scholarly journals Regulation of Neutrophil Degranulation and Cytokine Secretion: A Novel Model Approach Based on Linear Fitting

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Isabelle Naegelen ◽  
Nicolas Beaume ◽  
Sébastien Plançon ◽  
Véronique Schenten ◽  
Eric J. Tschirhart ◽  
...  
Keyword(s):  
Time Series ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Cytokine Secretion ◽  
Human Neutrophils ◽  
Cytokine Release ◽  
Linear Fitting ◽  
Proinflammatory Mediators ◽  
The Relationship ◽  
Model Approach

Neutrophils participate in the maintenance of host integrity by releasing various cytotoxic proteins during degranulation. Due to recent advances, a major role has been attributed to neutrophil-derived cytokine secretion in the initiation, exacerbation, and resolution of inflammatory responses. Because the release of neutrophil-derived products orchestrates the action of other immune cells at the infection site and, thus, can contribute to the development of chronic inflammatory diseases, we aimed to investigate in more detail the spatiotemporal regulation of neutrophil-mediated release mechanisms of proinflammatory mediators. Purified human neutrophils were stimulated for different time points with lipopolysaccharide. Cells and supernatants were analyzed by flow cytometry techniques and used to establish secretion profiles of granules and cytokines. To analyze the link between cytokine release and degranulation time series, we propose an original strategy based on linear fitting, which may be used as a guideline, to (i) define the relationship of granule proteins and cytokines secreted to the inflammatory site and (ii) investigate the spatial regulation of neutrophil cytokine release. The model approach presented here aims to predict the correlation between neutrophil-derived cytokine secretion and degranulation and may easily be extrapolated to investigate the relationship between other types of time series of functional processes.

scholarly journals Delayed Addition of Glucocorticoids Selectively Suppresses Cytokine Production in Stimulated Human Whole Blood

2010 ◽  
Vol 17 (6) ◽  
pp. 979-985 ◽  
Author(s):  
Devin L. Horton ◽  
Daniel G. Remick
Keyword(s):  
Whole Blood ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Human Whole Blood ◽  
Proinflammatory Mediators ◽  
Cytokine Levels ◽  
Tlr4 Agonist ◽  
Cytokine Inhibitors ◽  
Toll Like Receptor 2

ABSTRACT Glucocorticoids (GC) are potent drugs proven to effectively treat inflammatory diseases, although patients typically begin therapy after the onset of symptoms. Clinical studies with cytokine inhibitors prove that these mediators drive inflammatory responses in diseases such as rheumatoid arthritis and Crohn's disease. Despite the clear sequence of cytokine-induced inflammation followed by effective GC treatment, most basic science investigations have examined the ability of GC to prevent an inflammatory response rather than halt its progression. The current studies used the Toll-like receptor 2 (TLR2) agonist palmitoyl3-cysteine-serine-lysine4 (PAM) or the TLR4 agonist lipopolysaccharide (LPS) to stimulate human whole blood and determine whether postponing the addition of the GC dexamethasone (DEX) limits its ability to decrease cytokine production. Twenty-four hours after stimulation, tumor necrosis factor (TNF), interleukin-1β (IL-1β), IL-6, and IL-8 levels were measured, in addition to the cytokine inhibitors IL-1 soluble receptor II (SRII), IL-1 receptor antagonist, and TNF SRII. LPS rapidly induced all of the proinflammatory mediators over 24 h while failing to induce any of the cytokine inhibitors. PAM stimulation also induced IL-1β, IL-6, and IL-8. Concomitant addition of DEX plus LPS or PAM significantly suppressed all cytokine levels. Delaying the addition of DEX until 6 h after LPS stimulation failed to decrease TNF or IL-6. In contrast, delayed DEX addition significantly suppressed PAM-induced IL-1β, IL-6, or IL-8 and also suppressed LPS-induced IL-1β and IL-8. Our results show that cytokines which typically increase in concentration between 6 and 24 h after stimulation were significantly suppressed by the addition of DEX 6 h after stimulation.

Proinflammatory mediators elicit secretion of the intracellular B-lymphocyte stimulator pool (BLyS) that is stored in activated neutrophils: implications for inflammatory diseases

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 830-837 ◽  
Author(s):  
Patrizia Scapini ◽  
Antonio Carletto ◽  
Bernardetta Nardelli ◽  
Federica Calzetti ◽  
Viktor Roschke ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
B Lymphocyte ◽  
De Novo ◽  
Inflammatory Responses ◽  
Leukotriene B4 ◽  
Human Neutrophils ◽  
Immunogold Electron Microscopy ◽  
Proinflammatory Mediators ◽  
B Lymphocyte Stimulator

Abstract We have recently shown that granulocyte–colony-stimulating factor (G-CSF)– and interferon-γ (IFN-γ)–activated human neutrophils accumulate and release remarkable amounts of soluble B-lymphocyte stimulator (BLyS) in vitro. In this study, we provide evidence that neutrophils migrating into skin window exudates (SWEs) developed in healthy volunteers and in patients with rheumatoid arthritis (RA), synthesized, and released BLyS in response to locally produced G-CSF. Accordingly, the concentrations of soluble BLyS in SWEs were significantly more elevated than in serum. Because the levels of SWE BLyS, but not SWE G-CSF, were higher in patients with RA than in healthy subjects, we examined the effect of CXCL8/IL-8, C5a, and other proinflammatory mediators that dramatically accumulate in RA SWEs and in inflamed synovial fluids. We show that CXCL1/GROα, CXCL8/IL-8, C5a, immune complexes, tumor necrosis factor-α (TNF-α), leukotriene B4, N-formyl-methionyl-leucyl-phenylalanine (fMLP), and lipopolysaccharide (LPS), which by themselves do not induce BLyS de novo synthesis, act as potent secretagogues for BLyS, which is mainly stored in Golgi-related compartments within G-CSF–treated neutrophils, as determined by immunogold electron microscopy. This action is pivotal in greatly amplifying neutrophil-dependent BLyS release in SWEs of patients with RA compared with healthy subjects. Collectively, our data uncover a novel mechanism that might dramatically exacerbate the release of BLyS by neutrophils during pathologic inflammatory responses.

scholarly journals POS0376 MONOMERIC C REACTIVE PROTEIN (mCRP) REGULATES INFLAMMATORY RESPONSES IN HUMAN AND MOUSE CHONDROCYTES

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 418.2-418
Author(s):  
C. Ruiz-Fernández ◽  
M. González-Rodríguez ◽  
V. Francisco ◽  
I. M. Rajab ◽  
R. Gómez Bahamonde ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Intracellular Signaling ◽  
Inflammatory Responses ◽  
Proteolytic Enzymes ◽  
Inflammatory Diseases ◽  
Osteoclast Differentiation ◽  
Human Neutrophils ◽  
C Reactive Protein ◽  
Reactive Protein

Background:C-reactive protein (CRP) is an acute-phase protein that is used as an established biomarker to follow disease severity and progression in a plethora of inflammatory diseases. However, its pathophysiologic mechanisms of action are still poorly defined and remain elusive. CRP, in its pentameric form, exhibits weak anti-inflammatory activity. On the contrary, the monomeric isoform (mCRP) exhibits potent pro-inflammatory properties in endothelial cells, leukocytes, and platelets. So far, no data exists regarding mCRP effects in human or mouse chondrocytesObjectives:This work aimed to verify the pathophysiological relevance of mCRP in the etiology and/or progression of osteoarthritis (OA)Methods:We investigated the effects of mCRP in cultured human primary chondrocytes and in the chondrogenic ATDC5 mouse cell line. We determined mRNA and protein levels of relevant factors involved in inflammatory responses and the modulation of nitric oxide synthase type II (NOS2), an early inflammatory molecular target.Results:We demonstrate, for the first time, that monomeric C reactive protein increases NOS2, COX2, MMP13, VCAM1, IL-6, IL-8, and LCN2 expression in human and murine chondrocytes. We also demonstrated that NF-kB is a key factor in the intracellular signaling of mCRP-driven induction of pro-inflammatory and catabolic mediators in chondrocytes.Conclusion:mCRP exerts a sustained catabolic effect on human and murine chondrocytes, increasing the expression of inflammatory mediators and proteolytic enzymes, which can promote extracellular matrix (ECM) breakdown in healthy and OA cartilage. In addition, our results implicate the NF-kB signaling pathway in catabolic effects mediated by mCRP.References:[1]Sproston NR, Ashworth JJ. Role of C-reactive protein at sites of inflammation and infection. Front Immunol. 2018;9(APR). doi:10.3389/fimmu.2018.00754[2]Francisco V, Pérez T, Pino J, et al. Biomechanics, obesity, and osteoarthritis. The role of adipokines: When the levee breaks. J Orthop Res. 2018;36(2):594-604. doi:10.1002/jor.23788[3]Kozijn AE, Tartjiono MT, Ravipati S, et al. Human C-reactive protein aggravates osteoarthritis development in mice on a high-fat diet. Osteoarthr Cartil. 2019;27(1):118-128. doi:10.1016/j.joca.2018.09.007[4]Rajab IM, Majerczyk D, Olson ME, et al. C-reactive protein in gallbladder diseases: diagnostic and therapeutic insights. Biophys Reports. 2020;6(2-3):49-67. doi:10.1007/s41048-020-00108-9[5]Wu Y, Potempa LA, El Kebir D, Filep JG. C-reactive protein and inflammation: conformational changes affect function. Biol Chem. 2015;396(11):1181-1197. doi:10.1515/hsz-2015-0149[6]Thiele JR, Zeller J, Bannasch H, Stark GB, Peter K, Eisenhardt SU. Targeting C-Reactive Protein in Inflammatory Disease by Preventing Conformational Changes. Mediators Inflamm. 2015;2015(372432):9. doi:10.1155/2015/372432[7]Khreiss T, József L, Hossain S, Chan JSD, Potempa LA, Filep JG. Loss of pentameric symmetry of C-reactive protein is associated with delayed apoptosis of human neutrophils. J Biol Chem. 2002;277(43):40775-40781. doi:10.1074/jbc.M205378200[8]Jia ZK, Li HY, Liang YL, Potempa LA, Ji SR, Wu Y. Monomeric C-reactive protein binds and neutralizes receptor activator of NF-κB ligand-induced osteoclast differentiation. Front Immunol. 2018;9(FEB). doi:10.3389/fimmu.2018.00234[9]Francisco V, Ruiz-Fernández C, Pino J, et al. Adipokines: Linking metabolic syndrome, the immune system, and arthritic diseases. Biochem Pharmacol. 2019;165:196-206. doi:10.1016/j.bcp.2019.03.030[10]Ullah N, Ma FR, Han J, et al. Monomeric C-reactive protein regulates fibronectin mediated monocyte adhesion. Mol Immunol. 2020;117:122-130. doi:10.1016/j.molimm.2019.10.013[11]Boras E, Slevin M, Alexander MY, et al. Monomeric C-reactive protein and Notch-3 co-operatively increase angiogenesis through PI3K signalling pathway. Cytokine. 2014;69(2):165-179. doi:10.1016/j.cyto.2014.05.027Disclosure of Interests:None declared

Statistical Analysis of the Effect of Environmental Degradation on Mortality Rate: A Vector Autoregressive (VAR) Model Approach

2018 ◽  
Vol 4 (11) ◽  
Author(s):  
A. F. Adedotun ◽  
O. G. Obadina ◽  
O. S. Adesina ◽  
K. O. Omosanya ◽  
R. J. Dare
Keyword(s):  
United States ◽  
Air Pollution ◽  
Time Series ◽  
Environmental Pollution ◽  
Recent Time ◽  
Var Model ◽  
Vector Autoregressive ◽  
Stationarity Test ◽  
The Relationship ◽  
Model Approach

The relationship between air pollution and mortality calls for attention in recent time. Diverse analyses have been conducted globally, including important cities in Africa, United States, Europe, and Asia. In this study, a time-series analysis is proposed to analyze influence of environmental pollution on mortality in Nigeria using the Vector Autoregressive (VAR) Model. Stationarity test shows that the data is stationary and VAR model suitably fits the data. The study reveals that environmental pollution has significant impact on mortality in Nigeria. Some useful recommendations were made.

scholarly journals Nanoparticle-induced neutrophil apoptosis increases survival in sepsis and alleviates neurological damage in stroke

2019 ◽  
Vol 5 (11) ◽  
pp. eaax7964 ◽  
Author(s):  
Can Yang Zhang ◽  
Xinyue Dong ◽  
Jin Gao ◽  
Wenjing Lin ◽  
Ze Liu ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Tissue Injury ◽  
Inflammatory Diseases ◽  
Ischemia Reperfusion ◽  
Human Neutrophils ◽  
Immune Homeostasis ◽  
Neutrophil Apoptosis ◽  
Precise Control ◽  
Programed Cell Death

Human neutrophils are the most abundant circulating leukocytes and contribute to acute and chronic inflammatory disorders. Neutrophil apoptosis is programed cell death to maintain immune homeostasis, but inflammatory responses to infections or tissue injury disrupt neutrophil death program, leading to many diseases. Precise control of neutrophil apoptosis may resolve inflammation to return immune homeostasis. Here, we report a method in which doxorubicin (DOX)–conjugated protein nanoparticles (NPs) can in situ selectively target inflammatory neutrophils for intracellular delivery of DOX that induces neutrophil apoptosis. We showed that neutrophil uptake of NPs required their activation and was highly selective. DOX release was triggered by acidic environments in neutrophils, subsequently inhibiting neutrophil transmigration and inflammatory responses. In two disease models, DOX-conjugated NPs notably increased mouse survival in sepsis and prevented brain damage in cerebral ischemia/reperfusion, but the NPs did not suppress systemic immunity. Our studies offer a promising strategy to treat inflammatory diseases.

scholarly journals MiR30a Inhibits Inflammation by Targeting Klf14 in Autoimmune Hepatitis

2021 ◽  
Author(s):  
Xiaofeng Yuan ◽  
Shunwen Pan ◽  
Mingliang Li ◽  
Li Quan ◽  
Kouxing Zhang ◽  
...  
Keyword(s):  
Autoimmune Hepatitis ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Luciferase Reporter ◽  
Regulatory Function ◽  
Liver Inflammation ◽  
Con A ◽  
Qrt Pcr ◽  
Reporter Assays ◽  
The Relationship

Abstract MiR30a plays diverse roles in inflammatory diseases, including autoimmune hepatitis (AIH). Klf14 is associated with the inflammation in AIH. We investigated whether miR30a exerts its regulatory function via Klf14. Concanavalin A (Con A)-induced AIH mice were infected with a miR30a agomir or antagomir. MiR30a expression was quantified using qRT-PCR. TargetScan and luciferase reporter assays were used to predict the relationship between miR30a and Klf14. Liver inflammation was evaluated by measuring serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, performing histology, and measuring mRNA expressions of inflammatory cytokines and Klf14 by qRT-PCR, protein of Klf14 by western blotting, and Tregs by FACS. MiR30a was downregulated in the hepatocytes (HCs) of AIH mice, which was negatively associated with the liver inflammation. MiR30a overexpression alleviated the inflammation, whereas downregulation of endogenous miR30a aggravated it. The mRNA and protein level of Klf14 were inversely correlated with the miR30a expression. The luciferase reporter assay validated the relationship between Klf14 and miR30a. Moreover, the frequency of Tregs was consistently correlated with the expression of miR30a. MiR30a may play an essential role in AIH, and its ability to regulate the inflammatory responses may, at least partially, be mediated by targeting Klf14 to modulate Tregs.

The Immunomodulatory Role of G2013 (α-L-Guluronic Acid) on the Expression of TLR2 and TLR4 in HT29 cell line

2019 ◽  
Vol 16 (1) ◽  
pp. 91-95 ◽  
Author(s):  
Hamid Farhang ◽  
Laleh Sharifi ◽  
Mohammad Mehdi Soltan Dallal ◽  
Mona Moshiri ◽  
Zahra Norouzbabaie ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Rna Extraction ◽  
Cell Plate ◽  
Inhibitory Effect ◽  
Control Group ◽  
Ht29 Cells ◽  
Guluronic Acid ◽  
Tlr4 Mrna

Background: The non-steroidal anti-inflammatory drugs (NSAIDs) play crucial role in the controlling of inflammatory diseases. Due to the vast side effects of NSAIDs, its use is limited. G2013 or &amp;#945;-L-Guluronic Acid is a new NSAID with immunomodulatory features. Objectives: Considering the leading role of TLRs in inflammatory responses, in this study, we aimed to evaluate G2013 cytotoxicity and its effect on the expression of TLR2 and TLR4 molecules. Methods: HEK293-TLR2 and HEK293-TLR4 cells were cultured and seeded on 96-well cell plate, and MTT assay was performed for detecting the viability of the cells after treatment with different concentrations of G2013. HT29 cells were grown and treated with low and high doses of G2013. After total RNA extraction and cDNA synthesis, quantitative real-time PCR were performed to assess the TLR2 and TLR4 mRNA synthesis. Results: We found that concentrations of ≤125 &amp;#181;g/ml of G2013 had no apparent cytotoxicity effect on the HEK293-TLR2 and -TLR4 cells. Our results indicated that after G2013 treatment (5 &amp;#181;g/ml) in HT29 cells, TLR2 and TLR4 mRNA expression decreased significantly compared with the untreated control group (p=0.02 and p=0.001 respectively). Conclusion: The results of this study revealed that G2013 can down regulate the TLR2 and TLR4 gene expression and exerts its inhibitory effect. Our findings are parallel to our previous finding which showed G2013 ability to down regulate the signaling pathway of TLRs. However, further studies are needed to identify the molecular mechanism of G2013.<p&gt;

scholarly journals Integrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nan Xiao ◽  
Meng Nie ◽  
Huanhuan Pang ◽  
Bohong Wang ◽  
Jieli Hu ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Rhesus Macaques ◽  
Fatal Outcome ◽  
Organ Injury ◽  
Cytokine Release ◽  
Serum Samples ◽  
Peripheral Blood Mononuclear

AbstractCytokine release syndrome (CRS) is a major cause of the multi-organ injury and fatal outcome induced by SARS-CoV-2 infection in severe COVID-19 patients. Metabolism can modulate the immune responses against infectious diseases, yet our understanding remains limited on how host metabolism correlates with inflammatory responses and affects cytokine release in COVID-19 patients. Here we perform both metabolomics and cytokine/chemokine profiling on serum samples from healthy controls, mild and severe COVID-19 patients, and delineate their global metabolic and immune response landscape. Correlation analyses show tight associations between metabolites and proinflammatory cytokines/chemokines, such as IL-6, M-CSF, IL-1α, IL-1β, and imply a potential regulatory crosstalk between arginine, tryptophan, purine metabolism and hyperinflammation. Importantly, we also demonstrate that targeting metabolism markedly modulates the proinflammatory cytokines release by peripheral blood mononuclear cells isolated from SARS-CoV-2-infected rhesus macaques ex vivo, hinting that exploiting metabolic alterations may be a potential strategy for treating fatal CRS in COVID-19.

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