scholarly journals Metformin Suppresses Monocyte Inflammation and Metabolic Reprogramming by SARS-CoV-2 Spike Protein

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 332-332
Author(s):  
Theodore Cory ◽  
Russell Emmons ◽  
Johnathan Yarbro ◽  
Brandt Pence
Keyword(s):  
Older Adults ◽  
Inflammatory Cytokines ◽  
Cytokine Production ◽  
Immune Cell ◽  
Mitochondrial Metabolism ◽  
Metabolic Reprogramming ◽  
Spike Protein ◽  
Glycolytic Metabolism ◽  
Protein Subunit ◽  
Necrosis Factor Alpha

Abstract COVID-19 disproportionately affects older adults, and a hallmark of the disease is a hyperinflammatory state that is associated with severity. Various anti-inflammatory therapeutics have shown mixed efficacy in treating COVID-19, and the mechanisms by which hyperinflammation occurs are not well understood. Previous research indicated that monocytes, a key innate immune cell, undergo metabolic reprogramming and produce inflammatory cytokines when stimulated with SARS-CoV-2. We hypothesized that binding by the viral spike protein mediates this effect, and that drugs which regulate immunometabolism – including the geroprotector drug metformin – could inhibit the inflammatory response in monocytes. Monocytes stimulated with recombinant SARS-CoV-2 spike protein subunit 1 showed a dose-dependent increase in glycolytic metabolism that was associated with production of pro-inflammatory cytokines including interleukin-6 and tumor necrosis factor-alpha. This response was dependent on hypoxia-inducible factor-1alpha, as chetomin inhibited glycolysis and cytokine production. Inhibition of glycolytic metabolism by 2-deoxyglucose (2-DG) or glucose deprivation also inhibited the glycolytic response, and 2-DG strongly suppressed cytokine production. Glucose-deprived monocytes rescued cytokine production by upregulating oxidative phosphorylation, an effect which was not present in 2-DG-treated monocytes due to the known effect of 2-DG on suppressing mitochondrial metabolism. Finally, pre-treatment of monocytes with metformin strongly suppressed spike protein-mediated cytokine production in monocytes, and abrogated glycolytic and mitochondrial metabolism. In summary, the SARS-CoV-2 spike protein induces a pro-inflammatory immunometabolic response in monocytes that can be suppressed by treatments that interfere with glycolytic activation, including metformin. This has potential implications for the treatment of hyperinflammation during COVID-19, which disproportionately affects older adults.

scholarly journals Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 and Spike Protein Subunit 1

2021 ◽  
Author(s):  
Theodore J. Cory ◽  
Russell S. Emmons ◽  
Johnathan R. Yarbro ◽  
Kierstin L. Davis ◽  
Brandt D. Pence
Keyword(s):  
Inflammatory Cytokines ◽  
Cytokine Production ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Mitochondrial Metabolism ◽  
Metabolic Reprogramming ◽  
Spike Protein ◽  
Glycolytic Metabolism ◽  
Protein Subunit ◽  
Pre Treatment

A hallmark of COVID-19 is a hyperinflammatory state that is associated with severity. Various anti-inflammatory therapeutics have shown mixed efficacy in treating COVID-19, and the mechanisms by which hyperinflammation occurs are not well understood. Previous research indicated that monocytes, a key innate immune cell, undergo metabolic reprogramming and produce inflammatory cytokines when stimulated with SARS-CoV-2. We hypothesized that binding by the viral spike protein mediates this effect, and that drugs which regulate immunometabolism could inhibit the inflammatory response in monocytes. Monocytes stimulated with recombinant SARS-CoV-2 spike protein subunit 1 showed a dose-dependent increase in glycolytic metabolism that was associated with production of pro-inflammatory cytokines including interleukin-6 and tumor necrosis factor-α. This response was dependent on hypoxia-inducible factor-1α, as chetomin inhibited glycolysis and cytokine production. Inhibition of glycolytic metabolism by 2-deoxyglucose (2-DG) or glucose deprivation also inhibited the glycolytic response, and 2-DG strongly suppressed cytokine production. Glucose-deprived monocytes rescued cytokine production by upregulating oxidative phosphorylation, an effect which was not present in 2-DG-treated monocytes due to the known effect of 2-DG on suppressing mitochondrial metabolism. Finally, pre-treatment of monocytes with metformin strongly suppressed spike protein-mediated cytokine production in monocytes, and abrogated glycolytic and mitochondrial metabolism. Likewise, metformin pre-treatment blocked cytokine induction by SARS-CoV-2 strain WA1/2020 in direct infection experiments in monocytes. In summary, the SARS-CoV-2 spike protein induces a pro-inflammatory immunometabolic response in monocytes that can be suppressed by metformin, and metformin likewise suppresses inflammatory responses to live SARS-CoV-2. This has potential implications for the treatment of hyperinflammation during COVID-19.

scholarly journals Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 Spike Protein Subunit 1

2021 ◽  
Vol 12 ◽  
Author(s):  
Theodore J. Cory ◽  
Russell S. Emmons ◽  
Johnathan R. Yarbro ◽  
Kierstin L. Davis ◽  
Brandt D. Pence
Keyword(s):  
Inflammatory Cytokines ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Hypoxia Inducible Factor ◽  
Glucose Deprivation ◽  
Metabolic Reprogramming ◽  
Spike Protein ◽  
Glycolytic Metabolism ◽  
Protein Subunit ◽  
Pre Treatment

A hallmark of COVID-19 is a hyperinflammatory state associated with severity. Monocytes undergo metabolic reprogramming and produce inflammatory cytokines when stimulated with SARS-CoV-2. We hypothesized that binding by the viral spike protein mediates this effect, and that drugs which regulate immunometabolism could inhibit the inflammatory response. Monocytes stimulated with recombinant SARS-CoV-2 spike protein subunit 1 showed a dose-dependent increase in glycolytic metabolism associated with production of pro-inflammatory cytokines. This response was dependent on hypoxia-inducible factor-1α, as chetomin inhibited glycolysis and cytokine production. Inhibition of glycolytic metabolism by 2-deoxyglucose (2-DG) or glucose deprivation also inhibited the glycolytic response, and 2-DG strongly suppressed cytokine production. Glucose-deprived monocytes rescued cytokine production by upregulating oxidative phosphorylation, an effect which was not present in 2-DG-treated monocytes due to the known effect of 2-DG on suppressing mitochondrial metabolism. Finally, pre-treatment of monocytes with metformin strongly suppressed spike protein-mediated cytokine production and metabolic reprogramming. Likewise, metformin pre-treatment blocked cytokine induction by SARS-CoV-2 strain WA1/2020 in direct infection experiments. In summary, the SARS-CoV-2 spike protein induces a pro-inflammatory immunometabolic response in monocytes that can be suppressed by metformin, and metformin likewise suppresses inflammatory responses to live SARS-CoV-2. This has potential implications for the treatment of hyperinflammation during COVID-19.

Association of Erythropoietin and Inflammation with the Incidence of Anemia in Older Persons.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1292-1292
Author(s):  
Marion Faulhaber ◽  
Kushang V. Patel ◽  
Stefania Bandinelli ◽  
Dan L. Longo ◽  
Luigi Ferrucci ◽  
...  
Keyword(s):  
Older Adults ◽  
Inflammatory Cytokines ◽  
Inflammatory Markers ◽  
Older Persons ◽  
Synergistic Effects ◽  
Necrosis Factor Alpha ◽  
Increased Risk ◽  
Inflammatory State ◽  
Inflammation Score ◽  
Pro Inflammatory Cytokines

Abstract Background: Anemia is common in persons 65 years and older with a prevalance of 10–11%. It is associated with increased mortality, hospitalization and decreased quality of life. Recent findings suggest that age-associated dysregulation of pro-inflammatory cytokines may negatively impact hematopoiesis, and erythropoietin (EPO) levels rise significantly with increasing age. Objectives: To determine whether high EPO levels and pro-inflammatory cytokines increase the risk for anemia onset in older persons. Methods: We investigated the effect of EPO levels and pro-inflammatory markers (Interleukin-6, Interleukin-1beta, CRP and Tumor Necrosis Factor-alpha) on the incidence of anemia in the InCHIANTI study, a longitudinal cohort of older adults. A sample of 1155 persons aged 65 years and older were randomly selected from the Chianti area, Italy. Baseline data were collected in 1998–2000 and participants were followed up 3 years later. Anemia was defined according to the WHO criteria as hemoglobin (Hb) <13 g/dL in men and <12 g/dL in women. A total of 679 participants were non-anemic at baseline and available for a longitudinal analysis. To assess the inflammatory state, an inflammation score was calculated by summing the total number of inflammatory markers in the upper tertile (range 0–4). Results: The 3-year incidence of anemia was 9%. High levels of circulating EPO were significantly associated with an increased risk of developing anemia. Model 1 of Table 1 shows that participants in the highest tertile of EPO were 3 times more likely to develop anemia compared to those in the lowest tertile of EPO (p for trend=.002). Higher levels of inflammation were significantly associated with the onset of anemia. The incidence of anemia was 4 times higher in those with the highest inflammation score vs. those with the lowest score (Model 2, p for trend=.006). Model 3 shows that higher levels of EPO and inflammation remained significant predictors of anemia after adjusting for age, sex and Hb. As expected, those with low normal Hb were significantly more likely to develop anemia relative to those >=2 g/dl above the WHO cutoff (Model 3, p for trend<.0001). Adjusting for comorbidities did not substatively alter the results. Further, the combination of high levels of EPO and inflammation increased the risk for anemia by 9-fold compared to those with low levels of each [ORadj 9.1 (1.9, 43.3), p=0.006]. Conclusions: High levels of EPO and inflammation as well as low normal Hb levels and increasing age were associated with an increased risk of anemia in older adults. The synergistic effects between EPO and inflammation might reflect a compensatory effort to maintain Hb levels in the presence of high levels of inflammation. Table 1: Association of EPO, inflammation and Hb with 3−yr incidence of anemia. Odds Ratio (95% CI) Model 1 Model 2 Model 3 *p for trend<.25 65–74 yrs. 1.0* 1.0* 1.0* 75–84 yrs. 3.4 (1.7, 6.4) 3.3 (1.7, 6.4) 2.8 (1.4, 5.6) >=85yrs. 13.9 (6.2, 31.3) 14.4 (6.5, 32.0) 11.4 (4.9, 26.6) women (vs. men) .8 (.5, 1.4) .9 (.5, 1.6) .9, (.5, 1.6) Hb [g/dl above WHO] 0–1 4.3 (1.8, 10.4) 1−2 1.7 (.7, 4.5) >2 1.0* EPO tertiles low 1.0* 1.0* medium 1.4 (.6, 3.1) 1.4 (.6, 3.3) high 3.0 (1.4, 6.4) 2.4 (1.1, 5.4) Inflammation score 0−1 1.0* 1.0* 2 1.8 (.9, 3.5) 1.7 (.8, 3.4) 3 2.0 (.9, 4.5) 1.9 (.8, 4.5) 4 4.6 (1.4, 15.3) 3.4 (1.0, 11.4)

scholarly journals SARS-CoV-2 Spike protein promotes hyper-inflammatory response that can be ameliorated by Spike-antagonistic peptide and FDA-approved ER stress and MAP kinase inhibitors in vitro

2020 ◽  
Author(s):  
Alan C-Y. Hsu ◽  
Guoqiang Wang ◽  
Andrew T. Reid ◽  
Punnam Chander Veerati ◽  
Prabuddha S. Pathinayake ◽  
...  
Keyword(s):  
Lung Injury ◽  
Er Stress ◽  
Map Kinase ◽  
Inflammatory Cytokines ◽  
Kinase Inhibitors ◽  
Spike Protein ◽  
Protein Subunit ◽  
Epithelial Damage ◽  
Antagonistic Peptide ◽  
Pro Inflammatory Cytokines

SummarySARS-CoV-2 infection causes an inflammatory cytokine storm and acute lung injury. Currently there are no effective antiviral and/or anti-inflammatory therapies. Here we demonstrate that 2019 SARS-CoV-2 spike protein subunit 1 (CoV2-S1) induces high levels of NF-κB activations, production of pro-inflammatory cytokines and mild epithelial damage, in human bronchial epithelial cells. CoV2-S1-induced NF-κB activation requires S1 interaction with human ACE2 receptor and early activation of endoplasmic reticulum (ER) stress, and associated unfolded protein response (UPR), and MAP kinase signalling pathways. We developed an antagonistic peptide that inhibits S1-ACE2 interaction and CoV2-S1-induced productions of pro-inflammatory cytokines. The existing FDA-approved ER stress inhibitor, 4-phenylburic acid (4-PBA), and MAP kinase inhibitors, trametinib and ulixertinib, ameliorated CoV2-S1-induced inflammation and epithelial damage. These novel data highlight the potentials of peptide-based antivirals for novel ACE2-utilising CoVs, while repurposing existing drugs may be used as treatments to dampen elevated inflammation and lung injury mediated by SARS-CoV-2.

scholarly journals Bmal1 integrates mitochondrial metabolism and macrophage activation

2019 ◽  
Author(s):  
Ryan K. Alexander ◽  
Yae-Huei Liou ◽  
Nelson H. Knudsen ◽  
Kyle A. Starost ◽  
Chuanrui Xu ◽  
...  
Keyword(s):  
Immune Cell ◽  
Inflammatory Diseases ◽  
Redox Homeostasis ◽  
Tumor Burden ◽  
Mitochondrial Metabolism ◽  
Metabolic Reprogramming ◽  
Dimethyl Malonate ◽  
Melanoma Tumor ◽  
Immunosuppressive Tumor Microenvironment ◽  
Regulatory Loop

ABSTRACTMetabolic pathways and inflammatory processes are under circadian regulation. While rhythmic immune cell recruitment is known to impact infection outcomes, whether the circadian clock modulates immunometabolism remains unclear. We find the molecular clock Bmal1 is induced by inflammatory stimulants, including Ifn-γ/lipopolysaccharide (M1) and tumor conditioned medium, to maintain mitochondrial metabolism under these metabolically stressed conditions in mouse macrophages. Upon M1 stimulation, myeloid-specific Bmal1 knockout (M-BKO) renders macrophages unable to sustain mitochondrial function, enhancing succinate dehydrogenase (SDH)-mediated mitochondrial ROS production and Hif-1α-dependent metabolic reprogramming and inflammatory damage. In tumor-associated macrophages, the aberrant Hif-1α activation and metabolic dysregulation by M-BKO contribute to an immunosuppressive tumor microenvironment. Consequently, M-BKO increases melanoma tumor burden, while administrating an SDH inhibitor dimethyl malonate suppresses tumor growth. Therefore, Bmal1 functions as a metabolic checkpoint integrating macrophage mitochondrial metabolism, redox homeostasis and effector functions. This Bmal1-Hif-1α regulatory loop may provide therapeutic opportunities for inflammatory diseases and immunotherapy.

scholarly journals Bmal1 integrates mitochondrial metabolism and macrophage activation

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Ryan K Alexander ◽  
Yae-Huei Liou ◽  
Nelson H Knudsen ◽  
Kyle A Starost ◽  
Chuanrui Xu ◽  
...  
Keyword(s):  
Immune Cell ◽  
Inflammatory Diseases ◽  
Redox Homeostasis ◽  
Tumor Burden ◽  
Mitochondrial Metabolism ◽  
Metabolic Reprogramming ◽  
Dimethyl Malonate ◽  
Melanoma Tumor ◽  
Immunosuppressive Tumor Microenvironment ◽  
Regulatory Loop

Metabolic pathways and inflammatory processes are under circadian regulation. Rhythmic immune cell recruitment is known to impact infection outcomes, but whether the circadian clock modulates immunometabolism remains unclear. We find that the molecular clock Bmal1 is induced by inflammatory stimulants, including Ifn-γ/lipopolysaccharide (M1) and tumor-conditioned medium, to maintain mitochondrial metabolism under metabolically stressed conditions in mouse macrophages. Upon M1 stimulation, myeloid-specific Bmal1 knockout (M-BKO) renders macrophages unable to sustain mitochondrial function, enhancing succinate dehydrogenase (SDH)-mediated mitochondrial production of reactive oxygen species as well as Hif-1α-dependent metabolic reprogramming and inflammatory damage. In tumor-associated macrophages, aberrant Hif-1α activation and metabolic dysregulation by M-BKO contribute to an immunosuppressive tumor microenvironment. Consequently, M-BKO increases melanoma tumor burden, whereas administering the SDH inhibitor dimethyl malonate suppresses tumor growth. Therefore, Bmal1 functions as a metabolic checkpoint that integrates macrophage mitochondrial metabolism, redox homeostasis and effector functions. This Bmal1-Hif-1α regulatory loop may provide therapeutic opportunities for inflammatory diseases and immunotherapy.

scholarly journals Recombinant SARS-CoV-2 Spike Protein Mediates Glycolytic and Inflammatory Activation in Human Monocytes

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 955-955
Author(s):  
Brandt Pence
Keyword(s):  
Protein Expression ◽  
Specific Interaction ◽  
Metabolic Reprogramming ◽  
Spike Protein ◽  
Mouse Bone Marrow ◽  
Human Monocytes ◽  
Protein Subunit ◽  
Extracellular Acidification ◽  
Gene And Protein Expression ◽  
Inflammatory Activation

Abstract Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) in part through cytokine storm. Metabolic reprogramming in immune cells mediates inflammation, and recent evidence suggests SARS-CoV-2 activates glycolysis in monocytes to facilitate cytokine production. In this study I investigated the ability of the spike protein (subunit 1) from SARS-CoV-2 to cause glycolytic reprogramming and inflammatory activation in isolated human monocytes. Primary human monocytes were isolated from healthy young donors (N=4) by immunomagnetic negative selection and stimulated with recombinant SARS-CoV-2 spike protein subunit 1 (rS1) for 6 hr. Glycolysis was monitored by assessing extracellular acidification using a Seahorse assay. Supernatants and cell lysates were subsequently processed for gene and protein expression assays by qPCR and ELISA respectively. Treatment of monocytes with rS1 at 10 nM and 30 nM led to significant upregulation of glycolysis, as well as a substantial increase in gene and protein expression of interleukin-6. Mouse bone marrow-derived macrophages did not display enhanced glycolysis when stimulated with rS1, suggesting a specific interaction of the protein with the ACE2 receptor, rather than a general inflammatory response caused by contamination with endotoxin or similar. Glycolytic activation in monocytes in response to rS1 suggests that immunometabolic modulators, including common geroprotectors such as rapamycin and metformin, may have efficacy in treating COVID-19.

scholarly journals Distinct Effects of Escherichia coli,Pseudomonas aeruginosa and Staphylococcus aureus Cell Wall Component-Induced Inflammation on the Iron Metabolism of THP-1 Cells

2021 ◽  
Vol 22 (3) ◽  
pp. 1497
Author(s):  
Edina Pandur ◽  
Kitti Tamási ◽  
Ramóna Pap ◽  
Gergely Jánosa ◽  
Katalin Sipos
Keyword(s):  
Cell Wall ◽  
Inflammatory Cytokines ◽  
Iron Metabolism ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Storage Proteins ◽  
Iron Storage ◽  
E Coli ◽  
Iron Storage Proteins ◽  
Pro Inflammatory Cytokines

Macrophages are essential immune cells of the innate immune system. They participate in the development and regulation of inflammation. Macrophages play a fundamental role in fighting against bacterial infections by phagocytosis of bacteria, and they also have a specific role in immunomodulation by secreting pro-inflammatory cytokines. In bacterial infection, macrophages decrease the serum iron concentration by removing iron from the blood, acting as one of the most important regulatory cells of iron homeostasis. We examined whether the Gram-positive and Gram-negative cell wall components from various bacterial strains affect the cytokine production and iron transport, storage and utilization of THP-1 monocytes in different ways. We found that S. aureus lipoteichoic acid (LTA) was less effective in activating pro-inflammatory cytokine expression that may related to its effect on fractalkine production. LTA-treated cells increased iron uptake through divalent metal transporter-1, but did not elevate the expression of cytosolic and mitochondrial iron storage proteins, suggesting that the cells maintained iron efflux via the ferroportin iron exporter. E. coli and P. aeruginosa lipopolysaccharides (LPSs) acted similarly on THP-1 cells, but the rates of the alterations of the examined proteins were different. E. coli LPS was more effective in increasing the pro-inflammatory cytokine production, meanwhile it caused less dramatic alterations in iron metabolism. P. aeruginosa LPS-treated cells produced a smaller amount of pro-inflammatory cytokines, but caused remarkable elevation of both cytosolic and mitochondrial iron storage proteins and intracellular iron content compared to E. coli LPS. These results prove that LPS molecules from different bacterial sources alter diverse molecular mechanisms in macrophages that prepossess the outcome of the bacterial infection.

Retinal microglia polarization in diabetic retinopathy

2021 ◽  
Vol 38 ◽  
Author(s):  
Xin Li ◽  
Zi-Wei Yu ◽  
Hui-Yao Li ◽  
Yue Yuan ◽  
Xin-Yuan Gao ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Diabetic Retinopathy ◽  
Cytokine Production ◽  
Immune Cell ◽  
Microvascular Disease ◽  
Retinal Diseases ◽  
Microglia Polarization ◽  
Retinal Microglia ◽  
The Central Nervous System ◽  
Retinal Neurodegeneration

Abstract Microglia, the main immune cell of the central nervous system (CNS), categorized into M1-like phenotype and M2-like phenotype, play important roles in phagocytosis, cell migration, antigen presentation, and cytokine production. As a part of CNS, retinal microglial cells (RMC) play an important role in retinal diseases. Diabetic retinopathy (DR) is one of the most common complications of diabetes. Recent studies have demonstrated that DR is not only a microvascular disease but also retinal neurodegeneration. RMC was regarded as a central role in neurodegeneration and neuroinflammation. Therefore, in this review, we will discuss RMC polarization and its possible regulatory factors in early DR, which will provide new targets and insights for early intervention of DR.

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