scholarly journals Revisiting Platelets and Toll-Like Receptors (TLRs): At the Interface of Vascular Immunity and Thrombosis

2020 ◽  
Vol 21 (17) ◽  
pp. 6150 ◽  
Author(s):  
Kathryn Hally ◽  
Sebastien Fauteux-Daniel ◽  
Hind Hamzeh-Cognasse ◽  
Peter Larsen ◽  
Fabrice Cognasse
Keyword(s):  
Platelet Function ◽  
Immune Modulation ◽  
Human Platelets ◽  
Toll Like Receptors ◽  
Methodological Issues ◽  
Vascular Integrity ◽  
Danger Signals ◽  
Research Questions ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

While platelet function has traditionally been described in the context of maintaining vascular integrity, recent evidence suggests that platelets can modulate inflammation in a much more sophisticated and nuanced manner than previously thought. Some aspects of this expanded repertoire of platelet function are mediated via expression of Toll-like receptors (TLRs). TLRs are a family of pattern recognition receptors that recognize pathogen-associated and damage-associated molecular patterns. Activation of these receptors is crucial for orchestrating and sustaining the inflammatory response to both types of danger signals. The TLR family consists of 10 known receptors, and there is at least some evidence that each of these are expressed on or within human platelets. This review presents the literature on TLR-mediated platelet activation for each of these receptors, and the existing understanding of platelet-TLR immune modulation. This review also highlights unresolved methodological issues that potentially contribute to some of the discrepancies within the literature, and we also suggest several recommendations to overcome these issues. Current understanding of TLR-mediated platelet responses in influenza, sepsis, transfusion-related injury and cardiovascular disease are discussed, and key outstanding research questions are highlighted. In summary, we provide a resource—a “researcher’s toolkit”—for undertaking further research in the field of platelet-TLR biology.

scholarly journals Toll-Like Receptors in Hepatic Ischemia/Reperfusion and Transplantation

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
John Evankovich ◽  
Timothy Billiar ◽  
Allan Tsung
Keyword(s):  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Innate Immune ◽  
Toll Like Receptors ◽  
Hepatic Ischemia ◽  
Danger Signals ◽  
The Family ◽  
Hepatic Ischemia Reperfusion ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

The family of Toll-like receptors (TLRs) function as pattern-recognition receptors (PRRs) that respond to a myriad of highly conserved ligands. These substrates include pathogen-associated molecular patterns (PAMPs) for the recognition of invading pathogens, as well as damage-associated molecular patterns (DAMPs) for the recognition of endogenous tissue injury. While the functions of TLRs are diverse, they have received much attention for their roles in ischemia/reperfusion (I/R) injury of the liver and other organs. The TLRs play central roles in sensing tissue damage and activating the innate immune system following I/R. Engagement of TLRs by endogenous DAMPs activates proinflammatory signaling pathways leading to the production of cytokines, chemokines and further release of endogenous danger signals. This paper focuses on the most recent findings regarding TLR family members in hepatic I/R injury and transplantation.

scholarly journals Toll-Like Receptors and Myocardial Inflammation

2011 ◽  
Vol 2011 ◽  
pp. 1-21 ◽  
Author(s):  
Yan Feng ◽  
Wei Chao
Keyword(s):  
Animal Studies ◽  
Myocardial Injury ◽  
Myocardial Inflammation ◽  
Septic Cardiomyopathy ◽  
Toll Like Receptors ◽  
Tlr Signaling ◽  
Animal Data ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Toll-like receptors (TLRs) are a member of the innate immune system. TLRs detect invading pathogens through the pathogen-associated molecular patterns (PAMPs) recognition and play an essential role in the host defense. TLRs can also sense a large number of endogenous molecules with the damage-associated molecular patterns (DAMPs) that are produced under various injurious conditions. Animal studies of the last decade have demonstrated that TLR signaling contributes to the pathogenesis of the critical cardiac conditions, where myocardial inflammation plays a prominent role, such as ischemic myocardial injury, myocarditis, and septic cardiomyopathy. This paper reviews the animal data on (1) TLRs, TLR ligands, and the signal transduction system and (2) the important role of TLR signaling in these critical cardiac conditions.

scholarly journals Image-recognizing receptors of the innate immunity and their role in immunotherapy (review)

2020 ◽  
pp. 4-15
Author(s):  
О.Ю. Филатов ◽  
В.А. Назаров
Keyword(s):  
Innate Immunity ◽  
Membrane Surface ◽  
Immune Defense ◽  
Molecular Structures ◽  
Membrane Receptors ◽  
Toll Like Receptors ◽  
Lectin Receptors ◽  
Wide Range ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Данная статья обобщает накопившуюся на сегодняшний день информацию о многообразии образраспознающих рецепторов, их роли в регуляции иммунной системы. Распознавание патогена врожденным иммунитетом происходит с помощью рецепторов к широкому спектру антигенов за счет выделения нескольких высоко консервативных структур микроорганизмов. Эти структуры были названы патоген-ассоциированные образы (Patogen-Associated Molecular Patterns - PAMP). Наиболее изученными являются липополисахарид грамм отрицательных бактерий (LPS), липотейхоевые кислоты, пептидогликан (PGN), CpG мотивы ДНК и РНК. Рецепторы, распознающие PAMP, называются PRR. Данная группа рецепторов также распознает молекулы, образующиеся при повреждении собственных тканей. Такие молекулярные структуры называются Damage-Associated Molecular Patterns (DAMP), или образы, ассоциированные с повреждением. В качестве DAMP могут выступать белки теплового шока, хроматин, фрагменты ДНК. В зависимости от локализации, образраспознающие рецепторы принято разделять на: расположенные на мембране Toll-подобные рецепторы (Toll-like receptors, TLR) и рецепторы лектина С-типа (C-type lectin receptors, CLR), а также расположенные в цитоплазме NOD-подобные рецепторы (NOD-like receptors, NLR) и цитоплазматические РНК- и ДНК-сенсоры. Сегодня у человека известно 10 типов TLR, часть из которых расположена на поверхности (TLR1-TLR6, TLR10) большинства клеток, в том числе макрофагов, В-лимфоцитов и дендритных клеток, а часть - в эндосомах (TLR3, TLR7-TLR9). CLR представляет из себя семейство рецепторов, расположенных на мембране и имеющих домены распознавания углеводов (CRD), или структурно сходные лектиноподобные домены типа C (CTLD). В данном семействе рецепторов принято по происхождению и структуре выделять 17 групп. CLR активно участвуют в противогрибковой иммунной защите, а также они играют роль в защите и от других типов микроорганизмов. NOD (нуклеотидсвязывающий и олигомеризационный домен)-подобные рецепторы расположены в цитоплазме. Благодаря этим рецепторам, патоген, который избежал распознавания на поверхности мембраны, сталкивается со вторым уровнем распознавания уже внутри клетки. В данной статье рассматриваются пути активации образраспознающих рецепторов, их эффекты и применение данных эффектов в медицине. This article summarizes currently available information about the variety of image-recognizing receptors and their role in regulation of the immune system. Pathogen recognition by the innate immunity is mediated by receptors to a wide range of antigens via recognition of several highly conservative structures of microorganisms. These structures were named pathogen-associated images or PAMP (pathogen-associated molecular pattern). The best studied types of such structures include lipopolysaccharide (LPS) of gram-negative bacteria, lipoteichoic acids, peptidoglycan (PGN), and CpG DNA and RNA motifs. PAMP-recognizing receptors (PRRS) are a group of receptors, which also recognize molecules released during damage of host tissues. Such molecular structures are called DAMPS (damage-associated molecular patterns) or damage-associated images. Heat shock proteins, chromatin, and DNA fragments may act as DAMPS. Depending on the localization, image-recognizing receptors are generally classified as membrane-located Toll-like receptors (TLR) and C-type lectin receptors (CLR), as well as cytoplasmic NOD-like receptors (NLR) and cytoplasmic RNA and DNA sensors. Today, 10 types of human TLR are known. Some of them are located on the surface (TLR1-TLR6, TLR10) of most cells, including macrophages, B-cells, and dendritic cells, and some are present in endosomes (TLR3, TLR7-TLR9). CLR is a family of membrane receptors that have carbohydrate recognition domains (CRD) or structurally similar lectin-like type C domains (CTLD). Seventeen groups are distinguished within this receptor family based on their origin and structure. CLRs are actively involved in antifungal immune defense and also play a role in protection against other types of microorganisms. NOD (nucleotide-binding and oligomerization domain)-like receptors are present in the cytoplasm. These receptors provide the second level of recognition inside the cell for the pathogens that have escaped recognition on the membrane surface. This article discusses activation pathways of image-recognizing receptors, their effects, and the use of such effects in medicine.

scholarly journals P03.24 Calreticulin exposure on malignant blasts correlates with improved NK cell-mediated cytotoxicity in AML patients

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A32.1-A32
Author(s):  
I Truxova ◽  
L Kasikova ◽  
C Salek ◽  
M Hensler ◽  
D Lysak ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Type I ◽  
Danger Signals ◽  
Hla Dr ◽  
Patient Prognosis ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

In some settings, cancer cells responding to treatment undergo an immunogenic form of cell death that is associated with the abundant emission of danger signals in the form of damage-associated molecular patterns. Accumulating preclinical and clinical evidence indicates that danger signals play a crucial role in the (re-)activation of antitumor immune responses in vivo, thus having a major impact on patient prognosis. We have previously demonstrated that the presence of calreticulin on the surface of malignant blasts is a positive prognostic biomarker for patients with acute myeloid leukemia (AML). Calreticulin exposure not only correlated with enhanced T-cell-dependent antitumor immunity in this setting but also affected the number of circulating natural killer (NK) cells upon restoration of normal hematopoiesis. Here, we report that calreticulin exposure on malignant blasts is associated with enhanced NK cell cytotoxic and secretory functions, both in AML patients and in vivo in mice. The ability of calreticulin to stimulate NK-cells relies on CD11c+CD14high cells that, upon exposure to CRT, express higher levels of IL-15Rα, maturation markers (CD86 and HLA- DR) and CCR7. CRT exposure on malignant blasts also correlates with the upregulation of genes coding for type I interferon. This suggests that CD11c+CD14high cells have increased capacity to migrate to secondary lymphoid organs, where can efficiently deliver stimulatory signals (IL-15Rα/IL- 15) to NK cells. These findings delineate a multipronged, clinically relevant mechanism whereby surface-exposed calreticulin favors NK-cell activation in AML patients.Disclosure InformationI. Truxova: None. L. Kasikova: None. C. Salek: None. M. Hensler: None. D. Lysak: None. P. Holicek: None. P. Bilkova: None. M. Holubova: None. X. Chen: None. R. Mikyskova: None. M. Reinis: None. M. Kovar: None. B. Tomalova: None. J.P. Kline: None. L. Galluzzi: None. R. Spisek: None. J. Fucikova: None.

scholarly journals Toll-like Receptors from the Perspective of Cancer Treatment

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 297 ◽  
Author(s):  
Nasir Javaid ◽  
Sangdun Choi
Keyword(s):  
Pattern Recognition ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Toll Like Receptors ◽  
Mitogen Activated Protein Kinases ◽  
Mitogen Activated Protein ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Multiple Signaling ◽  
Anticancer Drug Discovery

Toll-like receptors (TLRs) represent a family of pattern recognition receptors that recognize certain pathogen-associated molecular patterns and damage-associated molecular patterns. TLRs are highly interesting to researchers including immunologists because of the involvement in various diseases including cancers, allergies, autoimmunity, infections, and inflammation. After ligand engagement, TLRs trigger multiple signaling pathways involving nuclear factor-κB (NF-κB), interferon-regulatory factors (IRFs), and mitogen-activated protein kinases (MAPKs) for the production of various cytokines that play an important role in diseases like cancer. TLR activation in immune as well as cancer cells may prevent the formation and growth of a tumor. Nonetheless, under certain conditions, either hyperactivation or hypoactivation of TLRs supports the survival and metastasis of a tumor. Therefore, the design of TLR-targeting agonists as well as antagonists is a promising immunotherapeutic approach to cancer. In this review, we mainly describe TLRs, their involvement in cancer, and their promising properties for anticancer drug discovery.

Inhibitory pattern recognition receptors

2021 ◽  
Vol 219 (1) ◽  
Author(s):  
Matevž Rumpret ◽  
Helen J. von Richthofen ◽  
Victor Peperzak ◽  
Linde Meyaard
Keyword(s):  
Pattern Recognition ◽  
Cell Death ◽  
Immune System ◽  
Immune Responses ◽  
Pattern Recognition Receptors ◽  
Inhibitory Receptors ◽  
Danger Signals ◽  
Molecular Pattern ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Pathogen- and damage-associated molecular patterns are sensed by the immune system’s pattern recognition receptors (PRRs) upon contact with a microbe or damaged tissue. In situations such as contact with commensals or during physiological cell death, the immune system should not respond to these patterns. Hence, immune responses need to be context dependent, but it is not clear how context for molecular pattern recognition is provided. We discuss inhibitory receptors as potential counterparts to activating pattern recognition receptors. We propose a group of inhibitory pattern recognition receptors (iPRRs) that recognize endogenous and microbial patterns associated with danger, homeostasis, or both. We propose that recognition of molecular patterns by iPRRs provides context, helps mediate tolerance to microbes, and helps balance responses to danger signals.

scholarly journals RNA Modifications Modulate Activation of Innate Toll-Like Receptors

Genes ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 92 ◽  
Author(s):  
Isabel Freund ◽  
Tatjana Eigenbrod ◽  
Mark Helm ◽  
Alexander Dalpke
Keyword(s):  
Immune Modulation ◽  
Innate Immune ◽  
Toll Like Receptors ◽  
Rna Modifications ◽  
Sequence Context ◽  
Rna Molecules ◽  
Naturally Occurring ◽  
New Findings ◽  
Molecular Patterns ◽  
Tlr7 Stimulation

Self/foreign discrimination by the innate immune system depends on receptors that identify molecular patterns as associated to pathogens. Among others, this group includes endosomal Toll-like receptors, among which Toll-like receptors (TLR) 3, 7, 8, and 13 recognize and discriminate mammalian from microbial, potentially pathogen-associated, RNA. One of the discriminatory principles is the recognition of endogenous RNA modifications. Previous work has identified a couple of RNA modifications that impede activation of TLR signaling when incorporated in synthetic RNA molecules. Of note, work that is more recent has now shown that RNA modifications in their naturally occurring context can have immune-modulatory functions: Gm, a naturally occurring ribose-methylation within tRNA resulted in a lack of TLR7 stimulation and within a defined sequence context acted as antagonist. Additional RNA modifications with immune-modulatory functions have now been identified and recent work also indicates that RNA modifications within the context of whole prokaryotic or eukaryotic cells are indeed used for immune-modulation. This review will discuss new findings and developments in the field of immune-modulatory RNA modifications.

scholarly journals Intestinal and enthesis innate immunity in early axial spondyloarthropathy

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_4) ◽  
pp. iv67-iv78
Author(s):  
Kassem Sharif ◽  
Charlie Bridgewood ◽  
Sayam Dubash ◽  
Dennis McGonagle
Keyword(s):  
Innate Immune ◽  
Biomechanical Stress ◽  
Danger Signals ◽  
Uveal Tract ◽  
Axial Spondyloarthropathy ◽  
Axial Disease ◽  
Key Drivers ◽  
Recent Classification ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Abstract Axial SpA (axSpA), encompassing AS, is a multifactorial disease that localizes to sites of high spinal biomechanical stress. Much has been written on T cells and adaptive immunity in axSpA, which is understandable given the very strong HLA-B27 disease association. Extra-axial disease characteristically involves the anterior uveal tract, aortic root, lung apex and terminal ileum. Under recent classification, axSpA is classified as an intermediate between autoimmunity and autoinflammatory disease, with the latter term being synonymous with innate immune dysregulation. The purpose of this review is to evaluate the ‘danger signals’ from both the exogenous intestinal microbiotal adjuvants or pathogen-associated molecular patterns that access the circulation and endogenously derived damaged self-tissue or damage-associated molecular patterns derived from entheses and other sites of high biomechanical stress or damage that may serve as key drivers of axSpA onset, evolution, disease flares and eventual outcomes.

scholarly journals Toll-Like Receptors 1/2/4/6 and Nucleotide-Binding Oligomerization Domain-Like Receptor 2 Are Key Damage-Associated Molecular Patterns Sensors on Periodontal Resident Cells

2021 ◽  
Vol 11 (11) ◽  
pp. 4724
Author(s):  
Yu Chen ◽  
Xiaoxiao Wang ◽  
Corrie H. C. Ng ◽  
Saiwah Tsao ◽  
Waikeung Leung
Keyword(s):  
Nucleotide Binding ◽  
Cross Sectional Study ◽  
Periodontal Tissue ◽  
Toll Like Receptors ◽  
Cross Sectional ◽  
Molecular Pattern ◽  
Health And Disease ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Oligomerization Domain

Background: Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are innate, damage-associated molecular patterns (DAMP) sensors. Their expressions in human periodontal resident cells and reactions toward irritations, such as hypoxia and lipopolysaccharide (LPS), remain not well characterized. This cross-sectional study aimed to investigate and characterize TLRs, NOD1/2 and NLRP1/2 expressions at the dento-gingival junction. Methods: Immunohistochemistry screening was carried out on periodontal tissue biopsies sections, while selected DAMP sensors signal and protein expression under Escherichia coli LPS (2 µg/mL) and/or hypoxia (1% O2), 24 h, by human gingival keratinocytes (HGK) or fibroblasts (HGF) were investigated. Results: Positive TLR1/2/4/5/6, NOD1/2 and NLRP1/2 immunostaining were observed in healthy and periodontitis biopsies with apparently more pocket epithelial cells positive for TLR2, TLR4 and NOD1/2. TLR1-6, NOD1/2 and NLRP1/2 messengers were detected in gingival/periodontal biopsies as well as healthy HGK and HGF explants. LPS and/or hypoxia induced signals and protein upregulation of NOD2 in HGKs or TLR1/6 and NOD2 in HGFs. Conclusion: Transcripts and proteins of TLR1/2/4/5/6, NOD1/2 and NLRP1/2 were expressed in human periodontal tissue in health and disease. Putting all observations together, NOD2, perhaps with TLR1/2/4/6, might be considered key, damage-associated molecular pattern sensors on periodontal resident cells.

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