scholarly journals Blood Immunoproteasome Activity Is Regulated by Sex, Age and in Chronic Inflammatory Diseases: A First Population-Based Study

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3336
Author(s):  
Ilona Elisabeth Kammerl ◽  
Claudia Flexeder ◽  
Stefan Karrasch ◽  
Barbara Thorand ◽  
Margit Heier ◽  
...  
Keyword(s):  
Active Sites ◽  
Mononuclear Cells ◽  
Inflammatory Diseases ◽  
Population Based ◽  
Chronic Inflammatory Disease ◽  
Chronic Obstructive ◽  
Peripheral Blood Mononuclear ◽  
Chronic Inflammatory Diseases ◽  
Study Participants ◽  
The Impact

Dysfunction of the immunoproteasome has been implicated in cardiovascular and pulmonary diseases. Its potential as a biomarker for predicting disease stages, however, has not been investigated so far and population-based analyses on the impact of sex and age are missing. We here analyzed the activity of all six catalytic sites of the proteasome in isolated peripheral blood mononuclear cells obtained from 873 study participants of the KORA FF4 study using activity-based probes. The activity of the immuno- and standard proteasome correlated clearly with elevated leukocyte counts of study participants. Unexpectedly, we observed a strong sex dimorphism for proteasome activity with significantly lower immunoproteasome activity in women. In aging, almost all catalytic activities of the proteasome were activated in aged women while maintained upon aging in men. We also noted distinct sex-related activation patterns of standard and immunoproteasome active sites in chronic inflammatory diseases such as diabetes, cardiovascular diseases, asthma, or chronic obstructive pulmonary disease as determined by multiple linear regression modeling. Our data thus provides a conceptual framework for future analysis of immunoproteasome function as a bio-marker for chronic inflammatory disease development and progression.

Level of toll-like receptor agonist exposure differentially determines chemokine production in humansThis article is one of a selection of papers published in the Special Issue on Recent Advances in Asthma Research.

2007 ◽  
Vol 85 (7) ◽  
pp. 739-746 ◽  
Author(s):  
Yuriy Lissitsyn ◽  
Allan B. Becker ◽  
Anita L. Kozyrskyj ◽  
Kent T. HayGlass
Keyword(s):  
Mononuclear Cells ◽  
Inflammatory Diseases ◽  
Healthy Children ◽  
Toll Like Receptor ◽  
Peripheral Blood Mononuclear ◽  
Chemokine Production ◽  
Cytokines And Chemokines ◽  
Immune Capacity ◽  
The Impact

Toll-like receptor (TLR) agonists, ubiquitously present in the environment, are key players in activating synthesis of cytokines and chemokines that control normal and pathophysiological processes, including multiple inflammatory diseases. TLR2 and TLR4 respond to bacterial cell wall products. We examined the impact of TLR activation on human immune capacity using stimuli ranging from the low levels seen in most environments to the high concentrations widely used for in vitro studies. Peripheral blood mononuclear cells from 117 healthy children were activated with lipopolysaccharide (TLR4 ligand) or peptidoglycan (TLR2 ligand) over a million-fold range of concentrations. Resulting interleukin-6, CCL2, and CCL22 production were quantified by ELISA. The intensity of cytokine production elicited was linearly related to the intensity of the stimulus up to maximal responses. In marked contrast, chemokine production was not linearly related to agonist concentration. Responses rose with increasing stimulation, and then were markedly reduced (40%–100%, p < 0.0001) in response to the high levels of TLR stimulation most commonly cited. Thus, the levels of TLR4 and TLR2 agonists typically used for in vitro interrogation of immune capacity yield results clearly distinct from those obtained using commonly occurring environmental levels of TLR ligands. These findings demonstrate the importance of utilizing TLR ligands at concentrations more closely mimicking environmental levels when assessing immune capacity.

Meta-inflammation in monocytes of patients with Acute Coronary Syndrome

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
F Canonico ◽  
R Vinci ◽  
D Pedicino ◽  
E Pisano ◽  
P Ciampi ◽  
...  
Keyword(s):  
Protein Identification ◽  
Mononuclear Cells ◽  
Inflammatory Diseases ◽  
Glycolytic Enzyme ◽  
Potential Interaction ◽  
Limiting Factor ◽  
Funding Source ◽  
Peripheral Blood Mononuclear ◽  
Coronary Syndrome ◽  
Key Enzyme

Abstract Background Several studies suggest that an alteration of monocyte metabolism might be implicated in inflammatory diseases. Enhanced glycolysis might be a hallmark of pro-inflammatory monocyte subsets. Improved glycolysis enables the immune cells to generate sufficient ATP and biosynthetic intermediates to carry out its particular effector functions. For macrophages this includes phagocytosis and inflammatory cytokine production. Pyruvate Kinase isozyme M2 (PKM-2) catalyzes the final step of glycolysis producing pyruvate and ATP. Latest studies have shown that a member of Jumonji family (JMJD8) acts as a positive regulator in TNF-induced NF-kB signaling leading to pro-inflammatory pathways in macrophages and is involved in angiogenesis and cellular metabolism through interacting with PKM-2 in endothelial cells. Purpose The aims of the study are to assess the expression of the glycolytic key enzyme PKM-2 in CD14+ monocytes obtained from patients with non-ST-elevation myocardial infarction (NSTEMI) or with stable angina (SA). Furthermore, the expression of JMJD8 was evaluated. Methods 30 patients with NSTEMI and 30 patients with SA were enrolled. Peripheral blood mononuclear cells were obtained from whole blood samples. For cytoplasmatic protein identification, cells were fixed and permeabilized and then incubated with fluorochrome-conjugated mAbs anti-CD14, anti-PKM-2 and anti-JMJD8. For analysis we used Two-tailed Mann-Whitney non parametric Comparison test. Results CD14+ monocytes from NSTEMI patients showed reduced expression of the key glycolytic enzyme PKM-2 as compared to CD14+ monocytes from SA patients (p=0.02) (Figure 1). JMJD8 expression in NSTEMI patients is increased compared with SA patients (p=0.02) (Figure 2). Conclusion This study introduces a role for immune-metabolism in the immunity dysregulation described in ACS patients and provides novel insights into the mechanisms responsible for coronary instability. Taking their potential interaction into account, our data suggest that in acute setting glycolysis key enzyme PKM2 expression is downregulated. Besides, JMJD8 protein levels increase in NSTEMI patients acting as potential limiting factor of PKM2 function. Moreover, our data propose the potential roles of immune-metabolism to detect novel therapeutic targets, associated with an accurate patient stratification based on immune-metabolic profiles, for prevention and treatment of atherosclerosis, in the perspective of a personalized medicine approach. Funding Acknowledgement Type of funding source: Private hospital(s). Main funding source(s): Fondazione Policlinico A. Gemelli

scholarly journals Regulation of CTLA-4 and PD-L1 Expression in Relapsing-Remitting Multiple Sclerosis Patients after Treatment with Fingolimod, IFNβ-1α, Glatiramer Acetate, and Dimethyl Fumarate Drugs

2021 ◽  
Vol 11 (8) ◽  
pp. 721
Author(s):  
Afshin Derakhshani ◽  
Zahra Asadzadeh ◽  
Hossein Safarpour ◽  
Patrizia Leone ◽  
Mahdi Abdoli Shadbad ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mononuclear Cells ◽  
Demyelinating Disease ◽  
Immune Checkpoints ◽  
Peripheral Blood Mononuclear ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Multiple Sclerosis Patients ◽  
Relapsing Remitting Multiple Sclerosis ◽  
The Impact

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) that is characterized by inflammation which typically results in significant impairment in most patients. Immune checkpoints act as co-stimulatory and co-inhibitory molecules and play a fundamental role in keeping the equilibrium of the immune system. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and Programmed death-ligand 1 (PD-L1), as inhibitory immune checkpoints, participate in terminating the development of numerous autoimmune diseases, including MS. We assessed the CTLA-4 and PD-L1 gene expression in the different cell types of peripheral blood mononuclear cells of MS patients using single-cell RNA-seq data. Additionally, this study outlines how CTLA-4 and PD-L1 expression was altered in the PBMC samples of relapsing-remitting multiple sclerosis (RRMS) patients compared to the healthy group. Finally, it investigates the impact of various MS-related treatments in the CTLA-4 and PD-L1 expression to restrain autoreactive T cells and stop the development of MS autoimmunity.

scholarly journals The immunoregulatory function of peripheral blood CD71+ erythroid cells in systemic-onset juvenile idiopathic arthritis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hikaru Kanemasa ◽  
Masataka Ishimura ◽  
Katsuhide Eguchi ◽  
Tamami Tanaka ◽  
Etsuro Nanishi ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Inflammatory Diseases ◽  
Active Phase ◽  
Serum Levels ◽  
Cell Interaction ◽  
Erythroid Cells ◽  
Peripheral Blood Mononuclear ◽  
Systemic Onset

AbstractCD71+ erythroid cells (CECs) are recognized to have an immunoregulatory function via direct cell–cell interaction and soluble mediators. Circulating CECs appear in newborns or patients with hemolytic and cardiopulmonary disorders. To assess the biological role of CECs in systemic inflammation, we studied the gene expression and function in systemic-onset juvenile idiopathic arthritis (SoJIA). Peripheral blood mononuclear cells of SoJIA patients expressed upregulated erythropoiesis-related genes. It represented the largest expansion of CECs during active phase SoJIA among other inflammatory diseases. Despite the opposing roles of erythropoietin and hepcidin in erythropoiesis, both serum levels were in concert with the amounts of SoJIA-driven CECs. Circulating CECs counts in inflammatory diseases were positively correlated with the levels of C-reactive protein, IL-6, IL-18, or soluble TNF receptors. Co-culture with active SoJIA-driven CECs suppressed secretions of IL-1β, IL-6, and IL-8 from healthy donor monocytes. The top upregulated gene in SoJIA-driven CECs was ARG2 compared with CECs from cord blood controls, although cytokine production from monocytes was suppressed by co-culture, even with an arginase inhibitor. CECs are driven to the periphery during the acute phase of SoJIA at higher levels than other inflammatory diseases. Circulating CECs may control excessive inflammation via the immunoregulatory pathways, partly involving arginase-2.

Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome

Blood ◽  
2009 ◽  
Vol 114 (16) ◽  
pp. 3439-3447 ◽  
Author(s):  
Francesco Parlati ◽  
Susan J. Lee ◽  
Monette Aujay ◽  
Erika Suzuki ◽  
Konstantin Levitsky ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Mononuclear Cells ◽  
Proteasome Inhibitors ◽  
Selective Inhibition ◽  
Tumor Cell Death ◽  
Clinical Safety ◽  
Peripheral Blood Mononuclear ◽  
Non Hodgkin Lymphoma ◽  
Proteasome Subunits ◽  
The Impact

Abstract Carfilzomib is a proteasome inhibitor in clinical development that primarily targets the chymotrypsin-like (CT-L) subunits in both the constitutive proteasome (c20S) and the immunoproteasome (i20S). To investigate the impact of inhibiting the CT-L activity with carfilzomib, we set out to quantitate the levels of CT-L subunits β5 from the c20S and LMP7 from the i20S in normal and malignant hematopoietic cells. We found that the i20S is a major form of the proteasome expressed in cells of hematopoietic origin, including multiple myeloma (MM) CD138+ tumor cells. Although specific inhibition of either LMP7 or β5 alone was insufficient to produce an antitumor response, inhibition of all proteasome subunits was cytotoxic to both hematologic tumor cells and peripheral blood mononuclear cells. However, selective inhibition of both β5 and LMP7 was sufficient to induce an antitumor effect in MM, non-Hodgkin lymphoma, and leukemia cells while minimizing the toxicity toward nontransformed cells. In MM tumor cells, CT-L inhibition alone was sufficient to induce proapoptotic sequelae, including proteasome substrate accumulation, Noxa and caspase 3/7 induction, and phospho-eIF2α suppression. These data support a hypothesis that hematologic tumor cells are uniquely sensitive to CT-L inhibition and provide a mechanistic understanding of the clinical safety profile and antitumor activity of proteasome inhibitors.

scholarly journals Integrated microRNA and mRNA Gene Expression in Peripheral Blood Mononuclear Cells in Response to Acute Psychosocial Stress: A Repeated-Measures Within-Subject Pilot Study

2021 ◽  
Author(s):  
Magdalena Maria Jurkiewicz ◽  
Anett Müller-Alcazar ◽  
Dirk Moser ◽  
Indralatha Jayatilaka ◽  
Anatoly Mikhailik ◽  
...  
Keyword(s):  
Gene Expression ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Psychosocial Stress ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Time Points ◽  
Blood Mononuclear Cells ◽  
The Impact ◽  
Acute Psychosocial Stress

Abstract Objective: The impact of psychosocial stress on a variety of negative health outcomes is well documented, with current research efforts directed at possible mechanisms. Here, we focused on a potential mechanism involving differential expression of mRNA and microRNA in response to acute psychosocial stress. We utilized a validated behavioral paradigm, the Trier Social Stress Test (TSST), to induce acute psychosocial stress in a cohort of volunteers. Stress reactivity was assessed repeatedly during the TSST using saliva samples that were analyzed for levels of cortisol. Peripheral blood mononuclear cells were extracted from blood drawn at baseline and at two time points following the stress paradigm. Total RNA was extracted, and mRNA and microRNA microarrays were utilized to assess within-subject changes in gene expression between baseline and the two post-stressor time points. Results: For microarray gene expression analysis, we focused on 12 participants who showed a robust cortisol response to the task, as an indicator of robust HPA-axis activation. We discovered a set of mRNAs and miRNAs that exhibited dynamic expression change in response to the TSST in peripheral blood mononuclear cells, further characterizing the link between psychosocial stress and cellular response mechanisms.

scholarly journals Gene-regulatory network study of rheumatoid arthritis in single-cell chromatin landscapes of peripheral blood mononuclear cells

2021 ◽  
Author(s):  
Cantong Zhang ◽  
Xiaoping Hong ◽  
Haiyan Yu ◽  
Hongwei Wu ◽  
Huixuan Xu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Single Cell ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
High Resolution Map ◽  
The Impact ◽  
Accessible Chromatin

Abstract Rheumatoid arthritis is a chronic autoinflammatory disease with an elusive etiology. Assays for transposase-accessible chromatin with single-cell sequencing (scATAC-seq) contribute to the progress in epigenetic studies. However, the impact of epigenetic technology on autoimmune diseases has not been objectively analyzed. Therefore, scATAC-seq was performed to generate a high-resolution map of accessible loci in peripheral blood mononuclear cells (PBMCs) of RA patients at the single-cell level. The purpose of our project was to discover the transcription factors (TFs) that were involved in the pathogenesis of RA at single-cell resolution. In our research, we obtained 22 accessible chromatin patterns. Then, 10 key TFs were involved in the RA pathogenesis by regulating the activity of MAP kinase. Consequently, two genes (PTPRC, SPAG9) regulated by 10 key TFs were found that may be associated with RA disease pathogenesis and these TFs were obviously enriched in RA patients (p<0.05, FC>1.2). With further qPCR validation on PTPRC and SPAG9 in monocytes, we found differential expression of these two genes, which were regulated by eight TFs (ZNF384, HNF1B, DMRTA2, MEF2A, NFE2L1, CREB3L4 (var. 2), FOSL2::JUNB (var. 2), MEF2B). What is more, the eight TFs showed highly accessible binding sites in RA patients. These findings demonstrate the value of using scATAC-seq to reveal transcriptional regulatory variation in RA-derived PBMCs, providing insights on therapy from an epigenetic perspective.

scholarly journals Glycemic Control & Morbidity in Diabetics With COPD Exacerbation. A Retrospective Study

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A414-A414
Author(s):  
Ibrahim Naoum ◽  
Abedalghani Abedalhalim ◽  
Amir Aker ◽  
Luai Khalaili ◽  
Sameer Kassem
Keyword(s):  
Mechanical Ventilation ◽  
Glycemic Control ◽  
Population Based ◽  
Chronic Obstructive ◽  
P Value ◽  
Diabetic Patients ◽  
Copd Exacerbation ◽  
Copd Exacerbations ◽  
Significant Difference ◽  
The Impact

Abstract Background: Diabetes and chronic obstructive pulmonary disease (COPD) are widely prevalent and comorbidity with these diseases is quite common. However, there is limited data on the interrelation between glycemic control and COPD exacerbations in diabetic patients. Objective: To study the association between pre-admission glycemic control and COPD clinical outcomes including mortality, risk of hospital readmission and the need for mechanical ventilation. Methods: A retrospective population-based cohort study. We screened for patients with both diabetes and COPD exacerbation aged 35 years and above. Pre-admission glycemic control was defined by the last HBA1C level prior to hospitalization. Patients with HBA1C&gt;8% were defined as uncontrolled. We evaluated the difference between controlled and uncontrolled groups in the rates of mortality, readmission and the need for mechanical ventilation. We examined demographic and clinical parameters that might reflect COPD severity including: COPD medication use, blood hemoglobin, platelets, LDH and CRP levels. Results: 513 hospitalizations with diabetes and COPD were screened. 222 hospitalization were excluded either due to unestablished diagnosis of COPD or due to lack of HBA1C test in the preceding year. Of the remaining 291, 208 admissions were with controlled diabetes whereas 83 were uncontrolled. Although not statistically significant, the rate of re-hospitalization was higher in the uncontrolled group (OR 1.99, CI 0.99–4.0, p-value 0.051). There was no statistically significant difference in mortality (OR 1.6, CI 0.73–3.5, p-value 0.243). The use of oxygen and the need for noninvasive mechanical ventilation were significantly higher in the uncontrolled group (67.5% vs. 52.4%, p-value 0.019, 33.7% versus 18.8%, p-value 0.006, respectively). There was no significant difference in possible confounders tested between the groups. Conclusion: Uncontrolled diabetes may adversely affect patients with COPD exacerbation. Larger studies are needed to conclusively determine the impact of glycemic control on COPD morbidity and mortality.

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