TNF-α and α-synuclein fibrils differently regulate human astrocyte immune reactivity and impair mitochondrial respiration

ABSTRACT Cytoadherence of Plasmodium falciparum-infected erythrocytes (PRBC) to endothelial cells causes severe clinical disease, presumably as a of result perfusion failure and tissue hypoxia. Cytoadherence to endothelial cells is increased by endothelial cell activation, which is believed to occur in a paracrine fashion by mediators such as tumor necrosis factor alpha (TNF-α) released from macrophages that initially recognize PRBC. Here we provide evidence that PRBC directly stimulate human endothelial cells in the absence of macrophages, leading to increased expression of adhesion-promoting molecules, such as intercellular adhesion molecule 1. Endothelial cell stimulation by PRBC required direct physical contact for a short time (30 to 60 min) and was correlated with parasitemia. Gene expression profiling of endothelial cells stimulated by PRBC revealed increased expression levels of chemokine and adhesion molecule genes. PRBC-stimulated endothelial cells especially showed increased expression of molecules involved in parasite adhesion but failed to express molecules promoting leukocyte adhesion, such as E-selectin and vascular cell adhesion molecule 1, even after challenge with TNF-α. Collectively, our data suggest that stimulation of endothelial cells by PRBC may have two effects: prevention of parasite clearance through increased cytoadherence and attenuation of leukocyte binding to endothelial cells, thereby preventing deleterious immune reactivity.

Download Full-text

Immune Responses after Heavy Alcohol Consumption: Cytokine Concentrations in Hangover-Sensitive and Hangover-Resistant Drinkers

Healthcare ◽

10.3390/healthcare9040395 ◽

2021 ◽

Vol 9 (4) ◽

pp. 395

Author(s):

Aurora JAE van de van de Loo ◽

S. Jorinde Raasveld ◽

Anna Hogewoning ◽

Raymond de Zeeuw ◽

Else R Bosma ◽

...

Keyword(s):

Alcohol Intake ◽

Immune Reactivity ◽

Cytokine Concentration ◽

Social Drinkers ◽

Tnf Α ◽

Heavy Alcohol Consumption ◽

Saliva Collection ◽

Alcohol Hangover ◽

High Level ◽

Necrosis Factor

This study investigated immunological changes during an alcohol hangover, and the possible difference between hangover-resistant and hangover-sensitive drinkers in terms of immune reactivity. Using a semi-naturalistic design, N = 36 healthy social drinkers (18 to 30 years old) provided saliva samples on a control day (after drinking no alcohol) and on a post-alcohol day. Hangover severity was rated directly after saliva collection. Cytokine concentrations, interleukin (IL)-1β, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α, and hangover severity were compared between both test days and between hangover-sensitive and -resistant drinkers. Data from N = 35 drinkers (17 hangover-sensitive and 18 hangover-resistant) were included in the statistical analyses. Relative to the control day, there were significant increases in saliva IL-6 and IL-10 concentrations on the post-alcohol day. No significant differences in cytokine concentrations were found between hangover-sensitive and hangover-resistant drinkers, nor did any change in cytokine concentration correlate significantly with hangover severity. In line with previous controlled studies assessing cytokines in blood, the current naturalistic study using saliva samples also demonstrated that the immune system responds to high-level alcohol intake. However, further research is warranted, as, in contrast to previous findings in blood samples, changes in saliva cytokine concentrations did not differ significantly between hangover-sensitive and hangover-resistant drinkers, nor did they correlate significantly with hangover severity.

Download Full-text

Immunomodulatory effect of melatonin supplementation in experimental diabetes

Pharmacia ◽

10.3897/pharmacia.67.e55437 ◽

2020 ◽

Vol 67 (4) ◽

pp. 223-228

Author(s):

Yana I. Ivankiv ◽

Oleksandra M. Oleshchuk

Keyword(s):

Inflammatory Responses ◽

Suppressive Effect ◽

Male Rats ◽

Immune Reactivity ◽

Standard Diet ◽

Tnf Α ◽

Experimental Type ◽

Necrosis Factor

Aim: To investigate the effect of melatonin on the immunomodulatory response in experimental type 1 and 2 diabetes mellitus. Methods: Experiments were performed on male rats (180–200 g), purchased from the Experimental Animal Holding,. Animals were maintained in standard diet conditions. Two pathological states were simulated on male rats: experimental type 1 and type 2 diabetes. Melatonin was introduced from 14 to 23 days of experiment intraperitoneally. Levels of immunoglobulin classes A, M and G (Ig A, M, G), circulating immune complexes (CIC), interleukin 1β (EE), interleukin 6 (IL-6), and tumor necrosis factor (TNF-a) were measured. Results: We demonstrated that melatonin in case of immune hyperactivity, can, provide a suppressive effect and is able to enhance immune reactivity under conditions of its limitation, indicating the immunostimulating activity. Furthermore, we found that administration of melatonin decreased inflammatory responses by mediating the levels of immunomodulatory factors, including TNF-α, IL-1β and IL-6. Conclusion: Melatonin is a positive regulator of immune system, may be a potential therapeutic agent, it has no reported side effects.

Download Full-text

AB0029 THE METABOLIC HIERARCHY OF IMMUNE PROCESSES IN HUMAN MONOCYTES

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.794 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1048.2-1048

Author(s):

P. L. Krauß ◽

F. Buttgereit ◽

T. Gaber ◽

M. Pfeiffenberger ◽

Y. Chen ◽

...

Keyword(s):

Flow Cytometry ◽

Steady State ◽

Mitochondrial Respiration ◽

Energy Supply ◽

Human Monocytes ◽

Immune Functions ◽

Activation Markers ◽

Atp Production ◽

Hla Dr ◽

Tnf Α

Background:At sites of inflammation, monocytes carry out specific immunological functions while facing challenging bioenergetic restrictions.Objectives:Here, we investigated the potential of human monocytes to adapt under conditions of reduced energy supply by gradually inhibiting oxidative phosphorylation (OXPHOS) under glucose free conditions.Methods:We modelled this reduced energy supply with myxothiazol, an inhibitor of mitochondrial respiration, at 0, 2 and 4 pmol/106 cells to decrease mitochondrial ATP production for 0%, 25% and 66% under glucose free conditions. For the three energy levels, we assessed (i) phagocytosis of FITC-labelled E.coli using flow cytometry, (i) production of reactive oxygen species (ROS) through NADPH oxidase (NOX) as determined by VAS2870-sensitive OCR using a Clark-type electrode, (iii) ATP generation and steady state level using a Clark-type electrode and luminometric assessment (iv) expression of surface activation markers CD16, CD80, CD11b, HLA-DR and (v) production of the inflammatory cytokines IL-1β, IL-6 and TNF-α using flow cytometry in peripheral blood-derived human monocytes with and without LPS-stimulation.Results:As a prerequisite for our study, we demonstrate that human monocytes survived strong inhibition of mitochondrial respiration without any sign of apoptosis as determined by flow cytometry. As a result of the inhibition of OXPHOS, we demonstrate a reduction of VAS2870-sensitive OCR (ROS production through NOX), ATPase-dependent OCR and ATP steady-state levels. Focusing on immune function, we observed that phagocytosis and the production of IL-6 were the least sensitive to reduced energy supply while surface expression of CD11b, HLA-DR, production of TNF-α and IL-1β were most affected by inhibition of OXPHOS.Conclusion:Our data demonstrate an energy-dependent hierarchy of immune functions in monocytes, which may represent a potential therapeutic target in monocyte-mediated inflammatory diseases.Disclosure of Interests:None declared

Download Full-text

Osteoclasts Lose Innate Inflammatory Reactivity to Metal and Polymer Implant Debris Compared to Monocytes/Macrophages

The Open Orthopaedics Journal ◽

10.2174/1874325001307010605 ◽

2013 ◽

Vol 7 (1) ◽

pp. 605-613 ◽

Cited By ~ 10

Author(s):

Jessica Yadav ◽

Lauryn Samelko ◽

Phil Gilvar ◽

Kyron McAllister ◽

Nadim James Hallab

Keyword(s):

Bone Cells ◽

Inflammatory Responses ◽

Immune Reactivity ◽

Nickel Ions ◽

Cobalt Ions ◽

Joint Replacements ◽

Polymer Implant ◽

Tnf Α ◽

Pmma Particles

Long-term aseptic failures of joint replacements are generally attributed to implant debris-induced inflammation and osteolysis. This response is largely mediated by immune and bone cells (monocytes/macrophages and osteoclasts, respectively), that in the presence of implant debris (e.g. metal particles and ions), release pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6. The relative degree to which implant debris can illicit inflammatory response(s) from osteoclasts vs monocytes/macrophages is unknown, i.e. are osteoclasts a viable target for anti-inflammatory therapy for implant debris? We investigated relative monocyte versus osteoclast inflammatory responses in a side-by-side comparison using implant debris from the perspective of both danger signaling (IL-1β) and pathogenic recognition (TNF-α) reactivity (Challenge Agents: Cobalt-alloy, Titanium-alloy, and PMMA particles, 0.9-1.8um-dia ECD and Cobalt, and Nickel-ions 0.01-0.1mM, all with and without LPS priming). Human monocytes/macrophages reacted to implant debris with >100 fold greater production of cytokines compared to osteoclast-like cells. Particulate Co-alloy challenge induced >1000 pg/ml of IL-1β and TNF-α, in monocytes and <50pg/mL IL-1β and TNF-α in osteoclasts. Cobalt ions induced >3000pg/mL IL-1β and TNF-α in monocytes/macrophages and <50pg/mL IL-1β and TNF-α in osteoclasts. The paracrine effect of supernatants from debris-treated monocytes/macrophages was capable of inducing greater osteoclastogenesis (TRAP+, p<0.06) and inflammation than direct debris challenge on osteoclasts. Our results indicate that as monocytes/macrophages differentiate into osteoclasts, they largely lose their innate immune reactivity to implant debris and thus may not be as relevant a therapeutic target as monocytes/macrophages for mitigating debris-induced inflammation.

Download Full-text

MiR-140/BDNF axis regulates normal human astrocyte proliferation and LPS-induced IL-6 and TNF-α secretion

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2017.05.016 ◽

2017 ◽

Vol 91 ◽

pp. 899-905 ◽

Cited By ~ 19

Author(s):

Zhiming Tu ◽

Yawei Li ◽

Yuliang Dai ◽

Lei Li ◽

Guohua Lv ◽

...

Keyword(s):

Astrocyte Proliferation ◽

Human Astrocyte ◽

Tnf Α ◽

Normal Human

Download Full-text

Topamax® and Ginger Oil Potential Neurotoxicity And Their Interaction in Mice Thru Oxidative Stress and Inflammatory Markers, Neurotransmitters Expression and Immunohistochemical Measurements

10.21203/rs.3.rs-1173182/v1 ◽

2022 ◽

Author(s):

Dalia M Mabrouk ◽

Aida El makawy ◽

Kawkab A Ahmed ◽

Faten M Ibrahim

Keyword(s):

Oxidative Stress ◽

Histopathological Examination ◽

Immune Reactivity ◽

Mrna Levels ◽

Oxidative Stress Markers ◽

Gamma Aminobutyric Acid ◽

Necrosis Factor Alpha ◽

Stress Markers ◽

Tnf Α ◽

Factor Alpha

Abstract Background: Topamax® ® has multiple pharmacological mechanisms that are efficient to treat epilepsy and migraine. Ginger has been demonstrated to have gingerols and shogaols compounds that proven to cross the blood-brain barrier causing migraine relief, implying that it is useful in the treatment of migraines. Moreover, Topamax has many off-label uses. So it was necessary to explore the possible neurotoxicity of Topamax®, Ginger oil and their interaction in the mice brain. Methods and Results: Male mice were orally gavage with Topamax®, ginger oil (400mg/kg), and Topamax® plus ginger oil with the same pattern for one month. Oxidative stress markers, acetylcholinesterase (AchE) and gamma aminobutyric acid (GABA) and tumor necrosis factor-alpha (TNF- α), were analyzed in brain tissue. Histopathological examination by hematoxylin and eosin, immunohistochemical glial fibrillary acidic protein (GFAP), and Bax expression analysis were done. The mRNA levels of GABAAR subunits, Gabra1, Gabra3, and Gabra5 were evaluated by RT qPCR. The analysis of data revealed that Topamax® elevated the levels of oxidative stress markers, neurotransmitters, TNF-α, and diminished the level of glutathione reduced (GSH). Topamax® exhibited various neuropathological alterations, strong Bax expression, and GFAP immune-reactivity in the cerebral cortex. The interaction effect of Topamax® plus ginger oil attenuated the changes induced by Topamax® in the abovementioned parameters. Both Topamax® and ginger oil upregulated the mRNA expression of gabra1 and gabra3 while their interaction markedly downregulated them. Conclusion: We can conclude that the Topamax® overdose could possibly cause neurotoxicity, but the interaction with ginger oil can reduce Topamax® -induced neurotoxicity and should be taken in parallel.

Download Full-text

Elevated level of circulatory sTLT1 induces inflammation through SYK/MEK/ERK signalling in coronary artery disease

Clinical Science ◽

10.1042/cs20190999 ◽

2019 ◽

Vol 133 (22) ◽

pp. 2283-2299

Author(s):

Apabrita Ayan Das ◽

Devasmita Chakravarty ◽

Debmalya Bhunia ◽

Surajit Ghosh ◽

Prakash C. Mandal ◽

...

Keyword(s):

Risk Factors ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Chronic Inflammation ◽

Ex Vivo ◽

Human Subjects ◽

Critical Role ◽

Atherosclerotic Cardiovascular Disease ◽

Tnf Α ◽

Artery Disease

Abstract The role of inflammation in all phases of atherosclerotic process is well established and soluble TREM-like transcript 1 (sTLT1) is reported to be associated with chronic inflammation. Yet, no information is available about the involvement of sTLT1 in atherosclerotic cardiovascular disease. Present study was undertaken to determine the pathophysiological significance of sTLT1 in atherosclerosis by employing an observational study on human subjects (n=117) followed by experiments in human macrophages and atherosclerotic apolipoprotein E (apoE)−/− mice. Plasma level of sTLT1 was found to be significantly (P<0.05) higher in clinical (2342 ± 184 pg/ml) and subclinical cases (1773 ± 118 pg/ml) than healthy controls (461 ± 57 pg/ml). Moreover, statistical analyses further indicated that sTLT1 was not only associated with common risk factors for Coronary Artery Disease (CAD) in both clinical and subclinical groups but also strongly correlated with disease severity. Ex vivo studies on macrophages showed that sTLT1 interacts with Fcɣ receptor I (FcɣRI) to activate spleen tyrosine kinase (SYK)-mediated downstream MAP kinase signalling cascade to activate nuclear factor-κ B (NF-kB). Activation of NF-kB induces secretion of tumour necrosis factor-α (TNF-α) from macrophage cells that plays pivotal role in governing the persistence of chronic inflammation. Atherosclerotic apoE−/− mice also showed high levels of sTLT1 and TNF-α in nearly occluded aortic stage indicating the contribution of sTLT1 in inflammation. Our results clearly demonstrate that sTLT1 is clinically related to the risk factors of CAD. We also showed that binding of sTLT1 with macrophage membrane receptor, FcɣR1 initiates inflammatory signals in macrophages suggesting its critical role in thrombus development and atherosclerosis.

Download Full-text