular assays. As self-association is key to TIR domain function, our studies are finally revealing common features of the molecular function of TIR domains across phyla.

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Interleukin-1 in the pathogenesis and treatment of inflammatory diseases

Blood ◽

10.1182/blood-2010-07-273417 ◽

2011 ◽

Vol 117 (14) ◽

pp. 3720-3732 ◽

Cited By ~ 1057

Author(s):

Charles A. Dinarello

Keyword(s):

Disease Severity ◽

Inflammatory Diseases ◽

Interleukin 1 ◽

Immunosuppressive Drugs ◽

Autoinflammatory Diseases ◽

Inflammatory Conditions ◽

Sustained Reduction ◽

Anti Inflammatory ◽

Smoldering Myeloma ◽

Acute And Chronic Inflammation

Abstract More than any other cytokine family, the IL-1 family of ligands and receptors is primarily associated with acute and chronic inflammation. The cytosolic segment of each IL-1 receptor family member contains the Toll-IL-1-receptor domain. This domain is also present in each Toll-like receptor, the receptors that respond to microbial products and viruses. Since Toll-IL-1-receptor domains are functional for both receptor families, responses to the IL-1 family are fundamental to innate immunity. Of the 11 members of the IL-1 family, IL-1β has emerged as a therapeutic target for an expanding number of systemic and local inflammatory conditions called autoinflammatory diseases. For these, neutralization of IL-1β results in a rapid and sustained reduction in disease severity. Treatment for autoimmune diseases often includes immunosuppressive drugs whereas neutralization of IL-1β is mostly anti-inflammatory. Although some autoinflammatory diseases are due to gain-of-function mutations for caspase-1 activity, common diseases such as gout, type 2 diabetes, heart failure, recurrent pericarditis, rheumatoid arthritis, and smoldering myeloma also are responsive to IL-1β neutralization. This review summarizes acute and chronic inflammatory diseases that are treated by reducing IL-1β activity and proposes that disease severity is affected by the anti-inflammatory members of the IL-1 family of ligands and receptors.

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The Role of IL-36 in Infectious Diseases: Potential Target for COVID-19?

Frontiers in Immunology ◽

10.3389/fimmu.2021.662266 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaofang Wang ◽

Panpan Yi ◽

Yuejin Liang

Keyword(s):

Infectious Diseases ◽

Immune Responses ◽

Lupus Erythematosus ◽

Fungal Infections ◽

Inflammatory Diseases ◽

Interleukin 1 ◽

Functional Roles ◽

Cellular Expression ◽

Inflammatory Bowel

IL-36 is a member of the interleukin 1 cytokine family, which is currently experiencing a renaissance due to the growing understanding of its context-dependent roles and advances in our understanding of the inflammatory response. The immunological role of IL-36 has revealed its profound and indispensable functional roles in psoriasis, as well as in several inflammatory diseases, including inflammatory bowel disease (IBD), systemic lupus erythematosus, rheumatoid arthritis (RA) and cancer. More recently, an increasing body of evidence suggests that IL-36 plays a crucial role in viral, bacterial and fungal infections. There is a growing interest as to whether IL-36 contributes to host protective immune responses against infection as well as the potential implications of IL-36 for the development of new therapeutic strategies. In this review, we summarize the recent progress in understanding cellular expression, regulatory mechanisms and biological roles of IL-36 in infectious diseases, which suggest more specific strategies to maneuver IL-36 as a diagnostic or therapeutic target, especially in COVID-19.

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Select targeting of intracellular Toll-interleukin-1 receptor resistance domains for protection against influenza-induced disease

Innate Immunity ◽

10.1177/1753425919846281 ◽

2020 ◽

Vol 26 (1) ◽

pp. 26-34

Author(s):

Kari Ann Shirey ◽

Wendy Lai ◽

Lindsey J Brown ◽

Jorge C G Blanco ◽

Robert Beadenkopf ◽

...

Keyword(s):

Immune Responses ◽

Intracellular Signaling ◽

Interleukin 1 ◽

Tir Domain ◽

Close Proximity ◽

Domain Interactions ◽

Tir Domains ◽

Molecular Patterns ◽

Lps Signaling

TLRs are a family of PRRs that respond to PAMPs or host-derived Danger-Associated Molecular Patterns (DAMPs) to initiate host inflammation and immune responses. TLR dimerization and recruitment of adapter molecules is critical for intracellular signaling and is mediated through intracellular Toll-Interleukin 1 Receptor Resistance (TIR) domain interactions. Human TIR domains, including reported structures of TIR1, TIR2, TIR6, TIR10, TIRAP, and MyD88, contain Cysteine (Cys) interactions or modifications that are disproportionally at, or near, reported biological TIR interfaces, or in close proximity to functionally important regions. Therefore, we hypothesized that intracellular TIR Cys regulation may have greater functional importance than previously appreciated. Expression of mutant TLR4-C747S or treatment of TLR4 reporter cells with a small molecule, Cys-binding inhibitor of TLR4, TAK-242, abrogated LPS signaling in vitro. Using TAK-242, mice were protected from lethal influenza challenge as previously reported for extracellular TLR4 antagonists. Molecular modeling and sequence analysis of the region surrounding TLR4-Cys747 indicate conservation of a WxxxE motif identified among bacterial and NAD+-consuming TIRs, as well as within the TIRs domains of surface TLRs 1, 2, 4, 6, and 10. Together, these data support the hypothesis that critical Cys within the TIR domain are essential for TLR4 functionality.

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