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The Warburg effect of PBMC in inflammatory diseases
Reporter: Chen Kuan-Yuan Advisor: Post-Doc Wu Sheng-Ming /Associate Prof. Lee Kang-Yun
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1. Glycolysis 2. TCA Cycle 3. ETC 4. Oxidative Phosphorylation
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1. Glycolysis Cytosol 2. TCA cycle Mitochondria 3. ETC 4. Oxidative
NADH 3. ETC 4. Oxidative 4. Phosphorylation Pyruvate O2 Lactate
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Vander Heiden M.G., et al., Sicence 2009
1956 Aerobic glycolysis Warburg effect 1. Carbon and nitrogen for macromolecules such as nucleotides, amino acids and lipids 2. PPP for NADPH 3. Lactate for selective pressure 4. Citrate for lipid systhesis, succinate for maintain glycolysis Beyond ATP 2 ATP vs 36 ATP Why? Proliferation Vander Heiden M.G., et al., Sicence 2009
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Proliferation Stemness iPSC CSC Ock4,Sox2,Klf4,c-Myc
Tumor cell Functional cell Self-renewal Ock4,Sox2,Klf4,c-Myc Differentiation Aerobic glycolysis Nicola Pacini and Fabio Borzianin Int.J.Mol.Sci 2014 Proliferation Stemness Douglas Hanahan and Robert A. Weinburg Cell 2011
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How to drive aerobic glycolysis
1. Genomic regulation Phosphoglycerate dehydrogenase (PHGDH) 2. Transcriptional regulation HIF1 MYC P53 3. Metabolic isoform switching Pyruvate kinase M2 (PKM2) 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) 4. Post-translational regulation Activation of PI3K/AKT pathway signaling PKM2 Palsson-McDermott E.M. and O’Neill LA.J. Bioessays 2013
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Warburg effect on immune cells
1963 Metabolic patterns changing when perform phagocytosis in three types - polymorphonuclear leukocytes - monocytes - alveolar macrophages Oren, P. et al., J.Cell. Biol 1963 1982 Lymphocyte exhibited increased glycolysis for proliferation in vivo graft versus host model Arwadi, M.S. et al., Biochem.J. 1982 Proliferation Activation
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Metabolic pathways in immune cell activation and quiescence
Pearce E.L. and Pearce E.J. Immunity 2013
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Glycolytic reprogramming in myofibroblast differentiation and lung fibrosis
3-PO TGF-β1 Smad2/3 Glycolysis Fibroblast Myo-fibroblast Differentiation Fibrosis HIF-1α Succinate Differentiation Zheng N.X. et al., AJRCCM 2015
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Background Aerobic glycolysis Warburg effect Sepsis
. Sepsis Aerobic glycolysis Warburg effect Chronic Obstructive Pulmonary Disease COPD Tumor cells Immune cells Stromal cells Functional Normal cells ? Stemness and proliferation Proliferation and activation Differentiation
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Finfer S.R. et al., N ENGL.J.MED 2013
Sepsis Systemic inflammation to infection complicated by acute organ dysfunction Clinical Phenotype Early mortality Over inflammation Late mortality Immunosuppression Finfer S.R. et al., N ENGL.J.MED 2013
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COPD persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients Clinical Phenotype Oxidative stress Inflammation Autoimmunity Th1 Th17 Protease-Antiprotease N M MMP NE A1AT TINE Stable COPD Accelerated aging Senescence associated secretory phenotype Inflammaging Frequent exacerbator Large airways (chronic bronchitis) Small airway disease Emphysema
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Warburg effect on THP1 cell lines in different single stressor
TNF- α LPS IL-1 β H2O2 IL-6 LPS IL-1 β H2O2
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Warburg effect on THP1 cell lines in different additive stressor
LPS+H2O2 TNF- α LPS+IL-1 β LPS+IL-1 β LPS+H2O2 IL-6
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Aerobic glycolysis inhibitors
In the future work Sepsis COPD Early mortality Late mortality Stable COPD Frequent exacerbator Blood: 8-OHG, CRP, TNF-α, IL-6, IL-1β Warburg effect of PBMC Day1/Day7 OPD/Admission Glucose transporter PI3K-AKT-mTOR , other pathways HIF-1α , other TFs Aerobic glycolysis inhibitors
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