Transcript Warburg effect Sepsis

The Warburg effect of PBMC in
inflammatory diseases
Reporter: Chen Kuan-Yuan
Advisor: Post-Doc Wu Sheng-Ming /Associate Prof. Lee Kang-Yun
1. Glycolysis
2. TCA Cycle
3. ETC
4. Oxidative Phosphorylation
1. Glycolysis
Cytosol
2. TCA cycle
Mitochondria
NADH
3. ETC
Pyruvate
Lactate
4. Phosphorylation
4. Oxidative
O2
1956
Aerobic glycolysis
Warburg effect
Beyond ATP
2 ATP vs 36 ATP
Why?
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
Proliferation
Vander Heiden M.G., et al., Sicence 2009
Ock4,Sox2,Klf4,c-Myc
Self-renewal
iPSC
Self-renewal
CSC
Differentiation
Differentiation
Functional
cell
Tumor cell
Aerobic glycolysis
Nicola Pacini and Fabio Borzianin Int.J.Mol.Sci 2014
Proliferation
Stemness
Douglas Hanahan and Robert A. Weinburg Cell 2011
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/fructose2,6-bisphosphatase (PFKFB)
4. Post-translational regulation
– Activation of PI3K/AKT pathway
signaling
– PKM2
Palsson-McDermott E.M. and O’Neill LA.J. Bioessays 2013
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
Metabolic pathways in immune cell activation and
quiescence
Pearce E.L. and Pearce E.J. Immunity 2013
Glycolytic reprogramming in myofibroblast
differentiation and lung fibrosis
3-PO
TGF-β1
Smad2/3
Glycolysis
Differentiation
Fibroblast
HIF-1α
Succinate
Fibrosis
Myofibroblast
Differentiation
Zheng N.X. et al., AJRCCM 2015
Background
.
Sepsis
Aerobic glycolysis
Warburg effect
Tumor
cells
Stemness and
proliferation
Chronic Obstructive
Pulmonary Disease
COPD
Immune
cells
Proliferation and
activation
Stromal
cells
Differentiation
Functional
Normal
cells ?
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
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
Oxidative stress
Inflammation
Autoimmunity
N
Th1
M
Clinical
Phenotype
Th17
Stable COPD
Protease-Antiprotease
MMP
NE
Accelerated aging
A1AT
Senescence
associated secretory
phenotype
TINE
Inflammaging
Large airways
(chronic bronchitis) Small airway disease
Emphysema
Frequent
exacerbator
Warburg effect on THP1 cell lines in different
single stressor
TNF- α
IL-6
LPS
LPS
IL-1 β
H2O2
IL-1 β
H2O2
Warburg effect on THP1 cell lines in different
additive stressor
TNF- α
LPS+IL-1 β
LPS+IL-1 β
IL-6
LPS+H2O2
LPS+H2O2
In the future work
Sepsis
Early mortality
COPD
Late mortality
Stable COPD
Frequent
exacerbator
Blood: 8-OHG, CRP, TNF-α, IL-6, IL-1β
Day1/Day7
Warburg effect of
PBMC
Glucose transporter
PI3K-AKT-mTOR , other pathways
HIF-1α , other TFs
Aerobic glycolysis inhibitors
OPD/Admission