scholarly journals Role of HMGB1 in the Interplay between NETosis and Thrombosis in Ischemic Stroke: A Review

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1794 ◽  
Author(s):  
Seung-Woo Kim ◽  
Ja-Kyeong Lee
Keyword(s):  
Critical Role ◽  
High Mobility ◽  
Coagulation Factors ◽  
Brain Parenchyma ◽  
Peptidylarginine Deiminase ◽  
Molecular Pattern ◽  
Decondensed Chromatin ◽  
The Brain ◽  
Possible Cause

Neutrophil extracellular traps (NETs) comprise decondensed chromatin, histones and neutrophil granular proteins and are involved in the response to infectious as well as non-infectious diseases. The prothrombotic activity of NETs has been reported in various thrombus-related diseases; this activity can be attributed to the fact that the NETs serve as a scaffold for cells and numerous coagulation factors and stimulate fibrin deposition. A crosstalk between NETs and thrombosis has been indicated to play a role in numerous thrombosis-related conditions including stroke. In cerebral ischemia, neutrophils are the first group of cells to infiltrate the damaged brain tissue, where they produce NETs in the brain parenchyma and within blood vessels, thereby aggravating inflammation. Increasing evidences suggest the connection between NETosis and thrombosis as a possible cause of “tPA resistance”, a problem encountered during the treatment of stroke patients. Several damage-associated molecular pattern molecules have been proven to induce NETosis and thrombosis, with high mobility group box 1 (HMGB1) playing a critical role. This review discusses NETosis and thrombosis and their crosstalk in various thrombosis-related diseases, focusing on the role of HMGB1 as a mediator in stroke. We also addresses the function of peptidylarginine deiminase 4 with respect to the interplay with HMGB1 in NET-induced thrombosis.

scholarly journals The Potential Roles of Blood–Brain Barrier and Blood–Cerebrospinal Fluid Barrier in Maintaining Brain Manganese Homeostasis

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1833
Author(s):  
Shannon Morgan McCabe ◽  
Ningning Zhao
Keyword(s):  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
Blood Circulation ◽  
Critical Role ◽  
Systemic Circulation ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Brain

Manganese (Mn) is a trace nutrient necessary for life but becomes neurotoxic at high concentrations in the brain. The brain is a “privileged” organ that is separated from systemic blood circulation mainly by two barriers. Endothelial cells within the brain form tight junctions and act as the blood–brain barrier (BBB), which physically separates circulating blood from the brain parenchyma. Between the blood and the cerebrospinal fluid (CSF) is the choroid plexus (CP), which is a tissue that acts as the blood–CSF barrier (BCB). Pharmaceuticals, proteins, and metals in the systemic circulation are unable to reach the brain and spinal cord unless transported through either of the two brain barriers. The BBB and the BCB consist of tightly connected cells that fulfill the critical role of neuroprotection and control the exchange of materials between the brain environment and blood circulation. Many recent publications provide insights into Mn transport in vivo or in cell models. In this review, we will focus on the current research regarding Mn metabolism in the brain and discuss the potential roles of the BBB and BCB in maintaining brain Mn homeostasis.

The Role of High Mobility Group Box 1 (HMGB1) in Neurodegeneration: A Systematic Review

2022 ◽  
Vol 20 ◽  
Author(s):  
Fathimath Zaha Ikram ◽  
Alina Arulsamy ◽  
Thaarvena Retinasamy ◽  
Mohd. Farooq Shaikh
Keyword(s):  
Systematic Review ◽  
Tissue Injury ◽  
High Mobility ◽  
High Mobility Group ◽  
Hmgb1 Protein ◽  
Toll Like Receptor 4 ◽  
Neuroinflammatory Response ◽  
Molecular Pattern ◽  
Glycation End Products

Background: High mobility group box 1 (HMGB1) protein is a damage-associated molecular pattern (DAMP) molecule that plays an important role in the repair and regeneration of tissue injury. It also acts as a pro-inflammatory cytokine through the activation of toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE), to elicit the neuroinflammatory response. HMGB1 may aggravate several cellular responses which may lead to pathological inflammation and cellular death. Thus, there have been a considerable amount of research into the pathological role of HMGB1 in diseases. However, whether the mechanism of action of HMGB1 is similar in all neurodegenerative disease pathology remains to be determined. Objective: Therefore, this systematic review aimed to critically evaluate and elucidate the role of HMGB1 in the pathology of neurodegeneration based on the available literature. Methods: A comprehensive literature search was performed on four databases; EMBASE, PubMed, Scopus, and CINAHL Plus. Results: A total of 85 articles were selected for critical appraisal, after subjecting to the inclusion and exclusion criteria in this study. The selected articles revealed that HMGB1 levels were found elevated in most neurodegeneration except in Huntington’s disease and Spinocerebellar ataxia, where the levels were found decreased. This review also showcased that HMGB1 may act on distinctive pathways to elicit its pathological response leading to the various neurodegeneration processes/diseases. Conclusion: While there have been promising findings in HMGB1 intervention research, further studies may still be required before any HMGB1 intervention may be recommended as a therapeutic target for neurodegenerative diseases.

A critical role for central vasopressin in regulation of fever during bacterial infection

1992 ◽  
Vol 263 (6) ◽  
pp. R1235-R1240
Author(s):  
R. A. Cridland ◽  
N. W. Kasting
Keyword(s):  
Body Temperature ◽  
Arginine Vasopressin ◽  
Continuous Measurement ◽  
Critical Role ◽  
Experimental Models ◽  
Bacterial Endotoxins ◽  
Chronic Infusion ◽  
Live Bacteria ◽  
The Brain

Previous investigations on the antipyretic properties of arginine vasopressin have used bacterial endotoxins or pyrogens to induce fever. Because these experimental models of fever fail to mimic all aspects of the responses to infection, we felt it was important to examine the role of endogenously released vasopressin as a neuromodulator in febrile thermoregulation during infection. Therefore the present study examines the effects of chronic infusion of a V1-receptor antagonist or saline (via osmotic minipumps into the ventral septal area of the brain) on a fever induced by injection of live bacteria. Telemetry was used for continuous measurement of body temperature in the awake unhandled rat. Animals infused with the V1-antagonist exhibited fevers that were greater in duration compared with those of saline-infused animals. These results support the hypothesis that vasopressin functions as an antipyretic agent or fever-reducing agent in brain. Importantly, they suggest that endogenously released vasopressin may play a role as a neuromodulator in natural fever.

scholarly journals PPAR Gamma and Viral Infections of the Brain

2021 ◽  
Vol 22 (16) ◽  
pp. 8876
Author(s):  
Pierre Layrolle ◽  
Pierre Payoux ◽  
Stéphane Chavanas
Keyword(s):  
Viral Infections ◽  
Ppar Gamma ◽  
Brain Parenchyma ◽  
Peroxisome Proliferator ◽  
Neural Cells ◽  
Peroxisome Proliferator Activated Receptor ◽  
Immunodeficiency Virus ◽  
Health And Disease ◽  
The Brain

Peroxisome Proliferator-Activated Receptor gamma (PPARγ) is a master regulator of metabolism, adipogenesis, inflammation and cell cycle, and it has been extensively studied in the brain in relation to inflammation or neurodegeneration. Little is known however about its role in viral infections of the brain parenchyma, although they represent the most frequent cause of encephalitis and are a major threat for the developing brain. Specific to viral infections is the ability to subvert signaling pathways of the host cell to ensure virus replication and spreading, as deleterious as the consequences may be for the host. In this respect, the pleiotropic role of PPARγ makes it a critical target of infection. This review aims to provide an update on the role of PPARγ in viral infections of the brain. Recent studies have highlighted the involvement of PPARγ in brain or neural cells infected by immunodeficiency virus 1, Zika virus, or human cytomegalovirus. They have provided a better understanding on PPARγ functions in the infected brain, and revealed that it can be a double-edged sword with respect to inflammation, viral replication, or neuronogenesis. They unraveled new roles of PPARγ in health and disease and could possibly help designing new therapeutic strategies.

scholarly journals Role of High-Mobility Group Box-1 in Liver Pathogenesis

2019 ◽  
Vol 20 (21) ◽  
pp. 5314 ◽  
Author(s):  
Bilon Khambu ◽  
Shengmin Yan ◽  
Nazmul Huda ◽  
Xiao-Ming Yin
Keyword(s):  
Liver Disease ◽  
Critical Role ◽  
High Mobility ◽  
High Mobility Group ◽  
Sterile Inflammation ◽  
Contributing Factors ◽  
Drug Induced ◽  
Ductular Reaction ◽  
Alcoholic Fatty Liver

High-mobility group box 1 (HMGB1) is a highly abundant DNA-binding protein that can relocate to the cytosol or undergo extracellular release during cellular stress or death. HMGB1 has a functional versatility depending on its cellular location. While intracellular HMGB1 is important for DNA structure maintenance, gene expression, and autophagy induction, extracellular HMGB1 acts as a damage-associated molecular pattern (DAMP) molecule to alert the host of damage by triggering immune responses. The biological function of HMGB1 is mediated by multiple receptors, including the receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs), which are expressed in different hepatic cells. Activation of HMGB1 and downstream signaling pathways are contributing factors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and drug-induced liver injury (DILI), each of which involves sterile inflammation, liver fibrosis, ductular reaction, and hepatic tumorigenesis. In this review, we will discuss the critical role of HMGB1 in these pathogenic contexts and propose HMGB1 as a bona fide and targetable DAMP in the setting of common liver diseases.

scholarly journals Syk and Hrs Regulate TLR3-Mediated Antiviral Response in Murine Astrocytes

2019 ◽  
Vol 2019 ◽  
pp. 1-21 ◽  
Author(s):  
Matylda B. Mielcarska ◽  
Magdalena Bossowska-Nowicka ◽  
Karolina P. Gregorczyk-Zboroch ◽  
Zbigniew Wyżewski ◽  
Lidia Szulc-Dąbrowska ◽  
...  
Keyword(s):  
Immune Responses ◽  
Signaling Pathway ◽  
Critical Role ◽  
Antiviral Response ◽  
Proteolytic Processing ◽  
Viral Dsrna ◽  
Kinase Substrate ◽  
Tlr3 Signaling ◽  
The Brain

Toll-like receptors (TLRs) sense the presence of pathogen-associated molecular patterns. Nevertheless, the mechanisms modulating TLR-triggered innate immune responses are not yet fully understood. Complex regulatory systems exist to appropriately direct immune responses against foreign or self-nucleic acids, and a critical role of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), endosomal sorting complex required for transportation-0 (ESCRT-0) subunit, has recently been implicated in the endolysosomal transportation of TLR7 and TLR9. We investigated the involvement of Syk, Hrs, and STAM in the regulation of the TLR3 signaling pathway in a murine astrocyte cell line C8-D1A following cell stimulation with a viral dsRNA mimetic. Our data uncover a relationship between TLR3 and ESCRT-0, point out Syk as dsRNA-activated kinase, and suggest the role for Syk in mediating TLR3 signaling in murine astrocytes. We show molecular events that occur shortly after dsRNA stimulation of astrocytes and result in Syk Tyr-342 phosphorylation. Further, TLR3 undergoes proteolytic processing; the resulting TLR3 N-terminal form interacts with Hrs. The knockdown of Syk and Hrs enhances TLR3-mediated antiviral response in the form of IFN-β, IL-6, and CXCL8 secretion. Understanding the role of Syk and Hrs in TLR3 immune responses is of high importance since activation and precise execution of the TLR3 signaling pathway in the brain seem to be particularly significant in mounting an effective antiviral defense. Infection of the brain with herpes simplex type 1 virus may increase the secretion of amyloid-β by neurons and astrocytes and be a causal factor in degenerative diseases such as Alzheimer’s disease. Errors in TLR3 signaling, especially related to the precise regulation of the receptor transportation and degradation, need careful observation as they may disclose foundations to identify novel or sustain known therapeutic targets.

α-Chemokine receptor blockade reduces high mobility group box 1 protein-induced lung inflammation and injury and improves survival in sepsis

2005 ◽  
Vol 289 (4) ◽  
pp. L583-L590 ◽  
Author(s):  
Xinchun Lin ◽  
Huan Yang ◽  
Tohru Sakuragi ◽  
Maowen Hu ◽  
Lin L. Mantell ◽  
...  
Keyword(s):  
Lung Injury ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Critical Role ◽  
High Mobility ◽  
High Mobility Group ◽  
Receptor Blockade ◽  
Inflammatory Injury ◽  
Receptor Inhibition

High mobility group box 1 (HMGB1) protein, a late mediator of lethality in sepsis, can induce acute inflammatory lung injury. Here, we identify the critical role of α-chemokine receptors in the HMGB1-induced inflammatory injury and show that α-chemokine receptor inhibition increases survival in sepsis, in a clinically relevant time frame. Intratracheal instillation of recombinant HMGB1 induces a neutrophilic leukocytosis, preceded by alveolar accumulation of the α-chemokine macrophage inflammatory protein-2 and accompanied by injury and increased inflammatory potential within the air spaces. To investigate the role of α-chemokine receptors in the injury, we instilled recombinant HMGB1 (0.5 μg) directly into the lungs and administered a subcutaneous α-chemokine receptor inhibitor, Antileukinate (200 μg). α-Chemokine receptor blockade reduced HMGB1-induced inflammatory injury (neutrophils: 2.9 ± 3.2 vs. 8.1 ± 2.4 × 104cells; total protein: 120 ± 48 vs. 311 ± 129 μg/ml; reactive nitrogen species: 2.3 ± 0.3 vs. 3.5 ± 1.3 μM; and macrophage migration inhibitory factor: 6.4 ± 4.2 vs. 37.4 ± 15.9 ng/ml) within the bronchoalveolar lavage fluid, indicating that HMGB1-induced inflammation and injury are α-chemokine mediated. Because HMGB1 can mediate late septic lethality, we administered Antileukinate to septic mice and observed increased survival (from 58% in controls to 89%) even when the inhibitor treatment was initiated 24 h after the induction of sepsis. These data demonstrate that α-chemokine receptor inhibition can reduce HMGB1-induced lung injury and lethality in established sepsis and may provide a novel treatment in this devastating disease.

scholarly journals Osteopontin Expression in the Brain Triggers Localized Inflammation and Cell Death When Immune Cells Are Activated by Pertussis Toxin

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Maria Cecilia Garibaldi Marcondes ◽  
Ryan Ojakian ◽  
Nikki Bortell ◽  
Claudia Flynn ◽  
Bruno Conti ◽  
...  
Keyword(s):  
Cell Death ◽  
Pertussis Toxin ◽  
Inflammatory Cells ◽  
Brain Inflammation ◽  
Molecular Pattern ◽  
Expression Site ◽  
Pattern Characteristic ◽  
Peripheral Cells ◽  
The Brain

Upregulation of osteopontin (OPN) is a characteristic of central nervous system pathologies. However, the role of OPN in inflammation is still controversial, since it can both prevent cell death and induce the migration of potentially damaging inflammatory cells. To understand the role of OPN in inflammation and cell survival, we expressed OPN, utilizing an adenoviral vector, in the caudoputamen of mice deficient in OPN, using beta-galactosidase- (β-gal-) expressing vector as control. The tissue pathology and the expression of proinflammatory genes were compared in both treatments. Interestingly, inflammatory infiltrate was only found when the OPN-vector was combined with a peripheral treatment with pertussis toxin (Ptx), which activated peripheral cells to express the OPN receptor CD44v6. Relative toβ-gal, OPN increased the levels of inflammatory markers, including IL13Rα1, CXCR3, and CD40L. In Ptx-treated OPN KOs, apoptotic TUNEL+ cells surrounding the OPN expression site increased, compared toβ-gal. Together, these results show that local OPN expression combined with a peripheral inflammatory stimulus, such as Ptx, may be implicated in the development of brain inflammation and induction of cell death, by driving a molecular pattern characteristic of cytotoxicity. These are characteristics of inflammatory pathologies of the CNS in which OPN upregulation is a hallmark.

scholarly journals Biallelic variants in the small optic lobe calpain CAPN15 are associated with congenital eye anomalies, deafness and other neurodevelopmental deficits

2020 ◽  
Vol 29 (18) ◽  
pp. 3054-3063
Author(s):  
Congyao Zha ◽  
Carole A Farah ◽  
Richard J Holt ◽  
Fabiola Ceroni ◽  
Lama Al-Abdi ◽  
...  
Keyword(s):  
Optic Lobe ◽  
Critical Role ◽  
Genetic Diagnosis ◽  
Compound Heterozygous ◽  
Clinical Genetic ◽  
Eye Disorders ◽  
Neurodevelopmental Deficits ◽  
Independent Families ◽  
The Brain

Abstract Microphthalmia, coloboma and cataract are part of a spectrum of developmental eye disorders in humans affecting ~12 per 100 000 live births. Currently, variants in over 100 genes are known to underlie these conditions. However, at least 40% of affected individuals remain without a clinical genetic diagnosis, suggesting variants in additional genes may be responsible. Calpain 15 (CAPN15) is an intracellular cysteine protease belonging to the non-classical small optic lobe (SOL) family of calpains, an important class of developmental proteins, as yet uncharacterized in vertebrates. We identified five individuals with microphthalmia and/or coloboma from four independent families carrying homozygous or compound heterozygous predicted damaging variants in CAPN15. Several individuals had additional phenotypes including growth deficits, developmental delay and hearing loss. We generated Capn15 knockout mice that exhibited similar severe developmental eye defects, including anophthalmia, microphthalmia and cataract, and diminished growth. We demonstrate widespread Capn15 expression throughout the brain and central nervous system, strongest during early development, and decreasing postnatally. Together, these findings demonstrate a critical role of CAPN15 in vertebrate developmental eye disorders, and may signify a new developmental pathway.

scholarly journals Role of the glymphatic system in ageing and diabetes mellitus impaired cognitive function

2019 ◽  
Vol 4 (2) ◽  
pp. 90-92 ◽  
Author(s):  
Li Zhang ◽  
Michael Chopp ◽  
Quan Jiang ◽  
Zhenggang Zhang
Keyword(s):  
Diabetes Mellitus ◽  
Cognitive Impairment ◽  
Interstitial Fluid ◽  
Amyloid Β ◽  
Brain Parenchyma ◽  
Glymphatic System ◽  
Impaired Cognitive Function ◽  
Increased Risk ◽  
The Brain

Diabetes mellitus (DM) is a common metabolic disease in the middle-aged and older population, and is associated with cognitive impairment and an increased risk of developing dementia. The glymphatic system is a recently characterised brain-wide cerebrospinal fluid and interstitial fluid drainage pathway that enables the clearance of interstitial metabolic waste from the brain parenchyma. Emerging data suggest that DM and ageing impair the glymphatic system, leading to accumulation of metabolic wastes including amyloid-β within the brain parenchyma, and consequently provoking cognitive dysfunction. In this review, we concisely discuss recent findings regarding the role of the glymphatic system in DM and ageing associated cognitive impairment.

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