scholarly journals RAGE and TLRs as Key Targets for Antiatherosclerotic Therapy

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Wioletta Olejarz ◽  
Dominika Łacheta ◽  
Alicja Głuszko ◽  
Ewa Migacz ◽  
Wojciech Kukwa ◽  
...  
Keyword(s):  
Immune System ◽  
Inflammatory Responses ◽  
Adaptive Immune System ◽  
Primary Response ◽  
Type I ◽  
Adaptive Responses ◽  
Effector Cells ◽  
Antiatherosclerotic Therapy ◽  
Molecular Patterns ◽  
Direct Killing

Receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs) are the key factors indicating a danger to the organism. They recognize the microbial origin pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). The primary response induced by PAMPs or DAMPs is inflammation. Excessive stimulation of the innate immune system occurs in arterial wall with the participation of effector cells. Persistent adaptive responses can also cause tissue damage and disease. However, inflammation mediated by the molecules innate responses is an important way in which the adaptive immune system protects us from infection. The specific detection of PAMPs and DAMPs by host receptors drives a cascade of signaling that converges at nuclear factor-κB (NF-κB) and interferon regulatory factors (IRFs) and induces the secretion of proinflammatory cytokines, type I interferon (IFN), and chemokines, which promote direct killing of the pathogen. Therefore, signaling of these receptors’ pathways also appear to present new avenue for the modulation of inflammatory responses and to serve as potential novel therapeutic targets for antiatherosclerotic therapy.

scholarly journals Danger-Associated Molecular Patterns (DAMPs): Molecular Triggers for Sterile Inflammation in the Liver

2018 ◽  
Vol 19 (10) ◽  
pp. 3104 ◽  
Author(s):  
Sabine Mihm
Keyword(s):  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Sterile Inflammation ◽  
Type I Interferons ◽  
Neutrophil Granulocytes ◽  
Type I ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion ◽  
Molecular Patterns

Inflammatory liver diseases in the absence of pathogens such as intoxication by xenobiotics, cholestatic liver injury, hepatic ischemia-reperfusion injury (I/R), non-alcoholic steatohepatitis (NASH), or alcoholic liver disease (ALD) remain threatening conditions demanding specific therapeutic options. Caused by various different noxae, all these conditions have been recognized to be triggered by danger- or death-associated molecular patterns (DAMPs), discompartmentalized self-structures released by dying cells. These endogenous, ectopic molecules comprise proteins, nucleic acids, adenosine triphosphate (ATP), or mitochondrial compounds, among others. This review resumes the respective modes of their release—passively by necrotic hepatocytes or actively by viable or apoptotic parenchymal cells—and their particular roles in sterile liver pathology. It addresses their sensors and the initial inflammatory responses they provoke. It further addresses a resulting second wave of parenchymal death that might be of different mode, boosting the release of additional, second-line DAMPs. Thus, triggering a more complex and pronounced response. Initial and secondary inflammatory responses comprise the activation of Kupffer cells (KCs), the attraction and activation of monocytes and neutrophil granulocytes, and the induction of type I interferons (IFNs) and their effectors. A thorough understanding of pathophysiology is a prerequisite for identifying rational therapeutic targets.

scholarly journals Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists

Blood ◽  
2008 ◽  
Vol 112 (5) ◽  
pp. 1750-1758 ◽  
Author(s):  
James L. Wynn ◽  
Philip O. Scumpia ◽  
Robert D. Winfield ◽  
Matthew J. Delano ◽  
Kindra Kelly-Scumpia ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Adaptive Immune System ◽  
Neutrophil Recruitment ◽  
Polymicrobial Sepsis ◽  
Type I ◽  
Sepsis Mortality ◽  
Tlr Agonists ◽  
Adaptive Immune ◽  
Increased Risk

Abstract Neonates exhibit an increased risk of sepsis mortality compared with adults. We show that in contrast to adults, survival from polymicrobial sepsis in murine neonates does not depend on an intact adaptive immune system and is not improved by T cell–directed adaptive immunotherapy. Furthermore, neonates manifest an attenuated inflammatory and innate response to sepsis, and have functional defects in their peritoneal CD11b+ cells. Activation of innate immunity with either a Toll-like receptor 4 (TLR4) or TLR7/8 agonist, but not a TLR3 agonist, increased the magnitude, but abbreviated the early systemic inflammatory response, reduced bacteremia, and improved survival to polymicrobial sepsis. TLR4 agonist pretreatment enhanced peritoneal neutrophil recruitment with increased oxidative burst production, whereas the TLR7/8 agonist also enhanced peritoneal neutrophil recruitment with increased phagocytic ability. These benefits were independent of the adaptive immune system and type I interferon signaling. Improving innate immune function with select TLR agonists may be a useful strategy to prevent neonatal sepsis mortality.

SLPI and elafin: one glove, many fingers

2005 ◽  
Vol 110 (1) ◽  
pp. 21-35 ◽  
Author(s):  
Steven E. Williams ◽  
Thomas I. Brown ◽  
Ali Roghanian ◽  
Jean-Michel Sallenave
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Immune Responses ◽  
Adaptive Immune Response ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Type I ◽  
Adaptive Immune ◽  
Pathological Conditions ◽  
Related Proteins

Elafin and SLPI (secretory leucocyte protease inhibitor) have multiple important roles both in normal homoeostasis and at sites of inflammation. These include antiprotease and antimicrobial activity as well as modulation of the response to LPS (lipopolysaccharide) stimulation. Elafin and SLPI are members of larger families of proteins secreted predominantly at mucosal sites, and have been shown to be modulated in multiple pathological conditions. We believe that elafin and SLPI are important molecules in the controlled functioning of the innate immune system, and may have further importance in the integration of this system with the adaptive immune response. Recent interest has focused on the influence of inflamed tissues on the recruitment and phenotypic modulation of cells of the adaptive immune system and, indeed, the local production of elafin and SLPI indicate that they are ideally placed in this regard. Functionally related proteins, such as the defensins and cathelicidins, have been shown to have direct effects upon dendritic cells with potential alteration of their phenotype towards type I or II immune responses. This review addresses the multiple functions of elafin and SLPI in the inflammatory response and discusses further their roles in the development of the adaptive immune response.

scholarly journals DAMPening Inflammation by Modulating TLR Signalling

2010 ◽  
Vol 2010 ◽  
pp. 1-21 ◽  
Author(s):  
A. M. Piccinini ◽  
K. S. Midwood
Keyword(s):  
Immune System ◽  
Tissue Damage ◽  
Tissue Repair ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Feedback Loops ◽  
Inflammatory Gene Expression ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Tlr Signalling

Damage-associated molecular patterns (DAMPs) include endogenous intracellular molecules released by activated or necrotic cells and extracellular matrix (ECM) molecules that are upregulated upon injury or degraded following tissue damage. DAMPs are vital danger signals that alert our immune system to tissue damage upon both infectious and sterile insult. DAMP activation of Toll-like receptors (TLRs) induces inflammatory gene expression to mediate tissue repair. However, DAMPs have also been implicated in diseases where excessive inflammation plays a key role in pathogenesis, including rheumatoid arthritis (RA), cancer, and atherosclerosis. TLR activation by DAMPs may initiate positive feedback loops where increasing tissue damage perpetuates pro-inflammatory responses leading to chronic inflammation. Here we explore the current knowledge about distinct signalling cascades resulting from self TLR activation. We also discuss the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.

scholarly journals Allergen-associated molecular patterns: a new trend in modern allergology

2019 ◽  
Vol 18 (1) ◽  
pp. 76-83
Author(s):  
V. S. Sviridova ◽  
P. Yu. Isaev ◽  
V. V. Klimov ◽  
M. I. Romanova ◽  
N. S. Koshkarova
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Adaptive Immune System ◽  
Conserved Motifs ◽  
Immune Mechanisms ◽  
Adaptive Immune ◽  
Molecular Patterns

Over the last decade the role of innate immunity has been known to be crucial for the activation of adaptive immune system. The main triggers that upregulate reactions of innate immunity are small exogenous molecules with conserved motifs, molecular patterns. The article discusses a variety of possible roles of molecular patterns in the immune mechanisms, including the participation of Allergen Associated Molecular Patterns (AAMPs) in allergic processes.

scholarly journals The Interactions between Nanoparticles and the Innate Immune System from a Nanotechnologist Perspective

Nanomaterials ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 2991
Author(s):  
Lena M. Ernst ◽  
Eudald Casals ◽  
Paola Italiani ◽  
Diana Boraschi ◽  
Victor Puntes
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Inorganic Nanoparticles ◽  
Cellular Debris ◽  
Abnormal Cells ◽  
Nanoparticle Design ◽  
Modes Of Interaction ◽  
Molecular Patterns

The immune system contributes to maintaining the body’s functional integrity through its two main functions: recognizing and destroying foreign external agents (invading microorganisms) and identifying and eliminating senescent cells and damaged or abnormal endogenous entities (such as cellular debris or misfolded/degraded proteins). Accordingly, the immune system can detect molecular and cellular structures with a spatial resolution of a few nm, which allows for detecting molecular patterns expressed in a great variety of pathogens, including viral and bacterial proteins and bacterial nucleic acid sequences. Such patterns are also expressed in abnormal cells. In this context, it is expected that nanostructured materials in the size range of proteins, protein aggregates, and viruses with different molecular coatings can engage in a sophisticated interaction with the immune system. Nanoparticles can be recognized or passed undetected by the immune system. Once detected, they can be tolerated or induce defensive (inflammatory) or anti-inflammatory responses. This paper describes the different modes of interaction between nanoparticles, especially inorganic nanoparticles, and the immune system, especially the innate immune system. This perspective should help to propose a set of selection rules for nanosafety-by-design and medical nanoparticle design.

scholarly journals Toll-Like Receptors: General Molecular and Structural Biology

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Payam Behzadi ◽  
Herney Andrés García-Perdomo ◽  
Tomasz M. Karpiński
Keyword(s):  
Immune System ◽  
Drug Discovery ◽  
Structural Biology ◽  
English Language ◽  
Inflammatory Diseases ◽  
Adaptive Immune System ◽  
Toll Like Receptors ◽  
Adaptive Immune ◽  
Molecular Patterns

Background/Aim. Toll-like receptors (TLRs) are pivotal biomolecules in the immune system. Today, we are all aware of the importance of TLRs in bridging innate and adaptive immune system to each other. The TLRs are activated through binding to damage/danger-associated molecular patterns (DAMPs), microbial/microbe-associated molecular patterns (MAMPs), pathogen-associated molecular patterns (PAMPs), and xenobiotic-associated molecular patterns (XAMPs). The immunogenetic molecules of TLRs have their own functions, structures, coreceptors, and ligands which make them unique. These properties of TLRs give us an opportunity to find out how we can employ this knowledge for ligand-drug discovery strategies to control TLRs functions and contribution, signaling pathways, and indirect activities. Hence, the authors of this paper have a deep observation on the molecular and structural biology of human TLRs (hTLRs). Methods and Materials. To prepare this paper and fulfill our goals, different search engines (e.g., GOOGLE SCHOLAR), Databases (e.g., MEDLINE), and websites (e.g., SCOPUS) were recruited to search and find effective papers and investigations. To reach this purpose, we tried with papers published in the English language with no limitation in time. The iCite bibliometrics was exploited to check the quality of the collected publications. Results. Each TLR molecule has its own molecular and structural biology, coreceptor(s), and abilities which make them unique or a complementary portion of the others. These immunogenetic molecules have remarkable roles and are much more important in different sections of immune and nonimmune systems rather than that we understand to date. Conclusion. TLRs are suitable targets for ligand-drug discovery strategies to establish new therapeutics in the fields of infectious and autoimmune diseases, cancers, and other inflammatory diseases and disorders.

scholarly journals Molecular half-full mechanisms by phagocityc cells on invasive Aspergilosis

2012 ◽  
pp. 95-102
Author(s):  
Karla Rossanet Dzul-Rosado ◽  
Viridiana Martínez-Campos ◽  
Gaspar Peniche-Lara ◽  
Jorge E Zavala-Castro
Keyword(s):  
Immune System ◽  
Host Immune System ◽  
Adaptive Responses ◽  
Phagocytic Cells ◽  
Effector Cells ◽  
Surface Receptors ◽  
Molecular Receptors ◽  
Tnf Α ◽  
Particle Recognition ◽  
Ifn Γ

Fungus from the Aspergillus genus mainly affects lung tissue, occurring when the integrity of the host immune system is compromised. The human body uses immunocompetence conditions from mechanical and enzymatic defenses and the action of the innate immune system cells and also uses adaptive responses to control infection. Neutrophils, macrophages, and dendritic cells are critical as antifungal effector cells possess surface receptors that recognize fungal structures and trigger specific responses. TLRs and Dectin-1 the most studied for this interaction. TLRs are responsible for the production and release of cytokines and Dectin-1 is essential in the phagocytosis of the particle recognition and production of ROS. The best-studied cytokines and its crucial role in the response to Aspergillus spp. are TNF-α, IFN-γ, and IL-12. In this work, we reviewed the main mechanisms related to molecular receptors on phagocytic cells involved in the recognition of Aspergillus spp. Understanding the immune response in situations of immunocompetence and its comparison in immunodeficient organisms could provide alternatives to control invasive aspergillosis.

Immunological response of the respiratory tract in the SARS-CoV-2 infection

Coronaviruses ◽  
2021 ◽  
Vol 02 ◽  
Author(s):  
Sanjiv Singh ◽  
Punita Aggarwal ◽  
Velayutham Ravichandiran
Keyword(s):  
Immune System ◽  
Respiratory Tract ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Virus Disease ◽  
Adaptive Immune System ◽  
Immunological Response ◽  
Immunological Responses ◽  
Corona Virus ◽  
Maximum Protection

: Severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) is a contagious pathogen responsible for the ongoing corona virus disease 2019 (COVID-19) pandemic. The pathogenesis and immunological response of SARS-CoV-2 infection is poorly understood until now. After a person is infected by SARS-COV-2 immunity is compromised as both innate and adaptive immunity is playing a major role in the same. The host innate immune system forms the first layer of defense for protection from viral infections and initiates activation of the adaptive immune system in order to give maximum protection. In order to protect from tissue damage and diseases, the respiratory tract maintains the balance of T cell, B cell pro- and anti-inflammatory responses. In this review, we discuss the current update in our understanding of the involvement of the immune system in the antiviral defense against SARS-CoV-2. These novel insights at the respiratory tract immunological responses may support the future development of vaccines and immunoregulatory therapy for SARS-CoV-2 infection.

Passive and active components of neonatal innate immune defenses

2005 ◽  
Vol 6 (2) ◽  
pp. 143-158 ◽  
Author(s):  
Matthew A. Firth ◽  
Patricia E. Shewen ◽  
Douglas C. Hodgins
Keyword(s):  
Immune System ◽  
Membrane Damage ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Pathogenic Microorganisms ◽  
Active Components ◽  
Adaptive Immune ◽  
Immune Defenses ◽  
Molecular Patterns ◽  
Cellular Components

AbstractInnate immune defenses are crucial for survival in the first days and weeks of life. At birth, newborns are confronted with a vast array of potentially pathogenic microorganisms that were not encountered in utero. At this age, cellular components of the adaptive immune system are in a naïve state and are slow to respond. Antibodies received from the dam are essential for defense, but represent a finite and dwindling resource. Innate components of the immune system detect pathogen-associated molecular patterns (PAMPs) on microorganisms (and their products) by means of pattern-recognition receptors (PRRs). Soluble mediators of the innate system such as complement proteins, pentraxins, collectins, ficolins, defensins, lactoferrin, lysozyme etc. can bind to structures on pathogens, leading to agglutination, interference with receptor binding, opsonization, neutralization, direct membrane damage and recruitment of additional soluble and cellular elements through inflammation. Cell-associated receptors such as the Toll-like receptors (TLRs) can activate cells and coordinate responses (both innate and adaptive). In this paper, accumulated knowledge of the receptors, soluble and cellular elements that contribute to innate defenses of young animals is reviewed. Research interest in this area has been intermittent, and the literature varies in quantity and quality. It is hoped that documentation of the limitations of our knowledge base will lead to more extensive and enlightening studies.

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