scholarly journals AB0052 ROLE OF TRAINED IMMUNITY AND IMMUNOMETABOLISM IN THE PATHOGENESIS OF ERDHEIM-CHESTER DISEASE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1328.2-1328
Author(s):  
R. Biavasco ◽  
R. Molteni ◽  
D. Stefanoni ◽  
M. Ferrarini ◽  
E. Ferrero ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Inflammatory Cytokines ◽  
Mapk Pathway ◽  
Inflammatory Activation ◽  
Cell Energy ◽  
Erdheim Chester ◽  
Chester Disease ◽  
Pro Inflammatory Cytokines ◽  
Cell Energy Metabolism

Background:Erdheim-Chester disease (ECD) is a chronic inflammatory disease characterized by infiltration of bone and other tissues by foamy macrophages. These cells exhibit activating mutations along the MAPK pathway, most commonly BRAFV600E, and increased production of pro-inflammatory cytokines. Although this dual neoplastic-inflammatory nature of ECD has long fascinated scientists, the mechanistic link between these two features remains elusive. We hypothesized that Trained Immunity (TI), a pro-inflammatory cell program physiologically elicited in monocytes/macrophages upon activation of the MAPK pathway, might represent the missing link between oncogenic transformation and pro-inflammatory activation in ECD.Objectives:In this study, we aimed at determining the role of TI in the pathogenesis of ECD, and to evaluate the therapeutic potential of targeting this mechanism for the treatment of inflammation.Methods:We developed innovative models to study ECD pathogenesisin vitro(based on lentiviral transduction and ectopic expression of BRAFV600E in primary human monocytes), as well asex vivo(3D culture of ECD tissue biopsies in bioreactor). Functional and mechanistic features of TI, including typical changes in cell energy metabolism and epigenetics, were investigated by assessing I) cytokine and lactate production; II) mitochondrial respiration with Seahorse flux analyzer; III) glucose, glutamine and cholesterol metabolism with unbiased and targeted metabolomics analyses; IV) epigenetic changes with ChIP PCR; V) transcriptome changes with RNA sequencing.Results:Activation of the MAPK pathway induced by BRAFV600E in macrophages induces changes in the epigenetic and gene expression landscape, cell energy metabolism, and cytokine production characteristic of TI. In particular, changes in cell energy metabolism of macrophages are characterized by increased glycolysis, glutamine metabolism, and cholesterol synthesis. This metabolic rewiring is needed to sustain rampant, constitutive production of pro-inflammatory cytokines.Conclusion:A role emerges for TI in the pathogenesis and pro-inflammatory activation of ECD. However, maladaptive activation of this mechanism is likely common to the pathogenesis of other inflammatory and rheumatologic diseases. Since drugs targeting TI programs are already entering the clinical arena, the identification of this mechanism in the pathogenesis of inflammatory and rheumatologic conditions may promptly translate into novel, effective treatment options for affected patients.Disclosure of Interests:Riccardo Biavasco Employee of: Bluebird, Raffaella Molteni: None declared, Davide Stefanoni: None declared, Marina Ferrarini: None declared, Elisabetta Ferrero: None declared, Simone Cenci: None declared, Simone Cardaci: None declared, Alessandra Boletta: None declared, Laura Cassina: None declared, Gianfranco Di Stefano: None declared, Jorge Dominguez Andres: None declared, Claudio Doglioni: None declared, Travis Nemkov: None declared, Ivan Merelli: None declared, Angelo D’Alessandro: None declared, Eugenio Montini: None declared, Mihai Netea: None declared, Lorenzo Dagna: None declared, Giulio Cavalli Consultant of: SOBI, Pfizer, Sanofi, Novartis, Paid instructor for: SOBI, Novartis, Speakers bureau: SOBI, Novartis

FRI0479 REWIRED CELL ENERGY METABOLISM IN A NOVEL KRAS-MUTATED HISTIOCYTOSIS CHARACTERIZED BY SEVERE SYNOVITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 836.1-837
Author(s):  
G. Cavalli ◽  
G. De Luca ◽  
R. Biavasco ◽  
T. Nemkov ◽  
A. D’alessandro ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Effective Treatment ◽  
Inflammatory Cytokines ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Activating Mutations ◽  
Cell Energy ◽  
Erdheim Chester ◽  
Chester Disease ◽  
Pro Inflammatory Cytokines

Background:Histiocytoses are disorders characterized by tissue infiltration by macrophages, dendritic cells, or monocyte-derived cells. These diseases are classified in five groups based on histologic, clinical, and molecular features: Langerhans-related, cutaneous/mucocutaneous and malignant histiocytoses, Rosai-Dorfman disease, and hemophagocytic lymphohistiocytosis (1). Langerhans-related histiocytoses comprise Langerhans cell histiocytosis and Erdheim-Chester disease, both inflammatory myeloid-driven diseases characterized by clonal activating mutations along the MAPK or related pathways, most commonlyBRAFV600E, and by severe tissue and systemic inflammation (2). Here, we describe and characterize a novel, related histiocytosis chiefly manifested with severe synovial involvement.Objectives:Here, we describe a novel histiocytosis whose histologic and clinical picture (severe synovial involvement, systemic inflammation, skin lesions, and diabetes insipidus) differed from known histiocytic disorder. In addition, we performed molecular studies aimed at identifying causative activating mutations. Finally, by means of a dynamic 3D tissue culture system we characterized immune-metabolic mechanisms underlying disease pathogenesis and clinical response to treatment.Methods:The mutational status of oncogenes was determined with a mass spectrometry multiplexed genotyping approach (PentaPanel). Biospy samples were cultured in RCCSTM bioreactor (Synthecon) in the presence/absence of a MEK inhibitor (GSK1120212, 1nM), and then either processed for immunohistochemical analyses, or lysed for western blot analysis. Culture supernatants were collected for cytokine, chemokine and metabolome determination. The Bio-Plex Multiple-Cytokine Assay (Bio-Rad) and the Ella assay (ProteinSimple) were used to determine cytokine concentrations in supernatants and serum, respectively. Metabolomic studies were performed as described (3).Results:We identified a causative mutation in the proto-oncogeneKRAS(KRASG12D, not previously reported in related histiocytoses). In addition, 3D culture studies of patient’s biopsies revealed KRAS-driven signaling, phenotypic, and immunometabolic features. These included constitutive ERK and AKT phosphorylation, up-regulated glucose metabolism with glycolysis and TCA cycle activation, and deregulated release of pro-inflammatory cytokines IL-1β, IL-6 and TNFα. All these features reverted upon pharmacologic inhibition of the MAPK pathway. Characterization of this novel condition instructed effective treatment of the patient with the MEK inhibitor cobimetinib.Conclusion:Genetic, clinical, and histopathology features differentiate this condition from known histiocytic disorders. Mechanistically,KRASG12Dcauses constitutive activation of the MAPK pathway in macrophages, which results in maladaptive changes in cell energy metabolism sustaining rampant production of pro-inflammatory cytokines. Besides instructing effective treatment of this patient, these studies revealed metabolic rewiring as key to pathologic inflammatory activation of macrophages in human disease.References:[1]Emile JF, et al. Revised classification of histiocytoses. Blood. 2016[2]Cavalli G, et al. The multifaceted clinical presentations and manifestations of Erdheim-Chester disease. Ann Rheum Dis. 2013[3]Cavalli G, et al. Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration, and improves exercise tolerance. Proc Natl Acad Sci U S A. 2017Disclosure of Interests:Giulio Cavalli Consultant of: SOBI, Pfizer, Sanofi, Novartis, Paid instructor for: SOBI, Novartis, Speakers bureau: SOBI, Novartis, Giacomo De Luca Speakers bureau: SOBI, Novartis, Celgene, Pfizer, MSD, Riccardo Biavasco Employee of: Bluebird, Travis Nemkov: None declared, Angelo D’Alessandro: None declared, Rob Arts: None declared, Antonello Villa: None declared, Daniela Belloni: None declared, Greta Grassini: None declared, Giulia Cangi: None declared, Claudio Doglioni: None declared, Elisabetta Ferrero: None declared, Marina Ferrarini: None declared, Lorenzo Dagna: None declared

scholarly journals Deleted in breast cancer-1 (DBC-1) in the interface between metabolism, aging and cancer

2013 ◽  
Vol 33 (4) ◽  
Author(s):  
Eduardo Nunes Chini ◽  
Claudia C. S. Chini ◽  
Veronica Nin ◽  
Carlos Escande
Keyword(s):  
Breast Cancer ◽  
Molecular Structure ◽  
Energy Metabolism ◽  
Cancer Cell ◽  
Nuclear Protein ◽  
Cellular Metabolism ◽  
New Developments ◽  
Cell Energy ◽  
Cell Energy Metabolism

DBC1 (deleted in breast cancer-1) is a nuclear protein that regulates cellular metabolism. Since alteration in cellular metabolism have been proposed to be the emerging ‘hallmark’ of cancer, it is possible that DBC1 may be implicated in the regulation of cancer cell energy metabolism. However, at this point any role of DBC1 in cancer is only speculative. In this review, we will discuss the new developments in DBC1 research, its molecular structure, regulatory roles and implication in metabolism, aging and cancer.

The role of inflammatory cytokines in the pathogenesis of premature labor in multiple pregnancy as a result of ART

2016 ◽  
pp. 73-76
Author(s):  
B.M. Ventskivskiy ◽  
◽  
I.V. Poladych ◽  
S.O. Avramenko ◽  
◽  
...  
Keyword(s):  
Assisted Reproductive Technology ◽  
Inflammatory Cytokines ◽  
Proinflammatory Cytokines ◽  
Local Level ◽  
Multiple Pregnancy ◽  
Reproductive Technology ◽  
System Level ◽  
Premature Labor ◽  
Pro Inflammatory Cytokines

In recent years there has been an increase in the frequency of multiple pregnancies and the associated perinatal losses. It is a result of multiple pregnancy in ART refers to a high-risk gestation, at which premature births occur in 2 times more often than in singleton pregnancies. The objective: to determine the role of pro-inflammatory cytokines in the pathogenesis of premature labor in multiple pregnancy, as a result of assisted reproductive technology. Patients and methods. to determine the pro-inflammatory cytokines that all pregnant with bagtopliddyam held immunosorbent assay, defined concentrations of interleukin (IL) in serum and cervical mucus. Results. The analysis of the levels of pro-inflammatory cytokines (IL-1, IL-8) in the test environment, found high concentrations in the surveyed women with multiple pregnancy, due to the use of ART, compared with spontaneous multiple and singleton pregnancy. Increased concentration of proinflammatory cytokines in patients with multiple pregnancy by ART is associated with their synthesis at the system level, it stimulated foci of inflammation in the female genitals and extragenital localization. This correlates with the clinical data and statistical analysis, patients with multiple pregnancy as a result of ART had weighed infectious-inflammatory history. Conclusion. The study showed that elevated levels of proinflammatory cytokines in the systemic and local level in patients with multiple pregnancy due to ART, typical for women with miscarriage, because of the physiological course of pregnancy characterized by the predominance of anti-inflammatory cytokines that prevent rejection of the fetus as a foreign factor. Based on the data obtained proved the role of systemic inflammatory factors in the genesis of preterm labor in women with a multiple pregnancy, as a result of assisted reproductive technology. Key words: multiple pregnancy, assisted reproductive technology, premature birth, interleukine-1, interleukine-8.

scholarly journals Evaluation of the role of CD47 in sickle cell disease

2021 ◽  
Author(s):  
Basmah Eldakhakhny ◽  
Hadeel Al Sadoun ◽  
Nehal Bin Taleb ◽  
Dunya Ahmed Nori ◽  
Nawal Helmi ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Annexin V ◽  
Cell Disease ◽  
Phagocytic Cells ◽  
Surface Marker Expression ◽  
Inflammatory Phenotype ◽  
Healthy Control ◽  
Cell Surface Marker Expression ◽  
Pro Inflammatory Cytokines

AbstractCD47 is a self-marker expressed on the surface of RBCs and work to prevent the process of phagocytosis. SIRPα is the ligand of CD47 that is expressed on the surface of phagocytic cells, such as macrophages, to control the removal of dead/diseased cells. This study aimed to examine the expression of CD47 on RBCs and SIRPα on PBMC cells in SCD patients and the apoptosis of SCD RBCs. We also measured the levels of pro-inflammatory cytokines in SCD patients and correlated it with the cell surface marker expression of CD47 and SIRPα to determine whether CD47 and/or SIRPα played a role in promoting the pro-inflammatory phenotype in SCD. Whole blood samples were drawn from SCD patients, and healthy control and PBMC were isolated and stained with SIRPα. Change in CD47, apoptosis by annexin V marker, and pro-inflammatory cytokines were measured and correlation among these variants was determined. The expression of CD47 was significantly decreased and the apoptosis was increased in RBCs of SCD patients. A higher level of pro-inflammatory cytokines, IL-6 and IL-1β, was found in SCD patients and IL-1β was found to be inversely correlated with SIRPα expression. Our data showed that CD47 of erythrocytes of SCD samples is reduced and that the apoptosis is increased in those patients. Based on the role of CD47, we suggest that increased apoptosis in SCD would be impacted by the reduced level of CD47. An inverse relationship was found between SIRPα marker on PBMC and the increased production of pro-inflammatory cytokines in SCD.

scholarly journals AB0827 SERUM NESPHATIN-1 IN PATHOGENESIS RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1437.2-1438
Author(s):  
T. Kvlividze ◽  
V. Polyakov ◽  
В. Zavodovsky ◽  
Y. Polyakova ◽  
L. Seewordova ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Blood Serum ◽  
Inflammatory Cytokines ◽  
Inflammatory Markers ◽  
Healthy People ◽  
Healthy Individuals ◽  
Markers Of Inflammation ◽  
High Level ◽  
Pro Inflammatory Cytokines

Background:Interest in highly specialized tissue cytokines contributed to the discovery of new biologically active molecules. Nesfatin-1 (NF) - discovered in 2006 as an anorexigenic factor. NF-1 is believed to be involved in the regulation of energy homeostasis by regulating appetite and water intake. The role of NF-1 in the pathogenesis of inflammatory diseases is poorly understood. Recently, studies have found a relationship between an increased level of NF-1 and inflammatory markers in various pathologies.Objectives:Study of the level of nesfatin-1 in the blood serum of healthy people, determination of the correlation between the level of NF-1 with the severity of clinical symptoms and classic markers of inflammation in patients with RA.Methods:120 persons were examined: 90 patients with RA and 30 healthy people. All patients underwent a complete clinical and laboratory examination. Plasma NF-1 levels were determined using commercial test systems (RaiBiotech, cat # EIA-NESF) according to the manufacturer’s instructions. Patients with various forms of RA were comparable in age to the group of healthy individuals. Statistical processing of clinical examination data was carried out using the “STATISTICA 10.0 for Windows” software package. Quantitative data were processed statistically using the parametric Student’s t-test, qualitative data using the non-parametric chi-square test. The significance of differences between groups was determined using analysis of variance. The results were considered statistically significant at p <0.05.Results:The average level of NF-1 in blood serum in healthy individuals was 31.79 ± 3.21 ng / ml (M ± σ). The level of normal NF-1 values in healthy individuals, defined as M ± 2σ, ranged from 25.3 to 37.83 ng / ml. There was no significant difference in the levels of circulating NF-1 and BMI in healthy individuals and patients with RA (p> 0.05). The inverse relationship of a lower level of NF-1 with an increase in BMI was not significant.Group 1 (66 patients with RA) with increased serum NF-1 levels (> 37.83 ng / ml), and group 2 (44 patients) with normal values (<37.83 ng / ml). A high level of NF-1 was characteristic for patients with high activity according to DAS28, RF seropositive, ACCP-positive, with extra-articular manifestations, who had been ill for 10 years or more. A reliable relationship between the level of NF-1 in the blood serum and laboratory parameters of RA activity - ESR, CRP, was shown, and secondary synovitis was more common. Our data show a direct correlation between the NF-1 level of the pro-inflammatory markers of RA.Conclusion:The positive correlation between the level of NF-1 and classical markers of inflammation, such as CRP and ESR, confirms the involvement of NF-1 in the pathophysiology of inflammation in RA. This is also evidenced by the correlation of a high level of NF-1 in the blood serum with a more severe clinical picture of RA. It is known that NF-1 can promote the release of pro-inflammatory cytokines such as interleukin-8 (IL-8), interleukin-6 (IL-6), and macrophage inflammatory protein-1a (MIP-1a) in the chondrocytes of RA patients.It is necessary to further study the role of NF-1 in the pathogenesis of systemic inflammatory reactions and the possibility of targeting pro-inflammatory cytokines, the possibility of regulating the level of NF-1 by drugs.References:[1]Kvlividze T.Z., Zavodovsky B.V., Akhverdyan Yu.R. Kvlividze T.Z., Zavodovsky B.V., Akhverdyan Yu.R., Polyakova Yu.V., Sivordova L.E., Yakovlev A.T., Zborovskaya I.A. Serum nesfatin -1 as a marker of systemic inflammation in rheumatoid arthritis. Klinicheskaya Laboratornaya Diagnostika (Russian Clinical Laboratory Diagnostics). 2019; 64 (1): 53-56 (in Russ.).Disclosure of Interests:None declared

scholarly journals Geongangbuja-Tang Decoction and Its Active Ingredient, Aconiti Lateralis Radix Preparata, Exerts Inhibitory Effects on Heat Stress-Induced Inflammation in Mice

2021 ◽  
Vol 11 (15) ◽  
pp. 6902
Author(s):  
Eugene Huh ◽  
Wonil Lee ◽  
Yujin Choi ◽  
Tae Hee Lee ◽  
Myung Sook Oh
Keyword(s):  
Heat Stress ◽  
Energy Metabolism ◽  
Inflammatory Cytokines ◽  
Hpa Axis ◽  
Inflammatory Responses ◽  
Heat Exposure ◽  
Mouse Serum ◽  
Dependent Manner ◽  
Active Constituent ◽  
Pro Inflammatory Cytokines

Heat stress induces the hypothalamic-pituitary-adrenal (HPA) axis activation, influences biological responses, and reduces energy metabolism. Geongangbuja-tang (GBT) and its components, Zingiberis Rhizoma (ZOR) and Aconiti Lateralis Radix Preparata (ALRP) have been used to induce energy metabolism; however, the effects of GBT and its ingredients on heat-induced inflammatory responses have not yet been investigated. In this study, we performed an open-field test to evaluate locomotor activity in mice. To assess the effects of GBT and its ingredients on inflammation, the protein levels of c-fos, pro-inflammatory cytokines, and cortisol were measured in the mouse hypothalamus and serum. The results showed that GBT alleviated locomotive activity and reduced c-fos levels in a dose-dependent manner under the heat exposure. After investigating the active constituent of GBT, we found that compared to GBT and ZOR, ALRP significantly suppressed c-fos expression under heat stress. Subsequently, ALRP decreased the expression of pro-inflammatory cytokines, such as interleukin-9 and -13 and prostaglandin, under the heat stress in the mouse hypothalamus. Moreover, treatment with ALRP inhibited cortisol secretion in the mouse serum following heat exposure. These results indicate that GBT and its active component, ALRP, could be the thermoregulatory agents that regulate the HPA axis.

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