Cytosolic Self-DNA—A Potential Source of Chronic Inflammation in Aging

Aging is the consequence of a lifelong accumulation of stochastic damage to tissues and cellular components. Advancing age closely associates with elevated markers of innate immunity and low-grade chronic inflammation, probably reflecting steady increasing incidents of cellular and tissue damage over the life course. The DNA sensing cGAS-STING signaling pathway is activated by misplaced cytosolic self-DNA, which then initiates the innate immune responses. Here, we hypothesize that the stochastic release of various forms of DNA from the nucleus and mitochondria, e.g., because of DNA damage, altered nucleus integrity, and mitochondrial damage, can result in chronic activation of inflammatory responses that characterize the aging process. This cytosolic self-DNA-innate immunity axis may perturb tissue homeostasis and function that characterizes human aging and age-associated pathology. Proper techniques and experimental models are available to investigate this axis to develop therapeutic interventions.

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Nuclear receptor Nur77: its role in chronic inflammatory diseases

Essays in Biochemistry ◽

10.1042/ebc20210004 ◽

2021 ◽

Author(s):

Sanne C. Lith ◽

Carlie J.M. de Vries

Keyword(s):

Nuclear Receptor ◽

Inflammatory Disease ◽

Inflammatory Responses ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Cell Types ◽

Experimental Models ◽

Therapeutic Interventions ◽

Alternative Mechanism ◽

Signaling Complex

Abstract Nur77 is a nuclear receptor that has been implicated as a regulator of inflammatory disease. The expression of Nur77 increases upon stimulation of immune cells and is differentially expressed in chronically inflamed organs in human and experimental models. Furthermore, in a variety of animal models dedicated to study inflammatory diseases, changes in Nur77 expression alter disease outcome. The available studies comprise a wealth of information on the function of Nur77 in diverse cell types and tissues. Negative cross-talk of Nur77 with the NFκB signaling complex is an example of Nur77 effector function. An alternative mechanism of action has been established, involving Nur77-mediated modulation of metabolism in macrophages as well as in T cells. In this review, we summarize our current knowledge on the role of Nur77 in atherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and sepsis. Detailed insight in the control of inflammatory responses will be essential in order to advance Nur77-targeted therapeutic interventions in inflammatory disease.

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The Interplay between Host Innate Immunity and Hepatitis E Virus

Viruses ◽

10.3390/v11060541 ◽

2019 ◽

Vol 11 (6) ◽

pp. 541 ◽

Cited By ~ 5

Author(s):

Yang Li ◽

Changbo Qu ◽

Peifa Yu ◽

Xumin Ou ◽

Qiuwei Pan ◽

...

Keyword(s):

Innate Immunity ◽

Immune System ◽

Hepatitis E Virus ◽

Inflammatory Responses ◽

Hepatitis E ◽

Experimental Models ◽

Innate Immune ◽

Host Immune System ◽

Global Health Issue ◽

Host Innate Immunity

Hepatitis E virus (HEV) infection represents an emerging global health issue, whereas the clinical outcomes vary dramatically among different populations. The host innate immune system provides a first-line defense against the infection, but dysregulation may partially contribute to severe pathogenesis. A growing body of evidence has indicated the active response of the host innate immunity to HEV infection both in experimental models and in patients. In turn, HEV has developed sophisticated strategies to counteract the host immune system. In this review, we aim to comprehensively decipher the processes of pathogen recognition, interferon, and inflammatory responses, and the involvement of innate immune cells in HEV infection. We further discuss their implications in understanding the pathogenic mechanisms and developing antiviral therapies.

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End-organ dysfunction and cardiovascular outcomes: the role of the microcirculation

Clinical Science ◽

10.1042/cs20080069 ◽

2009 ◽

Vol 116 (3) ◽

pp. 175-190 ◽

Cited By ~ 40

Author(s):

Christopher J. Lockhart ◽

Paul K. Hamilton ◽

Cathy E. Quinn ◽

Gary E. McVeigh

Keyword(s):

Cardiovascular Disease ◽

Organ Dysfunction ◽

Inflammatory Responses ◽

Structure And Function ◽

Therapeutic Interventions ◽

Pivotal Role ◽

Vascular Effects ◽

Microvascular Damage ◽

Arterial Blood ◽

And Function

Risk factors for cardiovascular disease mediate their effects by altering the structure and function of wall and endothelial components of arterial blood vessels. A pathological change in the microcirculation plays a pivotal role in promoting end-organ dysfunction that not only predisposes to further organ damage, but also increases the risk for future macrovascular events. The microcirculation is recognized as the site where the earliest manifestations of cardiovascular disease, especially inflammatory responses, occur that may play a pivotal role in driving the atherosclerotic process in conduit vessels. Furthermore, the vast surface area of the endothelium compared with conduit vessels means that the vascular effects of endothelial dysfunction or activation will be most apparent in this section of the vasculature. Current techniques providing indices of vascular health focus on large arteries without providing insight into the structure and function of small vessels. Techniques capable of detecting microvascular damage and monitoring the response to therapeutic interventions, especially in vulnerable target organs of interest, may improve risk stratification and represent a valuable surrogate for future cardiovascular outcome.

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Dodging the Host Interferon-Stimulated Gene Mediated Innate Immunity by HIV-1: A Brief Update on Intrinsic Mechanisms and Counter-Mechanisms

Frontiers in Immunology ◽

10.3389/fimmu.2021.716927 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kumaraswami Chintala ◽

Krishnaveni Mohareer ◽

Sharmistha Banerjee

Keyword(s):

Innate Immunity ◽

Life Cycle ◽

Innate Immune ◽

Therapeutic Interventions ◽

Innate Immune Responses ◽

Restriction Factors ◽

Host Restriction ◽

Interferon Stimulated Genes ◽

Host Restriction Factors ◽

Hiv 1

Host restriction factors affect different phases of a viral life cycle, contributing to innate immunity as the first line of defense against viruses, including HIV-1. These restriction factors are constitutively expressed, but triggered upon infection by interferons. Both pre-integration and post-integration events of the HIV-1 life cycle appear to play distinct roles in the induction of interferon-stimulated genes (ISGs), many of which encode antiviral restriction factors. However, HIV-1 counteracts the mechanisms mediated by these restriction factors through its encoded components. Here, we review the recent findings of pathways that lead to the induction of ISGs, and the mechanisms employed by the restriction factors such as IFITMs, APOBEC3s, MX2, and ISG15 in preventing HIV-1 replication. We also reflect on the current understanding of the counter-mechanisms employed by HIV-1 to evade innate immune responses and overcome host restriction factors. Overall, this mini-review provides recent insights into the HIV-1-host cross talk bridging the understanding between intracellular immunity and research avenues in the field of therapeutic interventions against HIV-1.

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Gut Microbiota and Cardiovascular Disease: Symbiosis Versus Dysbiosis

Current Medicinal Chemistry ◽

10.2174/0929867328666211213112949 ◽

2021 ◽

Vol 28 ◽

Author(s):

Antonis A. Manolis ◽

Theodora A. Manolis ◽

Helen Melita ◽

Antonis S. Manolis

Keyword(s):

Blood Circulation ◽

Inflammatory Responses ◽

Short Chain Fatty Acids ◽

Therapeutic Interventions ◽

Bile Acid Metabolism ◽

Gi Tract ◽

System A ◽

Increased Risk ◽

And Function ◽

Potential Use

: The gut microbiome interacts with host physiology through various mechanisms, including the cardiovascular (CV) system. A healthy microbiome has the ability to process and digest complex carbohydrates into short-chain fatty acids (SCFA). These SCFA function as signaling molecules, immune-modulating molecules, and energy sources. However, when the microbiome is altered, it produces gut dysbiosis with overgrowth of certain bacteria that may lead to overproduction of trimethylamine-N-oxide (TMAO) from the metabolism of phosphatidylcholine, choline, and carnitine; dysbiosis also leads to increased intestinal permeability allowing the microbiome-derived lipopolysaccharide (LPS), a bacterial endotoxin, to enter the blood circulation triggering inflammatory responses. An altered GI tract environment and microbiome-derived metabolites are associated with CV events. Disrupted content and function of the microbiome leading to elevated TMAO and LPS levels, altered bile acid metabolism pathways and SCFA production, is associated with an increased risk of CV diseases (CVD), including atherosclerosis, myocardial infarction, thrombosis, arrhythmias and stroke. Therapeutic interventions that may favorably influence a dysbiotic GI tract profile and promote a healthy microbiome may benefit the CV system and lead to a reduction of CVD incidence in certain situations. These issues are herein reviewed with a focus on the spectrum of microbiota-related CVD, the mechanisms involved and the potential use of microbiome modification as a possible therapeutic intervention.

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Review: Mammalian peptidoglycan recognition proteins (PGRPs) in innate immunity

Innate Immunity ◽

10.1177/1753425910366059 ◽

2010 ◽

Vol 16 (3) ◽

pp. 168-174 ◽

Cited By ~ 95

Author(s):

Roman Dziarski ◽

Dipika Gupta

Keyword(s):

Innate Immunity ◽

Polymorphonuclear Leukocytes ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Antibacterial Activities ◽

Gram Negative Bacteria ◽

Mucous Membranes ◽

And Function ◽

Bacterial Peptidoglycan ◽

Arthritic Joints

Peptidoglycan recognition proteins (PGRPs or PGLYRPs) are innate immunity proteins that are conserved from insects to mammals, recognize bacterial peptidoglycan, and function in antibacterial immunity and inflammation. Mammals have four PGRPs — PGLYRP1, PGLYRP2, PGLYRP3, and PGLYRP4. They are secreted proteins expressed in polymorphonuclear leukocytes (PGLYRP1), liver (PGLYRP2), or on body surfaces, mucous membranes, and in secretions (saliva, sweat) (PGLYRP3 and PGLYRP4). All PGRPs recognize bacterial peptidoglycan. Three PGRPs, PGLYRP1, PGLYRP3, and PGLYRP4 are directly bactericidal for both Gram-positive and Gram-negative bacteria and have no enzymatic activity, whereas PGLYRP2 is an N-acetylmuramoyl-L-alanine amidase that hydrolyzes bacterial cell wall peptidoglycan. Peptidoglycan recognition proteins influence host— pathogen interactions not only through their antibacterial or peptidoglycan-hydrolytic properties, but also through their pro-inflammatory and anti-inflammatory properties that are independent of their hydrolytic and antibacterial activities. The PGRPs likely play a role both in antibacterial defenses and several inflammatory diseases. They modulate local inflammatory responses in tissues (such as arthritic joints) and there is evidence for association of PGRPs with inflammatory diseases, such as psoriasis.

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Two to Tango: Dialogue between Adaptive and Innate Immunity in Type 1 Diabetes

Journal of Diabetes Research ◽

10.1155/2020/4106518 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Lin Sun ◽

Shugang Xi ◽

Guangyu He ◽

Zhuo Li ◽

Xiaokun Gang ◽

...

Keyword(s):

Innate Immunity ◽

T Cells ◽

Type 1 Diabetes ◽

Autoimmune Disorder ◽

Innate Immune ◽

Therapeutic Interventions ◽

T Cell Subsets ◽

And Function

Type 1 diabetes mellitus (T1DM) is a long-term and chronic autoimmune disorder, in which the immune system attacks the pancreatic β-cells. Both adaptive and innate immune systems are involved in T1DM development. Both B-cells and T-cells, including CD4+ and CD8+ T-cells, as well as other T-cell subsets, could affect onset of autoimmunity. Furthermore, cells involved in innate immunity, including the macrophages, dendritic cells, and natural killer (NK) cells, could also accelerate or decelerate T1DM development. In this review, the crosstalk and function of immune cells in the pathogenesis of T1DM, as well as the corresponding therapeutic interventions, are discussed.

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Innate immunity orchestrates adipose tissue homeostasis

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2017-0013 ◽

2017 ◽

Vol 31 (1) ◽

Cited By ~ 4

Author(s):

Yi-Wei Lin ◽

Li-Na Wei

Keyword(s):

Insulin Resistance ◽

Innate Immunity ◽

Adipose Tissue ◽

Inflammatory Responses ◽

Inflammatory Cells ◽

Whole Body ◽

M2 Macrophage ◽

Low Grade ◽

Metabolic Complications ◽

M1 Macrophage

AbstractObesity is strongly associated with multiple diseases including insulin resistance, type 2 diabetes, cardiovascular diseases, fatty liver disease, neurodegenerative diseases and cancers, etc. Adipose tissue (AT), mainly brown AT (BAT) and white AT (WAT), is an important metabolic and endocrine organ that maintains whole-body homeostasis. BAT contributes to non-shivering thermogenesis in a cold environment; WAT stores energy and produces adipokines that fine-tune metabolic and inflammatory responses. Obesity is often characterized by over-expansion and inflammation of WAT where inflammatory cells/mediators are abundant, especially pro-inflammatory (M1) macrophages, resulting in chronic low-grade inflammation and leading to insulin resistance and metabolic complications. Macrophages constitute the major component of innate immunity and can be activated as a M1 or M2 (anti-inflammatory) phenotype in response to environmental stimuli. Polarized M1 macrophage causes AT inflammation, whereas polarized M2 macrophage promotes WAT remodeling into the BAT phenotype, also known as WAT browning/beiging, which enhances insulin sensitivity and metabolic health. This review will discuss the regulation of AT homeostasis in relation to innate immunity.

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Obesity and lung inflammation

Journal of Applied Physiology ◽

10.1152/japplphysiol.00781.2009 ◽

2010 ◽

Vol 108 (3) ◽

pp. 722-728 ◽

Cited By ~ 99

Author(s):

Peter Mancuso

Keyword(s):

Adipose Tissue ◽

Lung Disease ◽

Inflammatory Responses ◽

Acute Phase Proteins ◽

Pulmonary Inflammation ◽

Therapeutic Interventions ◽

Low Grade ◽

Tissue Mass ◽

Proinflammatory Mediators ◽

Increased Risk

The prevalence of obesity has increased dramatically worldwide, predisposing individuals to an increased risk of morbidity and mortality due to cardiovascular disease and type 2 diabetes. Less recognized is the fact that obesity may play a significant role in the pathogenesis of pulmonary diseases through mechanisms that may involve proinflammatory mediators produced in adipose tissue that contribute to a low-grade state of systemic inflammation. In animal models, inflammatory responses in the lung have been shown to influence the production of the adipocytokines, leptin and adiponectin, cytokines, acute phase proteins, and other mediators produced by adipose tissue that may participate in immune responses of the lung. An increased adipose tissue mass may also influence susceptibility to pulmonary infections, enhance pulmonary inflammation associated with environmental exposures, and exacerbate airway obstruction in preexisting lung disease. An increased understanding of the mechanisms by which obesity influences pulmonary inflammation may facilitate the development of novel therapeutic interventions for the treatment of lung disease.

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Tissue-specific control of galectin-1-driven circuits during inflammatory responses

Glycobiology ◽

10.1093/glycob/cwab007 ◽

2021 ◽

Author(s):

Anabela M Cutine ◽

Camila A Bach ◽

Florencia Veigas ◽

Joaquín P Merlo ◽

Lorena Laporte ◽

...

Keyword(s):

Potential Role ◽

Inflammatory Responses ◽

Binding Protein ◽

Experimental Models ◽

Tissue Specific ◽

Inflammatory Conditions ◽

Evolutionarily Conserved ◽

And Function ◽

Specific Control

Abstract The relevance of glycan-binding protein in immune tolerance and inflammation has been well established, mainly by studies of C-type lectins, siglecs and galectins both in experimental models and patient samples. Galectins, a family of evolutionarily conserved lectins, are characterized by sequence homology in the carbohydrate-recognition domain (CRD), atypical secretion via an ER-Golgi-independent pathway and the ability to recognize β-galactoside-containing saccharides. Galectin-1 (Gal-1), a prototype member of this family displays mainly anti-inflammatory and immunosuppressive activities, although, similar to many cytokines and growth factors, it may also trigger paradoxical pro-inflammatory effects under certain circumstances. These dual effects could be associated to tissue-, time- or context-dependent regulation of galectin expression and function, including particular pathophysiologic settings and/or environmental conditions influencing the structure of this lectin, as well as the availability of glycosylated ligands in immune cells during the course of inflammatory responses. Here, we discuss the tissue-specific role of Gal-1 as a master regulator of inflammatory responses across different pathophysiologic settings, highlighting its potential role as a therapeutic target. Further studies designed at analyzing the intrinsic and extrinsic pathways that control Gal-1 expression and function in different tissue microenvironments may contribute to design tailored therapeutic strategies aimed at positively or negatively modulate this glycan-binding protein in pathologic inflammatory conditions.

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