The role of damage- and pathogen-associated molecular patterns in inflammation-mediated vulnerability of atherosclerotic plaques

2017 ◽  
Vol 95 (10) ◽  
pp. 1245-1253 ◽  
Author(s):  
Vikrant Rai ◽  
Devendra K. Agrawal
Keyword(s):  
High Mobility ◽  
Interferon Γ ◽  
Chronic Inflammatory Disease ◽  
Plaque Formation ◽  
Atheromatous Plaque ◽  
Surface Receptors ◽  
Downstream Signaling ◽  
Stable Plaque ◽  
Molecular Patterns

Atherosclerosis is a chronic inflammatory disease resulting in the formation of the atherosclerotic plaque. Plaque formation starts with the inflammation in fatty streaks and progresses through atheroma, atheromatous plaque, and fibroatheroma leading to development of stable plaque. Hypercholesterolemia, dyslipidemia, and hyperglycemia are the risk factors for atherosclerosis. Inflammation, infection with viruses and bacteria, and dysregulation in the endothelial and vascular smooth muscle cells leads to advanced plaque formation. Death of the cells in the intima due to inflammation results in secretion of damage-associated molecular patterns (DAMPs) such as high mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE), alarmins (S100A8, S100A9, S100A12, and oxidized low-density lipoproteins), and infection with pathogens leads to secretion of pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharides, lipoteichoic acids, and peptidoglycans. DAMPs and PAMPs further activate the inflammatory surface receptors such as TREM-1 and toll-like receptors and downstream signaling kinases and transcription factors leading to increased secretion of pro-inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)-1β, IL-6, and interferon-γ and matrix metalloproteinases (MMPs). These mediators and cytokines along with MMPs render the plaque vulnerable for rupture leading to ischemic events. In this review, we have discussed the role of DAMPs and PAMPs in association with inflammation-mediated plaque vulnerability.

scholarly journals Tumor Microenvironment: Key Players in Triple Negative Breast Cancer Immunomodulation

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3357
Author(s):  
Hongmei Zheng ◽  
Sumit Siddharth ◽  
Sheetal Parida ◽  
Xinhong Wu ◽  
Dipali Sharma
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Options ◽  
Combined Treatment ◽  
High Mobility ◽  
Sphingosine 1 Phosphate ◽  
Molecular Patterns

Triple negative breast cancer (TNBC) is a heterogeneous disease and is highly related to immunomodulation. As we know, the most effective approach to treat TNBC so far is still chemotherapy. Chemotherapy can induce immunogenic cell death, release of damage-associated molecular patterns (DAMPs), and tumor microenvironment (TME) remodeling; therefore, it will be interesting to investigate the relationship between chemotherapy-induced TME changes and TNBC immunomodulation. In this review, we focus on the immunosuppressive and immunoreactive role of TME in TNBC immunomodulation and the contribution of TME constituents to TNBC subtype classification. Further, we also discuss the role of chemotherapy-induced TME remodeling in modulating TNBC immune response and tumor progression with emphasis on DAMPs-associated molecules including high mobility group box1 (HMGB1), exosomes, and sphingosine-1-phosphate receptor 1 (S1PR1), which may provide us with new clues to explore effective combined treatment options for TNBC.

Abstract 288: High Mobility Group Box 1 (HMGB1) is Involved in the Physiopathology of Post-Cardiac Arrest Syndrome

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_2) ◽  
Author(s):  
Emilie Boissady ◽  
Cynthia El Hedjaj ◽  
Matthias Kohlhauer ◽  
Bijan Ghaleh ◽  
Renaud Tissier
Keyword(s):  
Cardiac Arrest ◽  
High Mobility ◽  
Brain Regions ◽  
Clinical Parameter ◽  
High Mobility Group ◽  
Neurological Dysfunction ◽  
Blood Levels ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Introduction: After cardiac arrest, a sepsis-like syndrome is observed and contributes to poor prognosis. Hypothesis: This syndrome could be provoked by the massive release of Damage Associated Molecular Patterns (DAMP). Our aim was to investigate the role of the High mobility group box 1 (HMGB1), a well-characterized nuclear DAMP, in an experimental model of cardiac arrest. Methods: Rabbits were anesthetized and submitted to 10 min of ventricular fibrillation. After resuscitation, they either received an administration of the inhibitor of HMGB1 release glycyrrhizin (4 mg/kg i.v.. (GL group, n=6), or saline (5 ml, i.v.; CT group, n=6). Two additional groups received glycyrrhizin (n=4) or saline (n=4) alone without cardiac arrest (Sham groups). Blood samples were withdrawn to evaluate the kinetics of HMGB1 release. After awakening, survival and neurological dysfunction were evaluated during 3 days. Animals were then euthanized and brain histologic damages were assessed (fluorojade-C staining). Results: In the Sham groups, glycyrrhizin did not modify hemodynamic nor clinical parameter as compared to saline. In the CT group, HMGB1 blood levels increased since 30 min after cardiac arrest and remained elevated until the end of the follow-up. This increase in HMGB1 concentrations was significantly attenuated in GL vs CR (18±1 vs 29±5 and ng/ml at 30 min after cardiac arrest, respectively). Neurological dysfunction score or survival were not significantly improved in GL vs CT (e.g., survival = 50 vs 33 % at day 3 in GT vs CT group). However, fluorojade C staining showed a dramatic attenuation of degenerating neurons in GL vs CT groups in all brain regions (e.g., 7±3 vs 32±10 neurons/field in cortex, respectively). Conclusion: HMGB1 played a key role in early inflammation and promoted neuronal death after cardiac arrest. Its inhibition alone does not provide sufficient benefits to improve the clinical outcome. It emphasizes the importance of other contributors, beyond inflammation and neurons cell death. Adjunction of HMGB1 inhibitors to other therapies could still be of interest.

scholarly journals Phloretin alleviates dinitrochlorobenzene-induced dermatitis in BALB/c mice

2020 ◽  
Vol 34 ◽  
pp. 205873842092944
Author(s):  
Chieh-Shan Wu ◽  
Shih-Chao Lin ◽  
Shiming Li ◽  
Yu-Chih Chiang ◽  
Nicole Bracci ◽  
...  
Keyword(s):  
Mouse Model ◽  
Serum Levels ◽  
Interferon Γ ◽  
Chronic Inflammatory Disease ◽  
Mitogen Activated Protein Kinase ◽  
Normal Ranges ◽  
Mitogen Activated Protein ◽  
Ifn Γ ◽  
Allergic Contact

Atopic dermatitis (AD) is a chronic inflammatory disease of the skin that substantially affects a patient’s quality of life. While steroids are the most common therapy used to temporally alleviate the symptoms of AD, effective and nontoxic alternatives are urgently needed. In this study, we utilized a natural, plant-derived phenolic compound, phloretin, to treat allergic contact dermatitis (ACD) on the dorsal skin of mice. In addition, the effectiveness of phloretin was evaluated using a mouse model of ACD triggered by 2,4-dinitrochlorobenzene (DNCB). In our experimental setting, phloretin was orally administered to BALB/c mice for 21 consecutive days, and then, the lesions were examined histologically. Our data revealed that phloretin reduced the process of epidermal thickening and decreased the infiltration of mast cells into the lesion regions, subsequently reducing the levels of histamine and the pro-inflammatory cytokines interleukin (IL)-6, IL-4, thymic stromal lymphopoietin (TSLP), interferon-γ (IFN-γ) and IL-17A in the serum. These changes were associated with lower serum levels after phloretin treatment. In addition, we observed that the mitogen-activated protein kinase (MAPK) and NF-κB pathways in the dermal tissues of the phloretin-treated rodents were suppressed compared to those in the AD-like skin regions. Furthermore, phloretin appeared to limit the overproliferation of splenocytes in response to DNCB stimulation, reducing the number of IFN-γ-, IL-4-, and IL-17A-producing CD4+ T cells in the spleen back to their normal ranges. Taken together, we discovered a new therapeutic role of phloretin using a mouse model of DNCB-induced ACD, as shown by the alleviated AD-like symptoms and the reversed immunopathological effects. Therefore, we believe that phloretin has the potential to be utilized as an alternative therapeutic agent for treating AD.

scholarly journals Monoclonal Antibody to CD14, TLR4, or CD11b: Impact of Epitope and Isotype Specificity on ROS Generation by Human Granulocytes and Monocytes

2020 ◽  
Vol 2020 ◽  
pp. 1-20
Author(s):  
Dmitry S. Kabanov ◽  
Sergey V. Grachev ◽  
Isabella R. Prokhorenko
Keyword(s):  
Cellular Response ◽  
Adaptive Immune System ◽  
Interferon Γ ◽  
Ros Generation ◽  
Ros Production ◽  
Therapeutic Approaches ◽  
Igg Antibody ◽  
Therapeutic Efficiency ◽  
Molecular Patterns

Lipopolysaccharides (LPSs or endotoxins) from Gram-negative bacteria represent pathogen-associated molecular patterns (PAMPs) that are recognized by CD14 and Toll-like receptor 4 (TLR4). Lipopolysaccharides prime polymorphonuclear leukocytes (PMNs) for substantial production of reactive oxygen species (ROS) during its response to secondary stimuli such as chemoattractants or pathogens. The excessive ROS production can damage surrounding host tissues, thereby amplifying the inflammatory reaction caused by pathogens. Today, specific antibodies against CD14, TLR4, and CD11b are being used as the essential tools to elucidate the role of these receptors in acute inflammation and some of these antibodies have advised as therapeutic agents for clinical use. Because each antibody has two antigen-binding arms [F(ab ′ )2] and one Fc arm, its effect on cellular response is much more complicated rather than simple blockage of target receptor. In fact, IgG antibody, once bound to target receptor, engages Fc receptors γ (FcγRs) and thereby is able to activate the adaptive immune system. The consequences of antibody-dependent binary heterotypic association of CD14, TLR4, or CD11b with FcγRs as well as homotypic one on ROS production are not well elucidated. Moreover, the consequences of antigenic recognition of CD14, TLR4, or CD11b by specific F(ab ′ )2 fragments are not always investigated. In this review, we will discuss known mechanisms underlying the therapeutic efficiency of CD14, TLR4, and CD11b/CD18 antibodies with a focus on LPS-dependent ROS or cytokine production by PMNs or monocytes. The impacts of F(ab ′ )2 as well as antibody IgG subclasses (isotypes) in therapeutic efficiency or agonistic potency of known antibodies against abovementioned receptors are presented. We also pay attention to how the efficiency of different IgG antibody subclasses is modulated during LPS-induced inflammation and by production of priming agents such as interferon γ (IFN-γ). Our review reinforces the molecular targets and therapeutic approaches to amelioration of harmful consequences of excessive activation of human pattern recognition receptors.

Linking proximal and downstream signalling events in hepatic ischaemia/reperfusion injury

2006 ◽  
Vol 34 (5) ◽  
pp. 957-959 ◽  
Author(s):  
G. Jeyabalan ◽  
A. Tsung ◽  
T.R. Billiar
Keyword(s):  
Reperfusion Injury ◽  
Immune Surveillance ◽  
High Mobility ◽  
Intracellular Signalling ◽  
Ischaemia Reperfusion Injury ◽  
Signalling Molecules ◽  
Ischaemia Reperfusion ◽  
The Many ◽  
Molecular Patterns

Hepatic I/R (ischaemia/reperfusion) injury occurs in a variety of clinical settings including transplantation, elective liver resections and trauma. One of the challenges in studying the pathophysiology of I/R injury is the fact that the liver plays a central role in a variety of metabolic pathways in addition to governing aspects of immune surveillance and tolerance. The pathways activated in response to insults as varied as toxins, microbial and endogenous ligands and I/R may share common elements. The multiple intracellular signalling cascades involved in this process and the initiating events are still under investigation. Recent work on the role of TLRs (Toll-like receptors) in I/R injury has elucidated some of the more proximal signalling events in the pathway. In addition to the well-established role of signalling molecules such as NO (nitric oxide) in mediating damage or protection following hepatic I/R, more recent studies have focused on the participation of endogenous danger signals or DAMPs (damage-associated molecular patterns) such as HMGB1 (high-mobility group box 1). The complex interplay between HMGB1, TLRs and the many intracellular signalling molecules and pathways is illustrative of how our understanding of hepatic I/R injury is continually evolving.

Alarmins at the maternal–fetal interface: involvement of inflammation in placental dysfunction and pregnancy complications

2019 ◽  
Vol 97 (3) ◽  
pp. 206-212 ◽  
Author(s):  
Marie-Eve Brien ◽  
Bernadette Baker ◽  
Cyntia Duval ◽  
Virginie Gaudreault ◽  
Rebecca L. Jones ◽  
...  
Keyword(s):  
Pregnancy Complications ◽  
Deoxyribonucleic Acid ◽  
High Mobility ◽  
Placental Dysfunction ◽  
Current State ◽  
Hofbauer Cells ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
In Pregnancy

Inflammation is known to be associated with placental dysfunction and pregnancy complications. Infections are well known to be a cause of inflammation but they are frequently undetectable in pregnancy complications. More recently, the focus has been extended to inflammation of noninfectious origin, namely caused by endogenous mediators known as “damage-associated molecular patterns (DAMPs)” or alarmins. In this manuscript, we review the mechanism by which inflammation, sterile or infectious, can alter the placenta and its function. We discuss some classical DAMPs, such as uric acid, high mobility group box 1 (HMGB1), cell-free fetal deoxyribonucleic acid (DNA) (cffDNA), S100 proteins, heat shock protein 70 (HSP70), and adenosine triphosphate (ATP) and their impact on the placenta. We focus on the main placental cells (i.e., trophoblast and Hofbauer cells) and describe the placental response to, and release of, DAMPs. We also covered the current state of knowledge about the role of DAMPs in pregnancy complications including preeclampsia, fetal growth restriction, preterm birth, and stillbirth and possible therapeutic strategies to preserve placental function.

Serum chromium and angiographically determined coronary artery disease.

1978 ◽  
Vol 24 (4) ◽  
pp. 541-544 ◽  
Author(s):  
H A Newman ◽  
R F Leighton ◽  
R R Lanese ◽  
N A Freedland
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Plaque Formation ◽  
Atheromatous Plaque ◽  
Lower Serum ◽  
Serum Chromium ◽  
Artery Disease

Abstract Human aortas sampled from populations where there is little advanced atheromatous plaque formation contain higher concentrations of chromium than do aortas from populations in which atheromatosis is prevalent. In the present study serum cholesterol, triacylglycerols, and chromium (Cr3+) concentrations were measured in 32 subjects in whom coronary artery disease was assessed by cineangiography. The distribution of subjects with diseased and normal arteries overlapped below 5.50 microgram of chromium per liter. Only subjects free of coronary artery disease had chromium concentrations greater than or equal to 5.50 microgram/liter. The role of chromium was assessed in the context of the selected risk factors: cholesterol, triacylglycerols, and systolic and diastolic blood pressure. The group with coronary artery disease had significantly lower serum chromium concentrations than did the group with normally patent arteries.

scholarly journals The Role of TLR2, TLR4, and TLR9 in the Pathogenesis of Atherosclerosis

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Mohsin H. K. Roshan ◽  
Amos Tambo ◽  
Nikolai P. Pace
Keyword(s):  
Adaptor Protein ◽  
Arterial Disease ◽  
Primary Response ◽  
Atheromatous Plaque ◽  
Nf Kappa B ◽  
Coronary Arterial Disease ◽  
Inflammatory Conditions ◽  
Inflammatory Processes ◽  
Molecular Patterns

Toll-like receptors (TLRs) are key players in the pathogenesis of inflammatory conditions including coronary arterial disease (CAD). They are expressed by a variety of immune cells where they recognize pathogen-associated molecular patterns (PAMPs). TLRs recruit adaptor molecules, including myeloid differentiation primary response protein (MYD88) and TIRF-related adaptor protein (TRAM), to mediate activation of MAPKs and NF-kappa B pathways. They are associated with the development of CAD through various mechanisms. TLR4 is expressed in lipid-rich and atherosclerotic plaques. In TLR2−/−and TLR4−/−mice, atherosclerosis-associated inflammation was diminished. Moreover, TLR2 and TLR4 may induce expression of Wnt5a in advanced staged atheromatous plaque leading to activation of the inflammatory processes. TLR9 is activated by CpG motifs in nucleic acids and have been implicated in macrophage activation and the uptake of oxLDL from the circulation. Furthermore, TLR9 also stimulates interferon-α(INF-α) secretion and increases cytotoxic activity of CD4+T-cells towards coronary artery tunica media smooth muscle cells. This review outlines the pathophysiological role of TLR2, TLR4, and TLR9 in atherosclerosis, focusing on evidence from animal models of the disease.

scholarly journals PKR deficiency alleviates pulmonary hypertension via inducing inflammasome adaptor ASC inactivation

2021 ◽  
Vol 11 (4) ◽  
pp. 204589402110461
Author(s):  
Yapei Li ◽  
Ying Li ◽  
Lijun Li ◽  
Minghui Yin ◽  
Jiangang Wang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Interleukin 1 ◽  
High Mobility ◽  
Interleukin 1 Beta ◽  
Therapeutic Approaches ◽  
Downstream Signaling ◽  
Dependent Protein ◽  
Pulmonary Arterial ◽  
Arterial Endothelial Cells

Pulmonary hypertension is a progressive fatal disease that currently has no specific therapeutic approaches. In this study, dsRNA-dependent protein kinase (PKR) was considered a candidate molecule in pulmonary hypertension. We demonstrated that PKR is activated in the endothelium of experimental pulmonary hypertension models. Deletion of PKR or treatment with the PKR activation inhibitor C16 inhibited the development of pulmonary hypertension. To explore the mechanism of PKR in pulmonary hypertension, we detected its downstream signaling and found that PKR knockout represses apoptosis-associated speck-like protein containing CARD (ASC) activation to inhibit high mobility group box 1 (HMGB1) and interleukin-1 beta release. To further explore whether ASC mediates the pro-pulmonary hypertension role of PKR, we used ASC deletion mice and found that ASC deletion inhibits the development of pulmonary hypertension and the release of HMGB1 and interleukin-1 beta. Furthermore, we co-cultured pulmonary arterial endothelial cells (PAECs) and pulmonary arterial smooth muscle cells (PASMCs) and found that endothelial PKR promotes PASMCs proliferation through the release of HMGB1 and interleukin-1 beta. In conclusion, these data indicate that endothelial PKR promotes the excessive proliferation of PASMCs by inducing ASC activation to release HMGB1 and interleukin-1 beta, which lead to the development of pulmonary hypertension. Our study will provide a novel insight that PKR is a potential target in the future treatment of pulmonary hypertension.

scholarly journals Involvement of HMGB1 in Resistance to Tumor Vessel-Targeted, Monoclonal Antibody-Based Immunotherapy

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Vito Pistoia ◽  
Annalisa Pezzolo
Keyword(s):  
Monoclonal Antibody ◽  
Immune Regulation ◽  
High Mobility ◽  
Genomic Stability ◽  
Tumor Resistance ◽  
Tumor Vessel ◽  
Human Neuroblastoma ◽  
Molecular Patterns ◽  
Resistance To Chemotherapy

High mobility group box 1 (HMGB1) is a member of the “danger associated molecular patterns” (DAMPs) than can localize in various compartments of the cell (from the nucleus to the cell surface) and subserve different functions accordingly. HMGB1 is implicated in maintenance of genomic stability, autophagy, immune regulation, and tumor growth. HMGB1-induced autophagy promotes tumor resistance to chemotherapy, as shown in different models of malignancy, for example, osteosarcoma, leukemia, and gastric cancer. To the best of our knowledge, there is virtually no information on the relationships between HMGB1 and resistance to immunotherapy. A recent study from our group has shed new light on this latter issue. We have demonstrated that targeting of tumor-derived endothelial cells with an anti-human CD31 monoclonal antibody in a human neuroblastoma model was unsuccessful due to a complex chain of events involving the participation of HMGB1. These results are discussed in detail since they provide the first evidence for a role of HMGB1 in resistance of tumor cells to monoclonal antibody-based immunotherapy.

Sign in / Sign up

Export Citation Format

Share Document