scholarly journals Neurovascular Inflammaging in Health and Disease

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1614 ◽  
Author(s):  
Ádám Mészáros ◽  
Kinga Molnár ◽  
Bernát Nógrádi ◽  
Zsófia Hernádi ◽  
Ádám Nyúl-Tóth ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Current Knowledge ◽  
Neurovascular Unit ◽  
Sterile Inflammation ◽  
Inflammasome Activation ◽  
Low Grade ◽  
Intrinsic Factors ◽  
Age Related ◽  
Cellular Debris ◽  
The Central Nervous System

Aging is characterized by a chronic low-grade sterile inflammation dubbed as inflammaging, which in part originates from accumulating cellular debris. These, acting as danger signals with many intrinsic factors such as cytokines, are sensed by a network of pattern recognition receptors and other cognate receptors, leading to the activation of inflammasomes. Due to the inflammasome activity-dependent increase in the levels of pro-inflammatory interleukins (IL-1β, IL-18), inflammation is initiated, resulting in tissue injury in various organs, the brain and the spinal cord included. Similarly, in age-related diseases of the central nervous system (CNS), inflammasome activation is a prominent moment, in which cells of the neurovascular unit occupy a significant position. In this review, we discuss the inflammatory changes in normal aging and summarize the current knowledge on the role of inflammasomes and contributing mechanisms in common CNS diseases, namely Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and stroke, all of which occur more frequently with aging.

Energy provisioning and inflammasome activation: The pivotal role of AMPK in sterile inflammation and associated metabolic disorders

2020 ◽  
Vol 19 ◽  
Author(s):  
Akhila Hosur Shrungeswara ◽  
Mazhuvancherry Kesavan Unnikrishnan
Keyword(s):  
Metabolic Regulation ◽  
Metabolic Disorders ◽  
Energy Homeostasis ◽  
Sedentary Lifestyle ◽  
Sterile Inflammation ◽  
Inflammasome Activation ◽  
Common Denominator ◽  
Low Grade ◽  
Sudden Increase ◽  
Free Environment

Background: Body defenses and metabolic processes probably co-evolved in such a way that rapid, energyintensive acute inflammatory repair is functionally integrated with energy allocation in a starvation/ infection / injury-prone primitive environment. Disruptive metabolic surplus, aggravated by sedentary lifestyle, induces chronic under-activation of AMPK, the master regulator of intracellular energy homeostasis. Sudden increase in chronic, dysregulated ‘sterile’ inflammatory disorders probably results from a shift towards calorie rich, sanitized, cushioned, injury/ infection free environment, repositioning inflammatory repair pathways towards chronic, non-microbial, ‘sterile’, ‘low grade’, ‘parainflammation’. AMPK, (at the helm of energy provisioning) supervises the metabolic regulation of inflammasome activation, a common denominator in lifestyle disorders. Discussion: In this review we discuss various pathways linking AMPK under-activation and inflammasome activation. AMPK under-activation, the possible norm in energy-rich sedentary lifestyle, could be the central agency that stimulates inflammasome activation by multiple pathways such as: [1] decreasing autophagy, and accumulation of intracellular DAMPs, (particulate crystalline molecules, advanced glycation end-products, oxidized lipids etc.) [2] stimulating a glycolytic shift (pro-inflammatory) in metabolism, [3] promoting NF-kB activation and decreasing Nrf2 activation, [4] increasing reactive oxygen species (ROS) formation, unfolded protein response( UPR) and endoplasmic reticulum (ER) stress. Conclusion: The ‘inverse energy crisis’, associated with calorie-rich, sedentary lifestyle, advocates dietary and pharmacological interventions for treating chronic metabolic disorders by overcoming / reversing AMPK under-activation.

scholarly journals Role of Microglia in CNS Autoimmunity

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Tobias Goldmann ◽  
Marco Prinz
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Tissue Repair ◽  
Tissue Injury ◽  
Current Knowledge ◽  
Complex Function ◽  
Western World ◽  
Cns Autoimmunity ◽  
The Central Nervous System

Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system (CNS) in the Western world. The disease is characterized histologically by the infiltration of encephalitogenicTH1/TH17-polarized CD4+T cells, B cells, and a plethora of myeloid cells, resulting in severe demyelination ultimately leading to a degeneration of neuronal structures. These pathological processes are substantially modulated by microglia, the resident immune competent cells of the CNS. In this overview, we summarize the current knowledge regarding the highly diverse and complex function of microglia during CNS autoimmunity in either promoting tissue injury or tissue repair. Hence, understanding microglia involvement in MS offers new exciting paths for therapeutic intervention.

scholarly journals MicroRNA-34a: the bad guy in age-related vascular diseases

2021 ◽  
Author(s):  
Angela Raucci ◽  
Federica Macrì ◽  
Stefania Castiglione ◽  
Ileana Badi ◽  
Maria Cristina Vinci ◽  
...  
Keyword(s):  
Risk Factors ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Vascular Diseases ◽  
B Cell Lymphoma ◽  
Sirtuin 1 ◽  
Inflammatory Factors ◽  
Low Grade ◽  
Genetic Ablation ◽  
Age Related

AbstractThe age-related vasculature alteration is the prominent risk factor for vascular diseases (VD), namely, atherosclerosis, abdominal aortic aneurysm, vascular calcification (VC) and pulmonary arterial hypertension (PAH). The chronic sterile low-grade inflammation state, alias inflammaging, characterizes elderly people and participates in VD development. MicroRNA34-a (miR-34a) is emerging as an important mediator of inflammaging and VD. miR-34a increases with aging in vessels and induces senescence and the acquisition of the senescence-associated secretory phenotype (SASP) in vascular smooth muscle (VSMCs) and endothelial (ECs) cells. Similarly, other VD risk factors, including dyslipidemia, hyperglycemia and hypertension, modify miR-34a expression to promote vascular senescence and inflammation. miR-34a upregulation causes endothelial dysfunction by affecting ECs nitric oxide bioavailability, adhesion molecules expression and inflammatory cells recruitment. miR-34a-induced senescence facilitates VSMCs osteoblastic switch and VC development in hyperphosphatemia conditions. Conversely, atherogenic and hypoxic stimuli downregulate miR-34a levels and promote VSMCs proliferation and migration during atherosclerosis and PAH. MiR34a genetic ablation or miR-34a inhibition by anti-miR-34a molecules in different experimental models of VD reduce vascular inflammation, senescence and apoptosis through sirtuin 1 Notch1, and B-cell lymphoma 2 modulation. Notably, pleiotropic drugs, like statins, liraglutide and metformin, affect miR-34a expression. Finally, human studies report that miR-34a levels associate to atherosclerosis and diabetes and correlate with inflammatory factors during aging. Herein, we comprehensively review the current knowledge about miR-34a-dependent molecular and cellular mechanisms activated by VD risk factors and highlight the diagnostic and therapeutic potential of modulating its expression in order to reduce inflammaging and VD burn and extend healthy lifespan.

scholarly journals Molecular Regulation of Cell Fate in Cerebral Ischemia: Role of the Inflammasome and Connected Pathways

2014 ◽  
Vol 34 (12) ◽  
pp. 1857-1867 ◽  
Author(s):  
George Trendelenburg
Keyword(s):  
Cell Fate ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Sterile Inflammation ◽  
Inflammasome Activation ◽  
Stroke Incidence ◽  
Multifactorial Diseases ◽  
Relevant Role ◽  
Metabolic Conditions

Analogous to Toll-like receptors, NOD-like receptors represent a class of pattern recognition receptors, which are cytosolic and constitute part of different inflammasomes. These large protein complexes are activated not only by different pathogens, but also by sterile inflammation or by specific metabolic conditions. Mutations can cause hereditary autoinflammatory systemic diseases, and inflammasome activation has been linked to many multifactorial diseases, such as diabetes or cardiovascular diseases. Increasing data also support an important role in different central nervous diseases such as stroke. Thus, the current knowledge of the functional role of this intracellular ‘master switch’ of inflammation is discussed with a focus on its role in ischemic stroke, neurodegeneration, and also with regard to the recent data which argues for a relevant role in other organs or biologic systems which influence stroke incidence or prognosis.

scholarly journals Hedgehog dysregulation contributes to tissue-specific inflammaging of resident macrophages

2020 ◽  
Author(s):  
Mahamat Babagana ◽  
Kyu-Seon Oh ◽  
Sayantan Chakraborty ◽  
Alicja Pacholewska ◽  
Mohammad Aqdas ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Innate Immune ◽  
Sterile Inflammation ◽  
Low Grade ◽  
Immune Functions ◽  
Tissue Specific ◽  
Physiological Aging ◽  
Age Related ◽  
Hh Signaling

AbstractAge-associated low-grade sterile inflammation, commonly referred to as inflammaging, is a recognized hallmark of aging, which contributes to many age-related diseases. While tissue-resident macrophages are innate immune cells that secrete many types of inflammatory cytokines in response to various stimuli, it is not clear whether they have a role in driving inflammaging. Here we characterized the transcriptional changes associated with physiological aging in mouse resident macrophage populations across different tissues and sexes. Although the age-related transcriptomic signatures of resident macrophages were strikingly tissue-specific, the differentially expressed genes were collectively enriched for those with important innate immune functions such as antigen presentation, cytokine production, and cell adhesion. The brain-resident microglia had the most wide-ranging age-related alterations, with compromised expression of tissue-specific genes and relatively exaggerated responses to endotoxin stimulation. Despite the tissue-specific patterns of aging transcriptomes, components of the hedgehog (Hh) signaling pathway were decreased in aged macrophages across multiple tissues. In vivo suppression of Hh signaling in young animals increased the expression of pro-inflammatory cytokines, while in vitro activation of Hh signaling in old macrophages, in turn, suppressed the expression of these inflammatory cytokines. This suggests that hedgehog signaling could be a potential intervention axis for mitigating age-associated inflammation and related diseases. Overall, our data represent a resourceful catalog of tissue-specific and sex-specific transcriptomic changes in resident macrophages of peritoneum, liver, and brain, during physiological aging.

scholarly journals Mitochondria, immunosenescence and inflammaging: a role for mitokines?

2020 ◽  
Vol 42 (5) ◽  
pp. 607-617 ◽  
Author(s):  
Maria Conte ◽  
Morena Martucci ◽  
Antonio Chiariello ◽  
Claudio Franceschi ◽  
Stefano Salvioli
Keyword(s):  
Immune Responses ◽  
Acute Inflammation ◽  
Current Knowledge ◽  
Low Grade ◽  
Mitochondrial Stress ◽  
Age Related ◽  
Metabolic Mechanism ◽  
Anti Inflammatory ◽  
Low Grade Inflammation

AbstractA global reshaping of the immune responses occurs with ageing, indicated as immunosenescence, where mitochondria and mitochondrial metabolism play an important role. However, much less is known about the role of mitochondrial stress response in this reshaping and in particular of the molecules induced by such response, collectively indicated as mitokines. In this review, we summarize the current knowledge on the role of mitokines in modulating immune response and inflammation focusing on GDF15, FGF21 and humanin and their possible involvement in the chronic age-related low-grade inflammation dubbed inflammaging. Although many aspects of their biology are still controversial, available data suggest that these mitokines have an anti-inflammatory role and increase with age. Therefore, we hypothesize that they can be considered part of an adaptive and integrated immune-metabolic mechanism activated by mitochondrial dysfunction that acts within the framework of a larger anti-inflammatory network aimed at controlling both acute inflammation and inflammaging.

scholarly journals The Absence of NLRP3-inflammasome Modulates Hepatic Fibrosis Progression, Lipid Metabolism, and Inflammation in KO NLRP3 Mice during Aging

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2148
Author(s):  
Paloma Gallego ◽  
Beatriz Castejón-Vega ◽  
José A. del Campo ◽  
Mario D. Cordero
Keyword(s):  
Lipid Metabolism ◽  
Nlrp3 Inflammasome ◽  
Oxidative Stress Marker ◽  
Inflammasome Activation ◽  
Low Grade ◽  
Sod Activity ◽  
Protein Levels ◽  
Age Related ◽  
Nlrp3 Inflammasome Activation ◽  
Liver Changes

Aging is associated with metabolic changes and low-grade inflammation in several organs, which may be due to NLRP3 inflammasome activation. Methods: Here, we asked whether age-related liver changes such as lipid metabolism and fibrosis are reduced in aged mice lacking the NLRP3 inflammasome. We report reduced protein levels of lipid markers (MTP, FASN, DGAT1), SOD activity, oxidative stress marker PTPRG, and the fibrotic markers TPM2β, COL1-α1 associated with increased GATA4, in NLRP3 deficient mice. Fibrotic, lipid, and oxidative reduction in liver tissues of mice was more pronounced in those old KO NLRP3 mice than in the younger ones, despite their greater liver damage. These results suggest that absence of the NLRP3 inflammasome attenuates age-related liver fibrotic pathology in mice, suggesting that pharmacological targeting may be beneficial.

scholarly journals JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

2015 ◽  
Vol 112 (46) ◽  
pp. E6301-E6310 ◽  
Author(s):  
Ming Xu ◽  
Tamara Tchkonia ◽  
Husheng Ding ◽  
Mikolaj Ogrodnik ◽  
Ellen R. Lubbers ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Cellular Senescence ◽  
Umbilical Vein ◽  
Sterile Inflammation ◽  
Low Grade ◽  
Jak Inhibitors ◽  
Ecm Remodeling ◽  
Age Related ◽  
Secretory Phenotype

Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction.

Neurotoxic and Neuroprotective Role of Exosomes in Parkinson’s Disease

2020 ◽  
Vol 25 (42) ◽  
pp. 4510-4522 ◽  
Author(s):  
Biancamaria Longoni ◽  
Irene Fasciani ◽  
Shivakumar Kolachalam ◽  
Ilaria Pietrantoni ◽  
Francesco Marampon ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Potential Role ◽  
Current Knowledge ◽  
Biological Fluids ◽  
Cell Communication ◽  
Target Cells ◽  
Cellular Debris ◽  
The Brain

: Exosomes are extracellular vesicles produced by eukaryotic cells that are also found in most biological fluids and tissues. While they were initially thought to act as compartments for removal of cellular debris, they are now recognized as important tools for cell-to-cell communication and for the transfer of pathogens between the cells. They have attracted particular interest in neurodegenerative diseases for their potential role in transferring prion-like proteins between neurons, and in Parkinson’s disease (PD), they have been shown to spread oligomers of α-synuclein in the brain accelerating the progression of this pathology. A potential neuroprotective role of exosomes has also been equally proposed in PD as they could limit the toxicity of α-synuclein by clearing them out of the cells. Exosomes have also attracted considerable attention for use as drug vehicles. Being nonimmunogenic in nature, they provide an unprecedented opportunity to enhance the delivery of incorporated drugs to target cells. In this review, we discuss current knowledge about the potential neurotoxic and neuroprotective role of exosomes and their potential application as drug delivery systems in PD.

Resolution-Associated Molecular Patterns (RAMPs) as Endogenous Regulators of Glia Functions in Neuroinflammatory Disease

2020 ◽  
Vol 19 (7) ◽  
pp. 483-494
Author(s):  
Tyler J. Wenzel ◽  
Evan Kwong ◽  
Ekta Bajwa ◽  
Andis Klegeris
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Bioactive Lipids ◽  
Prothymosin Α ◽  
Neuroinflammatory Disease ◽  
Cellular Debris ◽  
Αb Crystallin ◽  
Endogenous Regulators ◽  
The Central Nervous System ◽  
Molecular Patterns

: Glial cells, including microglia and astrocytes, facilitate the survival and health of all cells within the Central Nervous System (CNS) by secreting a range of growth factors and contributing to tissue and synaptic remodeling. Microglia and astrocytes can also secrete cytotoxins in response to specific stimuli, such as exogenous Pathogen-Associated Molecular Patterns (PAMPs), or endogenous Damage-Associated Molecular Patterns (DAMPs). Excessive cytotoxic secretions can induce the death of neurons and contribute to the progression of neurodegenerative disorders, such as Alzheimer’s disease (AD). The transition between various activation states of glia, which include beneficial and detrimental modes, is regulated by endogenous molecules that include DAMPs, cytokines, neurotransmitters, and bioactive lipids, as well as a diverse group of mediators sometimes collectively referred to as Resolution-Associated Molecular Patterns (RAMPs). RAMPs are released by damaged or dying CNS cells into the extracellular space where they can induce signals in autocrine and paracrine fashions by interacting with glial cell receptors. While the complete range of their effects on glia has not been described yet, it is believed that their overall function is to inhibit adverse CNS inflammatory responses, facilitate tissue remodeling and cellular debris removal. This article summarizes the available evidence implicating the following RAMPs in CNS physiological processes and neurodegenerative diseases: cardiolipin (CL), prothymosin α (ProTα), binding immunoglobulin protein (BiP), heat shock protein (HSP) 10, HSP 27, and αB-crystallin. Studies on the molecular mechanisms engaged by RAMPs could identify novel glial targets for development of therapeutic agents that effectively slow down neuroinflammatory disorders including AD.

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