scholarly journals PDCD4-MAPKs-NF-κB positive loop simultaneously promotes microglia activation and neuron apoptosis during neuroinflammation

2021 ◽  
Author(s):  
Quan Chen ◽  
Hongjian Lu ◽  
Chengwei Duan ◽  
Xiangyang Zhu ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Damage Model ◽  
Therapeutic Targets ◽  
Pdcd4 Expression ◽  
Inflammatory Activation ◽  
Elevated Expression ◽  
The Central Nervous System ◽  
Apoptotic Activity ◽  
Signaling Activation

Abstract Neuroinflammation and neuron injury are common features of the central nervous system (CNS) diseases. It will be of great significance to identify their shared regulatory mechanisms and explore the potential therapeutic targets. Programmed cell death factor 4 (PDCD4), an apoptosis-related molecule, extensively participates in tumorigenesis and inflammatory diseases, but its expression and biological function during CNS neuroinflammation remain unclear. In the present study, utilizing the lipopolysaccharide (LPS)-induced neuroinflammation model on mice, we first reported an elevated expression of PDCD4 in both injured neurons and activated microglia of the inflamed mice brain. A similar change of PDCD4 expression was observed in the in vitro microglial activation model. Silencing PDCD4 by shRNA significantly inhibited the phosphorylation of MAPKs (p38, ERK, and JNK), prevented the phosphorylation and nuclear transportation of NF-κB p65, and thus attenuated the LPS-induced microglial inflammatory activation. Interestingly, LPS also required the MAPKs/NF-κB signaling activation to boost PDCD4 expression in microglia, and thus form a positive loop. Moreover, a persistent elevation of PDCD4 expression was detected in the H2O2-induced neuronal oxidative damage model. Knocking down PDCD4 significantly inhibited the expression of pro-apoptotic protein BAX, suggesting the pro-apoptotic activity of PDCD4 in the neuron. Taken together, our data indicated that PDCD4 may serve as a hub regulatory molecule that simultaneously promotes both the microglial inflammatory activation and the oxidative stress-induced neuronal apoptosis within CNS. The microglial PDCD4/MAPKs/NF-κB positive feedback loop may exaggerate the vicious cycle of neuroinflammation and neuronal injury, and thus may become potential therapeutic targets for neuroinflammatory diseases.

scholarly journals PDCD4–MAPK–NF-κB Positive Loop Simultaneously Promotes Microglia Activation and Neuron Apoptosis During Neuroinflammation

2021 ◽  
Author(s):  
Quan Chen ◽  
Hongjian Lu ◽  
Chengwei Duan ◽  
Xiangyang Zhu ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Inflammatory Diseases ◽  
Damage Model ◽  
Pdcd4 Expression ◽  
Proapoptotic Protein ◽  
Inflammatory Activation ◽  
Elevated Expression ◽  
The Central Nervous System ◽  
Signaling Activation

Abstract Neuroinflammation and neuron injury are common features of the central nervous system (CNS) diseases. It is of great significance to identify their shared regulatory mechanisms and explore the potential therapeutic targets. Programmed cell death factor 4 (PDCD4), an apoptosis-related molecule, extensively participates in tumorigenesis and inflammatory diseases, but its expression and biological function during CNS neuroinflammation remain unclear. In the present study, utilizing the lipopolysaccharide (LPS)-induced neuroinflammation model in mice, we reported an elevated expression of PDCD4 both in injured neurons and activated microglia of the inflamed brain. A similar change in PDCD4 expression was observed in vitro in the microglial activation model. Silencing PDCD4 by shRNA significantly inhibited the phosphorylation of MAPKs (p38, ERK, and JNK), prevented the phosphorylation and nuclear translocation of NF-κB p65, and thus attenuated the LPS-induced microglial inflammatory activation. Interestingly, LPS also required the MAPK/NF-κB signaling activation to boost PDCD4 expression in microglia, indicating the presence of a positive loop. Moreover, a persistent elevation of PDCD4 expression was detected in the H2O2-induced neuronal oxidative damage model. Knocking down PDCD4 significantly inhibited the expression of proapoptotic protein BAX, suggesting the proapoptotic activity of PDCD4 in neurons. Taken together, our data indicated that PDCD4 may serve as a hub regulatory molecule that simultaneously promotes the microglial inflammatory activation and the oxidative stress-induced neuronal apoptosis within CNS. The microglial PDCD4–MAPK–NF-κB positive feedback loop may exaggerate the vicious cycle of neuroinflammation and neuronal injury and thus may become a potential therapeutic target for neuroinflammatory diseases.

scholarly journals Activated Macrophages of Monocytic Origin Predominantly Express Proinflammatory Cytokine Genes, Whereas Kupffer Cells Predominantly Express Anti-Inflammatory Cytokine Genes

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Anastasia Lokhonina ◽  
Andrey Elchaninov ◽  
Timur Fatkhudinov ◽  
Andrey Makarov ◽  
Irina Arutyunyan ◽  
...  
Keyword(s):  
Kupffer Cells ◽  
Differential Distribution ◽  
Cytokine Genes ◽  
Elevated Expression ◽  
The Central Nervous System ◽  
Macrophage Populations ◽  
Monocytic Lineage ◽  
Anti Inflammatory Cytokine

In the central nervous system and in the liver, the macrophage populations are represented exclusively by descendants of the hematopoietic progenitor cells of the yolk sac. The reasons for such differential distribution of macrophages are not fully understood. We found that, as can be judged by corresponding changes in the expression of CD86 and CD163 markers, the transient macrophages of monocytic lineage are more sensitive to activating stimuli. The two macrophage populations have distinct patterns of gene expression, which is particularly noticeable for M1- and M2-associated genes. For instance, Kupffer cells more readily develop and longer maintain the elevated expression levels of Il4, Il10, and Il13 upon the activation; by contrast, the macrophages of monocytic lineage express Il1b, Il12a, and Tnfα upon the activation. The obtained results allow us to conclude that the in vitro activated Kupffer cells of the liver are committed to M2 phenotype, whereas the in vitro activated monocyte-derived macrophages show a typical M1 behavior. These observations are likely to reflect the situation in the in vivo microenvironments.

Chlamydia pneumoniae infection of microglial cells in vitro: a model of microbial infection for neurological disease

2006 ◽  
Vol 55 (7) ◽  
pp. 947-952 ◽  
Author(s):  
Hideaki Ikejima ◽  
Herman Friedman ◽  
Yoshimasa Yamamoto
Keyword(s):  
Neurological Disease ◽  
Chlamydia Pneumoniae ◽  
Inflammatory Diseases ◽  
Microglial Cells ◽  
Infection Model ◽  
Microbial Infection ◽  
Microglial Cell Line ◽  
The Central Nervous System ◽  
Metalloproteinase 9

Chlamydia pneumoniae is the aetiological cause of a wide variety of chronic inflammatory diseases and may be associated with neurological disease. Microbiological and immunological aspects of the interaction between C. pneumoniae and the central nervous system (CNS) are not well understood because of the lack of a suitable infection model for neuronal studies. In the present study, an in vitro C. pneumoniae infection model was developed in the established microglial cell line EOC 20. Infection of the cells resulted in obvious induction of proinflammatory cytokines. The infection also selectively induced matrix metalloproteinase-9 (MMP-9) but not MMP-2. Moreover, beta interferon, which is known to modulate CNS disease, inhibited induction of MMP-9 following C. pneumoniae infection. These results support the view that C. pneumoniae infection may be associated with marked alteration of the ability of microglial cells to enhance cytokine production as well as induction of an MMP.

scholarly journals Anti-Inflammatory Activity of a CB2 Selective Cannabinoid Receptor Agonist: Signaling and Cytokines Release in Blood Mononuclear Cells

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 64
Author(s):  
Antonella Capozzi ◽  
Daniela Caissutti ◽  
Vincenzo Mattei ◽  
Francesca Gado ◽  
Stefano Martellucci ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Cannabinoid Receptor ◽  
Inflammatory Diseases ◽  
Jurkat Cells ◽  
Parp Cleavage ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Anti Inflammatory ◽  
Apoptotic Activity

The endocannabinoid system (ECS) exerts immunosuppressive effects, which are mostly mediated by cannabinoid receptor 2 (CBR2), whose expression on leukocytes is higher than CBR1, mainly localized in the brain. Targeted CBR2 activation could limit inflammation, avoiding CBR1-related psychoactive effects. Herein, we evaluated in vitro the biological activity of a novel, selective and high-affinity CBR2 agonist, called JT11, studying its potential CBR2-mediated anti-inflammatory effect. Trypan Blue and MTT assays were used to test the cytotoxic and anti-proliferative effect of JT11 in Jurkat cells. Its pro-apoptotic activity was investigated analyzing both cell cycle and poly PARP cleavage. Finally, we evaluated its impact on LPS-induced ERK1/2 and NF-kB-p65 activation, TNF-α, IL-1β, IL-6 and IL-8 release in peripheral blood mononuclear cells (PBMCs) from healthy donors. Selective CB2R antagonist SR144528 and CBR2 knockdown were used to further verify the selectivity of JT11. We confirmed selective CBR2 activation by JT11. JT11 regulated cell viability and proliferation through a CBR2-dependent mechanism in Jurkat cells, exhibiting a mild pro-apoptotic activity. Finally, it reduced LPS-induced ERK1/2 and NF-kB-p65 phosphorylation and pro-inflammatory cytokines release in human PBMCs, proving to possess in vitro anti-inflammatory properties. JT11 as CBR2 ligands could enhance ECS immunoregulatory activity and our results support the view that therapeutic strategies targeting CBR2 signaling could be promising for the treatment of chronic inflammatory diseases.

scholarly journals TAAR1 Expression in Human Macrophages and Brain Tissue: A Potential Novel Facet of MS Neuroinflammation

2021 ◽  
Vol 22 (21) ◽  
pp. 11576
Author(s):  
David A. Barnes ◽  
Dylan A. Galloway ◽  
Marius C. Hoener ◽  
Mark D. Berry ◽  
Craig S. Moore
Keyword(s):  
Brain Tissue ◽  
Nuclear Localization ◽  
Demyelinating Disease ◽  
Border Region ◽  
Human Macrophages ◽  
Immune Mediated ◽  
Inflammatory Activation ◽  
The Central Nervous System

TAAR1 is a neuroregulator with emerging evidence suggesting a role in immunomodulation. Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. Here, we investigate TAAR1 expression in human primary monocytes, peripherally-derived macrophages, and MS brain tissue. RT-qPCR was used to assess TAAR1 levels in MS monocytes. Using a previously validated anti-human TAAR1 antibody and fluorescence microscopy, TAAR1 protein was visualized in lipopolysaccharide-stimulated or basal human macrophages, as well as macrophage/microglia populations surrounding, bordering, and within a mixed active/inactive MS lesion. In vivo, TAAR1 mRNA expression was significantly lower in MS monocytes compared to age- and sex-matched healthy controls. In vitro, TAAR1 protein showed a predominant nuclear localization in quiescent/control macrophages with a shift to a diffuse intracellular distribution following lipopolysaccharide-induced activation. In brain tissue, TAAR1 protein was predominantly expressed in macrophages/microglia within the border region of mixed active/inactive MS lesions. Considering that TAAR1-mediated anti-inflammatory effects have been previously reported, decreased mRNA in MS patients suggests possible pathophysiologic relevance. A shift in TAAR1 localization following pro-inflammatory activation suggests its function is altered in pro-inflammatory states, while TAAR1-expressing macrophages/microglia bordering an MS lesion supports TAAR1 as a novel pharmacological target in cells directly implicated in MS neuroinflammation.

scholarly journals Integrin-Targeting Dye-Doped PEG-Shell/Silica-Core Nanoparticles Mimicking the Proapoptotic Smac/DIABLO Protein

Nanomaterials ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 1211
Author(s):  
Rossella De Marco ◽  
Enrico Rampazzo ◽  
Junwei Zhao ◽  
Luca Prodi ◽  
Mayra Paolillo ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Mitochondrial Protein ◽  
Cell Uptake ◽  
Peptide Ligand ◽  
Integrin Subunit ◽  
Elevated Expression ◽  
Silica Core ◽  
Apoptotic Activity ◽  
Core Nanoparticles

Cancer cells demonstrate elevated expression levels of the inhibitor of apoptosis proteins (IAPs), contributing to tumor cell survival, disease progression, chemo-resistance, and poor prognosis. Smac/DIABLO is a mitochondrial protein that promotes apoptosis by neutralizing members of the IAP family. Herein, we describe the preparation and in vitro validation of a synthetic mimic of Smac/DIABLO, based on fluorescent polyethylene glycol (PEG)-coated silica-core nanoparticles (NPs) carrying a Smac/DIABLO-derived pro-apoptotic peptide and a tumor-homing integrin peptide ligand. At low μM concentration, the NPs showed significant toxicity towards A549, U373, and HeLa cancer cells and modest toxicity towards other integrin-expressing cells, correlated with integrin-mediated cell uptake and consequent highly increased levels of apoptotic activity, without perturbing cells not expressing the α5 integrin subunit.

scholarly journals IL-21 Receptor Expression in Human Tendinopathy

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Abigail L. Campbell ◽  
Nicola C. Smith ◽  
James H. Reilly ◽  
Shauna C. Kerr ◽  
William J. Leach ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Inflammatory Diseases ◽  
Convincing Evidence ◽  
Receptor Expression ◽  
Inflammatory Cytokine Production ◽  
Elevated Expression ◽  
Human Tendon ◽  
Inflammatory Bowel ◽  
Early Human

The pathogenetic mechanisms underlying tendinopathy remain unclear, with much debate as to whether inflammation or degradation has the prominent role. Increasing evidence points toward an early inflammatory infiltrate and associated inflammatory cytokine production in human and animal models of tendon disease. The IL-21/IL-21R axis is a proinflammatory cytokine complex that has been associated with chronic inflammatory diseases including rheumatoid arthritis and inflammatory bowel disease. This project aimed to investigate the role and expression of the cytokine/receptor pair IL-21/IL-21R in human tendinopathy. We found significantly elevated expression of IL-21 receptor message and protein in human tendon samples but found no convincing evidence of the presence of IL-21 at message or protein level. The level of expression of IL-21R message/protein in human tenocytes was significantly upregulated by proinflammatory cytokines (TNFα/IL-1β)in vitro. These findings demonstrate that IL-21R is present in early human tendinopathy mainly expressed by tenocytes and macrophages. Despite a lack of IL-21 expression, these data again suggest that early tendinopathy has an inflammatory/cytokine phenotype, which may provide novel translational targets in the treatment of tendinopathy.

Clinical applications of single photon emission tomography in neuromedicine

2000 ◽  
Vol 39 (08) ◽  
pp. 218-231 ◽  
Author(s):  
F. Grünwald ◽  
T. Kuwert ◽  
K. Tatsch ◽  
O. Sabri ◽  
O. Benkert ◽  
...  
Keyword(s):  
Single Photon ◽  
Inflammatory Diseases ◽  
Photon Emission ◽  
Clinical Applications ◽  
Emission Tomography ◽  
Receptor Ligands ◽  
Single Photon Emission ◽  
The Central Nervous System ◽  
Dementing Disorders ◽  
Photon Emission Tomography

SummaryThis article gives in his second part a critical review of the clinical applications of SPECT with perfusion markers and receptor ligands in dementing disorders and psychosis. In addition this review discusses clinical applications of SPECT investigations with perfusion markers in inflammatory diseases of the central nervous system and in brain trauma.

Effect of [Asu,]eel calcitonin on prolactin release in normal subjects and patients with prolactinoma

1985 ◽  
Vol 108 (3) ◽  
pp. 297-304 ◽  
Author(s):  
Hidesuke Kaji ◽  
Kazuo Chihara ◽  
Naoto Minamitani ◽  
Hitoshi Kodama ◽  
Tetsuya Kita ◽  
...  
Keyword(s):  
Body Weight ◽  
Bolus Injection ◽  
Normal Subjects ◽  
Regular Insulin ◽  
Prolactin Release ◽  
Saline Administration ◽  
The Central Nervous System ◽  
Plasma Prl ◽  
Male Subjects

Abstract. The effect of [Asu]eel calcitonin (ECT), an equipotent analogue of eel CT, on prolactin (Prl) secretion was examined in 12 healthy male subjects and in 6 patients with prolactinoma. In healthy subjects, ECT (0.5 μg/kg body weight · h) or saline was infused for 2 h and TRH was injected iv as a bolus of 500 μg at 1 h of ECT or saline administration. ECT did not affect basal Prl levels during 1 h of infusion. TRH caused a significant increase of plasma Prl with peak values of 75.2 ± 11.6 ng/ml in ECT-infused subjects, which did not differ from those infused with saline (68.5 ± 8.3 ng/ml). Next, an iv bolus injection of regular insulin (0.1 U/kg body weight) was followed by an infusion of ECT or saline alone. Plasma Prl peaks after hypoglycaemic stress were significantly lower in ECT-infused subjects than those in saline-injected controls (ECT, 16.5 ± 3.1 vs 33.5 ± 9.6 ng/ml, P < 0.05). In patients with prolactinoma, basal levels of plasma Prl ranging from 42.0–4130 ng/ml failed to change during iv infusion of ECT. Moreover, ECT (10−9–10−6m) did not affect Prl release from prolactinoma tissues perifused in vitro. These findings suggest that ECT may not act directly on the pituitary to modify Prl release. Rather, peripherally administered ECT appears to suppress Prl release via the central nervous system.

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