interleukin-8 and Neurodegenerative-Diseases

Chemokine CXCL8 is a low molecular weight neutrophil chemoattractant implicated in various neurodegenerative disorders including Alzheimer's disease and stroke. Increased expression of CXCL8 has been reported in serum, plasma and brain of human immunodeficiency virus (HIV)-1 infected individuals with neurocognitive impairment, indicating its role in neuroinflammation associated with HIV-1 infection of the brain. Since chemokines are critical in eliciting immune responses in the central nervous system (CNS), CXCL8 is of particular importance for being one of the first chemokines described in the brain. Activation of astrocytes and microglia by HIV-1 and virus associated proteins results in production of this chemokine in the brain microenvironment. Consequently, CXCL8 exerts its effect on target cells via Gprotein coupled receptors CXCR1 and CXCR2. Neutrophils are the main target cells for CXCL8; however, microglia and neurons also express CXCR1/CXCR2 and therefore are important targets for CXCL8-mediated crosstalk. The objective of this review is to focus on CXCL8 production, signaling and regulation in neuronal and glial cells in response to HIV-1 infection. We highlight the role of HIV-1 secreted proteins such as trans-activator of transcription, envelope glycoprotein, negative regulatory factor and viral protein r in the regulation of CXCL8. We discuss dual role of CXCL8 in neurodegeneration as well as neuroprotection in the CNS. Thus, targeting CXCL8 through the development of CXCR1/CXCR2-based therapeutic strategies to either selectively agonize or antagonize receptors may be able to selectively promote neuroprotective and anti-inflammatory outcomes, leading to significant clinical applications in many neuroinflammatory CNS diseases, including HIV-associated neurocognitive disorders.

Topics: AIDS Dementia Complex; Central Nervous System; Drug Discovery; Humans; Interleukin-8; Neurodegenerative Diseases; Neuroprotection; Receptors, Interleukin-8A; Receptors, Interleukin-8B

Diabetic retinopathy (DR) is a microvascular inflammatory and neurodegenerative disease. The purpose of this study was to analyze the relationship between DR severity and the levels of potential biomarkers in the serum and/or vitreous.. A prospective, consecutive, controlled, observational study was performed between June 2018 and January 2020. Blood and vitreous samples were collected on the day of vitrectomy in patients without diabetes and in patients with diabetes with epiretinal membrane, macular edema, and indication for vitrectomy.. Transthyretin (TTR) was the only blood biomarker with levels statistically higher in patients with diabetes (p = 0.037). However, no correlation with DR severity was observed. Erythropoietin (EPO) was the only blood biomarker whose levels were associated with DR severity (p = 0.036). In vitreous samples, levels of EPO (p = 0.011), interleukin (IL)-6 (p < 0.001), IL-8 (p < 0.001), IL-17 (p = 0.022), monokine induced by interferon-γ (MIG) (p < 0.001), and interferon gamma-induced protein 10 (IP-10) (p = 0.005) were significantly higher in patients with diabetes. Additionally, in vitreous, IL-6, IL-8, MIG, and IPL-10 levels were also higher in more severe DR cases (p < 0.05).. Among the studied biomarkers, vitreous IL-6, IL-8, MIG, and IP-10 were the ones whose levels had the strongest coherent relationship with DR severity prediction and, thus, have the best potential post-vitrectomy prognostic value.

Topics: Biomarkers; Chemokine CXCL10; Diabetes Mellitus; Diabetic Retinopathy; Humans; Interleukin-6; Interleukin-8; Neurodegenerative Diseases; Prospective Studies; Vitrectomy; Vitreous Body

In recent years, there has been discussion that essential tremor (ET) might be a neurodegenerative disease. Indicators of inflammation are considered as possible biomarkers of neurodegeneration. In this connection, the aim of our study was to identify the relationship between serum inflammation markers and clinical features in ET, including the severity of tremor, cognitive decline, depression.. The serum interleukin-1β (IL-1β), IL-6, IL-8, IL-10, and tumor necrosis factor-α (TNF-α) levels were measured in 90 ET patients and 90 healthy control people of the corresponding age and gender. Fahn-Tolosa-Marin scale was used for the severity of the tremor. Cognitive function was assessed using the MoCA. Affective symptoms were measured by the Beck Depression Inventory.. Our findings demonstrate that neuroinflammation makes a certain contribution to the development of ET.

Topics: Biomarkers; Essential Tremor; Humans; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Neurodegenerative Diseases; Tremor; Tumor Necrosis Factor-alpha

The mechanisms of neuronal degeneration and associated acute alterations in intraretinal cytokine and protein levels remain poorly understood in variable ischaemic retinopathies such as in branch retinal vein occlusion (BRVO). Herein we investigate neuronal damage and alterations in retinal cytokines and proteins in a pig model of acute BRVO. Twelve pigs had a BRVO induced photothrombotically in both eyes. Three pigs (6 eyes) each at 2, 6, 10 and 20 days were sacrificed together with an additional 3 control (6 eyes), enucleated, retinas dissected and processed. Apoptosis in the inner retina was determined by terminal deoxyynuclotidyl transferase mediated dUTP nick end labelling (TUNEL) and histology. Expression of glial acidic fibrillary protein (GFAP), aquaporin-4 (AQP4), inward rectifier potassium channel 10 protein (K

Topics: Animals; Aquaporin 4; Chemokine CXCL12; Cytokines; Disease Models, Animal; Eye Proteins; Glial Fibrillary Acidic Protein; Interleukin-6; Interleukin-8; Neurodegenerative Diseases; Potassium Channels, Inwardly Rectifying; Retinal Neurons; Retinal Vein Occlusion; RNA, Messenger; Swine; Vascular Endothelial Growth Factor A

It is widely accepted that central nervous system inflammation and systemic inflammation play a significant role in the progression of chronic neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, neurotropic viral infections, stroke, paraneoplastic disorders, traumatic brain injury, and multiple sclerosis. Therefore, it seems reasonable to propose that the use of anti-inflammatory drugs might diminish the cumulative effects of inflammation. Indeed, some epidemiological studies suggest that sustained use of anti-inflammatory drugs may prevent or slow down the progression of neurodegenerative diseases. However, the anti-inflammatory drugs and biologics used clinically have the disadvantage of causing side effects and a high cost of treatment. Alternatively, natural products offer great potential for the identification and development of bioactive lead compounds into drugs for treating inflammatory diseases with an improved safety profile. In this work, we present a validated high-throughput screening approach in 96-well plate format for the discovery of new molecules with anti-inflammatory/immunomodulatory activity. The in vitro models are based on the quantitation of nitrite levels in RAW264.7 murine macrophages and interleukin-8 in Caco-2 cells. We have used this platform in a pilot project to screen a subset of 5976 noncytotoxic crude microbial extracts from the MEDINA microbial natural product collection. To our knowledge, this is the first report on an high-throughput screening of microbial natural product extracts for the discovery of immunomodulators.

Topics: Animals; Anti-Inflammatory Agents; Biological Products; Caco-2 Cells; Central Nervous System; Complex Mixtures; High-Throughput Screening Assays; Humans; Immunologic Factors; Inflammation; Interleukin-8; Mice; Nerve Degeneration; Neurodegenerative Diseases; Nitrites; RAW 264.7 Cells

Neuroinflammation, mediated in part by activated brain astrocytes, plays a critical role in the development of neurodegenerative disorders, including Alzheimer's disease (AD). Adiponectin is the most abundant adipokine secreted from adipose tissue and has been reported to exert both anti- and pro-inflammatory effects in peripheral tissues; however, the effects of adiponectin on astrocytes remain unknown. Shifts in peripheral concentrations of adipokines, including adiponectin, could contribute to the observed link between midlife adiposity and increased AD risk. The aim of the present study was to characterize the effects of globular adiponectin (gAd) on pro-inflammatory cytokine mRNA expression and secretion in human U373 MG astrocytic cells and to explore the potential involvement of nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and phosphatidylinositide 3-kinases (PI3K) signaling pathways in these processes. We demonstrated expression of adiponectin receptor 1 (adipoR1) and adipoR2 in U373 MG cells and primary human astrocytes. gAd induced secretion of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1, and gene expression of IL-6, MCP-1, IL-1β and IL-8 in U373 MG cells. Using specific inhibitors, we found that NF-κB, p38MAPK and ERK1/2 pathways are involved in gAd-induced induction of cytokines with ERK1/2 contributing the most. These findings provide evidence that gAd may induce a pro-inflammatory phenotype in human astrocytes.

Topics: Adiponectin; Astrocytes; Cell Line; Chemokine CCL2; Cytokines; Flavonoids; Humans; Imidazoles; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Interleukin-8; MAP Kinase Signaling System; Neurodegenerative Diseases; NF-kappa B; Phenotype; Phosphatidylinositol 3-Kinases; Pyridines; Receptors, Adiponectin; RNA, Messenger

Chronic inflammatory events appear to play a fundamental role in Alzheimer's disease (AD)-related neuropathological changes, and to result in neuronal dysfunction and death. The inflammatory responses observed in the AD brain include activation and proliferation of glial cells, together with up-regulation of inflammatory mediators and of free radicals. Along with glial cells, neurons themselves can also react and contribute to neuroinflammatory changes in the AD brain, by serving as sources of inflammatory mediators. Because excess cholesterol cannot be degraded in the brain, it must be excreted from that organ as cholesterol oxidation products (oxysterols), in order to prevent its accumulation. Among risk factors for this neurodegenerative disease, a mechanistic link between altered cholesterol metabolism and AD has been suggested; oxysterols appear to be the missing linkers between the two, because of their neurotoxic effects. This study shows that 24-hydroxycholesterol, 27-hydroxycholesterol, and 7β-hydroxycholesterol, the three oxysterols potentially implicated in AD pathogenesis, induce some pro-inflammatory mediator expression in human neuroblastoma SH-SY5Y cells, via Toll-like receptor-4/cyclooxygenase-2/membrane bound prostaglandin E synthase (TLR4/COX-2/mPGES-1); this clearly indicates that oxysterols may promote neuroinflammatory changes in AD. To confirm this evidence, cells were incubated with the anti-inflammatory flavonoid quercetin; remarkably, its anti-inflammatory effects in SH-SY5Y cells were enhanced when it was loaded into β-cyclodextrin-dodecylcarbonate nanoparticles, versus cells pretreated with free quercetin. The goal of loading quercetin into nanoparticles was to improve its permeation across the blood-brain barrier into the brain, and its bioavailability to reach target cells. The findings show that this drug delivery system might be a new therapeutic strategy for preventing or reducing AD progression.

Topics: Antioxidants; beta-Cyclodextrins; Cell Line, Tumor; Cell Survival; Chemokine CCL2; Gene Expression Regulation; Humans; Hydroxycholesterols; Inflammation; Inflammation Mediators; Integrin beta1; Interleukin-8; Matrix Metalloproteinase 9; Nanoparticles; Neurodegenerative Diseases; Quercetin

Astrocytes play an important role in astrocyte-neuron homeostasis. In HIV-1-infected brain, interleukin 1 beta (IL-1β) activation of astrocytes contributes to neurodegeneration. However, the molecular mechanisms underlying IL-1β-activated-astrocytes-induced neurodegeneration in HIV-1-infected brain are largely unknown. We hypothesize that secretory factors from the activated astrocytes affect N-methyl-d-aspartate (NMDA) receptor, a major pathway implicated in HIV-1-associated neurodegeneration. To test this hypothesis, we studied effects of IL-1β-stimulated astrocyte conditioned medium (ACM+) for its ability to activate NR1a/NR2B receptors expressed on Xenopus oocytes. Astrocytes treated with IL-1β 20ng/ml for 24h induced CXCL8, CCL2, MMP1 and MMP7. Pressure ejection of the ACM(+) produced an inward current in NR1a/NR2B-expressing oocytes. The inward current produced by ACM(+) was blocked by NMDA receptor antagonist, APV but not by non-NMDA receptor antagonist, CNQX. These results suggest that IL-1β stimulated astrocytes activate NR1a/NR2B receptors which may have implications in HIV-1-associated neurodegeneration.

Topics: Animals; Astrocytes; Cells, Cultured; Chemokine CCL2; Culture Media, Conditioned; HIV-1; Humans; Interleukin-1beta; Interleukin-8; Matrix Metalloproteinase 1; Matrix Metalloproteinase 7; Neurodegenerative Diseases; Oocytes; Receptors, N-Methyl-D-Aspartate; Xenopus

Among the chemokine family, fractalkine shows unusual properties: it exists as a membrane-bound and soluble protein, and both fractalkine and its receptor CX(3)CR1 are expressed predominantly in the central nervous system. In rat cell culture models, the chemokine fractalkine was expressed in neurons and microglia, but not in astrocytes and its receptor exclusively localized to microglial cells, where its expression was downregulated by treatment with the bacterial endotoxin (LPS). In microglial cultures, LPS (10 ng/ml) induced a marked increase in the release of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). The effects of LPS on TNF-alpha secretion were partially blocked (30%) by fractalkine and the effects of fractalkine were reversed by a polyclonal anti-fractalkine antibody. When microglial-associated fractalkine was neutralized by anti-fractalkine antibody, the LPS response was increased by 80%, suggesting tonic activation of microglial fractalkine receptors by endogenous fractalkine. The effects of the antibody were antagonized by the addition of fractalkine. LPS-activated microglia were neurotoxic when added to neuronal hippocampal culture, producing 20% neuronal death, as measured by NeuN-positive cell counting. An anti-fractalkine antibody produced neurotoxic effects of similar magnitude in this co-culture system and also markedly potentiated the neurotoxic effects of LPS-activated microglia (40% neuronal death). These results suggest that endogenous fractalkine might act tonically as an anti-inflammatory chemokine in cerebral tissue through its ability to control and suppress certain aspects of microglial activation. These data may have relevance to degenerative conditions such as multiple sclerosis, in which cerebral inflammatory processes may be activated.

Topics: Animals; Astrocytes; Cell Survival; Cells, Cultured; Chemokine CX3CL1; Chemokines, CX3C; Chemokines, CXC; Coculture Techniques; CX3C Chemokine Receptor 1; Encephalitis; Hippocampus; Interleukin-8; Lipopolysaccharides; Membrane Proteins; Microglia; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurons; Rats; Receptors, Cytokine; Receptors, HIV; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha