Beyond Tissue Injury—Damage-Associated Molecular Patterns, Toll-Like Receptors, and Inflammasomes Also Drive Regeneration and Fibrosis

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.

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Toll-Like Receptors and Myocardial Inflammation

International Journal of Inflammation ◽

10.4061/2011/170352 ◽

2011 ◽

Vol 2011 ◽

pp. 1-21 ◽

Cited By ~ 39

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21176150 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6150 ◽

Cited By ~ 2

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.

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

Nauchno-prakticheskii zhurnal «Patogenez» ◽

10.25557/2310-0435.2020.04.4-15 ◽

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.

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Acetaminophen-Induced Rat Hepatotoxicity Based on M1/M2-Macrophage Polarization, in Possible Relation to Damage-Associated Molecular Patterns and Autophagy

International Journal of Molecular Sciences ◽

10.3390/ijms21238998 ◽

2020 ◽

Vol 21 (23) ◽

pp. 8998

Author(s):

Yuka Tsuji ◽

Mizuki Kuramochi ◽

Hossain M. Golbar ◽

Takeshi Izawa ◽

Mitsuru Kuwamura ◽

...

Keyword(s):

Mhc Class Ii ◽

Rat Model ◽

Tissue Injury ◽

Macrophage Polarization ◽

Coagulation Necrosis ◽

M2 Macrophage ◽

Old Rats ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns ◽

M1 Type

Overdose of acetaminophen (APAP), an antipyretic drug, is an important cause of liver injury. However, the mechanism in the rat model remains undetermined. We analyzed APAP-induced hepatotoxicity using rats based on M1/M2-macrophage functions in relation to damage-associated molecular patterns (DAMPs) and autophagy. Liver samples from six-week-old rats injected with APAP (1000 mg/kg BW, ip, once) after 15 h fasting were collected at hour 10, and on days 1, 2, 3, and 5. Liver lesions consisting of coagulation necrosis and inflammation were seen in the affected centrilobular area on days 1 and 2, and then, recovered with reparative fibrosis by day 5. Liver exudative enzymes increased transiently on day 1. CD68+ M1-macrophages increased significantly on days 1 and 2 with increased mRNAs of M1-related cytokines such as IFN-g and TNF-α, whereas CD163+ M2-macrophages appeared later on days 2 and 3. Macrophages reacting to MHC class II and Iba1 showed M1-type polarization, and CD204+ macrophages tended to be polarized toward M2-type. At hour 10, interestingly, HMGB1 (representative DAMPs) and its related signals, TLR-9 and MyD88, as well as LC3B+ autophagosomes began to increase. Collectively, the pathogenesis of rat APAP hepatotoxicity, which is the first, detailed report for a rat model, might be influenced by macrophage functions of M1 type for tissue injury/inflammation and M2-type for anti-inflammatory/fibrosis; particularly, M1-type may function in relation to DAMPs and autophagy. Understanding the interplayed mechanisms would provide new insight into hepato-pathogenesis and contribute to the possible development of therapeutic strategies.

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Association between early airway damage-associated molecular patterns and subsequent bacterial infection in patients with inhalational and burn injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00321.2014 ◽

2015 ◽

Vol 308 (9) ◽

pp. L855-L860 ◽

Cited By ~ 17

Author(s):

Robert Maile ◽

Samuel Jones ◽

Yinghao Pan ◽

Haibo Zhou ◽

Ilona Jaspers ◽

...

Keyword(s):

North Carolina ◽

Bacterial Infection ◽

Injury Severity ◽

Burn Injury ◽

Tissue Injury ◽

Cell Damage ◽

Inhalation Injury ◽

High Mobility Group Protein ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

Bacterial infection is a major cause of morbidity affecting outcome following burn and inhalation injury. While experimental burn and inhalation injury animal models have suggested that mediators of cell damage and inflammation increase the risk of infection, few studies have been done on humans. This is a prospective, observational study of patients admitted to the North Carolina Jaycee Burn Center at the University of North Carolina who were intubated and on mechanical ventilation for treatment of burn and inhalational injury. Subjects were enrolled over a 2-yr period and followed till discharge or death. Serial bronchial washings from clinically indicated bronchoscopies were collected and analyzed for markers of tissue injury and inflammation. These include damage-associated molecular patterns (DAMPs) such as hyaluronic acid (HA), double-stranded DNA (dsDNA), heat-shock protein 70 (HSP-70), and high-mobility group protein B-1 (HMGB-1). The study population was comprised of 72 patients who had bacterial cultures obtained for clinical indications. Elevated HA, dsDNA, and IL-10 levels in bronchial washings obtained early (the first 72 h after injury) were significantly associated with positive bacterial respiratory cultures obtained during the first 14 days postinjury. Independent of initial inhalation injury severity and extent of surface burn, elevated levels of HA dsDNA and IL-10 in the central airways obtained early after injury are associated with subsequent positive bacterial respiratory cultures in patients intubated after acute burn/inhalation injury.

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Interactions between tumor-derived proteins and Toll-like receptors

Experimental & Molecular Medicine ◽

10.1038/s12276-020-00540-4 ◽

2020 ◽

Vol 52 (12) ◽

pp. 1926-1935

Author(s):

Gun-Young Jang ◽

Ji won Lee ◽

Young Seob Kim ◽

Sung Eun Lee ◽

Hee Dong Han ◽

...

Keyword(s):

Tumor Microenvironment ◽

T Cell Activation ◽

Immune Cells ◽

Cell Activation ◽

Tissue Injury ◽

Suppressor Cells ◽

Toll Like Receptors ◽

Molecular Pattern ◽

Molecular Patterns ◽

Dying Cells

AbstractDamage-associated molecular patterns (DAMPs) are danger signals (or alarmins) alerting immune cells through pattern recognition receptors (PRRs) to begin defense activity. Moreover, DAMPs are host biomolecules that can initiate a noninflammatory response to infection, and pathogen-associated molecular pattern (PAMPs) perpetuate the inflammatory response to infection. Many DAMPs are proteins that have defined intracellular functions and are released from dying cells after tissue injury or chemo-/radiotherapy. In the tumor microenvironment, DAMPs can be ligands for Toll-like receptors (TLRs) expressed on immune cells and induce cytokine production and T-cell activation. Moreover, DAMPs released from tumor cells can directly activate tumor-expressed TLRs that induce chemoresistance, migration, invasion, and metastasis. Furthermore, DAMP-induced chronic inflammation in the tumor microenvironment causes an increase in immunosuppressive populations, such as M2 macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). Therefore, regulation of DAMP proteins can reduce excessive inflammation to create an immunogenic tumor microenvironment. Here, we review tumor-derived DAMP proteins as ligands of TLRs and discuss their association with immune cells, tumors, and the composition of the tumor microenvironment.

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Toll-like Receptors from the Perspective of Cancer Treatment

Cancers ◽

10.3390/cancers12020297 ◽

2020 ◽

Vol 12 (2) ◽

pp. 297 ◽

Cited By ~ 4

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.

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NLRP3 Inflammasome Inhibitors in Cardiovascular Diseases

Molecules ◽

10.3390/molecules26040976 ◽

2021 ◽

Vol 26 (4) ◽

pp. 976

Author(s):

Eleonora Mezzaroma ◽

Antonio Abbate ◽

Stefano Toldo

Keyword(s):

Cardiovascular Diseases ◽

Inflammatory Response ◽

Nlrp3 Inflammasome ◽

Tissue Injury ◽

Scientific Evidence ◽

Rapid Induction ◽

Pyrin Domain ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns ◽

Inflammasome Inhibitors

Virtually all types of cardiovascular diseases are associated with pathological activation of the innate immune system. The NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome is a protein complex that functions as a platform for rapid induction of the inflammatory response to infection or sterile injury. NLRP3 is an intracellular sensor that is sensitive to danger signals, such as ischemia and extracellular or intracellular alarmins during tissue injury. The NLRP3 inflammasome is regulated by the presence of damage-associated molecular patterns and initiates or amplifies inflammatory response through the production of interleukin-1β (IL-1β) and/or IL-18. NLRP3 activation regulates cell survival through the activity of caspase-1 and gasdermin-D. The development of NLRP3 inflammasome inhibitors has opened the possibility to targeting the deleterious effects of NLRP3. Here, we examine the scientific evidence supporting a role for NLRP3 and the effects of inhibitors in cardiovascular diseases.

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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

Applied Sciences ◽

10.3390/app11114724 ◽

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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