immunometabolism - tomáš doležal
DESCRIPTION
Pattern recognition receptors of immune system recognize pathogen-associated molecular patterns Bacteria Pathogen-associated molecular pattern Pattern recognition receptor Drosophila PGRP Peptidoglycan-recognition protein TLRs in mammals cytoplasm nucleusTRANSCRIPT
IMMUNOMETABOLISM - Tomáš Doležal
Cell regulation and signaling – 12.11.2015 České Budějovice
Pathogen-associated molecular pattern
Bacteria
nucleus
cytoplasm
Pattern recognitionreceptor
TLRsin mammals
Drosophila PGRPPeptidoglycan-recognition protein
Pattern recognition receptors of immune system recognize pathogen-associated molecular patterns
Mammalian TLRs are direct pattern-recognition receptors involved in the recognition of infectious agents
Drosophila Toll does not directly recognize microbial patterns!
INFLAMMATION
clonal expansion
Pathogen-associated molecular pattern
Bacteria
nucleus
cytoplasm
Pattern recognitionreceptor
Immune cell activation - differentiation - proliferation and differentiationTurning ON immune effector genesRelease of cytokines
Inflammatory response
RECOGNITION
PATHOGEN ELIMINATION
IMMUNOLOGY
METABOLIC SWITCHessentialimmunomodulatory
IMMUNOMETABOLISM
What is going on inside the cell?
How does it affect systemic metabolism?
Vander Heiden Science 2009
Warburg effect – increased glycolysis even under aerobic conditions
Metabolic switch in carbon source for lipid synthesis
Bioessays 35: 965–973
Hypoxia inducible factor HIF – master regulator of Warburg effect
Warburg used by immune cells
Tripmacher Eur. J. Immunol. 2008
CD4+ T cells: in glucose-containing medium, both cytokine production and proliferation were unaffected, even under complete OXPHOS suppression.
Warburg used by immune cells
Verbist Seminars in Immunology 2012
Warburg used by immune cells
Krawczyk BLOOD 2010
Dendritic cell
No proliferation, important for survival while travelling to lymph node and presenting to T cells.β-oxidation/OXPHOS
in resting DC
Front. Immunol., 30 January 2014 | http://dx.doi.org/10.3389/fimmu.2014.00024
Pathogen recognition receptor (e.g. TLR) activation stimulates PI3K/Akt and HIF
Warburg effect
Two types of macrophages – pro-inflammatory M1 (Warburg) and healing M2
IMMUNOMETABOLISM
What is going on inside the cell?
How does it affect systemic metabolism?
Energy expenditure of systems and organs under various conditionsSystem/organ Energy expenditure per day (kJ/day)
Total body basal metabolic rate 7,000
Total body metabolic rate with usual activity 10,000Total body metabolic rate during minor surgery 11,000
Total body metabolic rate with multiple bone fractures Up to 13,000
Total body metabolic rate with sepsis 15,000Total body metabolic rate with extensive burns 20,000
Total body daily uptake (absorptive capacity in the gut) 20,000
Immune system metabolic rate under normal conditions 1,600
Immune system metabolic rate moderately activated 2,100Central nervous system metabolic rate 2,000
Muscle metabolic rate at rest 2,500Muscle metabolic rate activated 2,500 to 10,000 and more
Spies Arthritis research & therapy 2012
Activated immune response is energetically costly
glucose
nutrientsfor pathogen
loss of energy reserves (wasting)
ENERGYRELEASE
Negative feedbackREGULATION
?
Insulin signaling Insulin
FOXO
IRS
PI3K/Akt
YInR
FOXO
growth
GluT
glucose
trans-location
glycolysis
glucose
FOXO
growth
JNK
Insulin resistance
FOXO
growth
Inflammation – pro-inflammatory cytokines released by immune cells
activation of immune response
TNF-αIL-6
IFN-γ
TNF-α
Insulin signaling Insulin
FOXO
IRS
PI3K/Akt
YInR
FOXO
growth
GluT
glucose
trans-location
glycolysis
glucose
FOXO
growth
JNK
Insulin resistance
FOXO
growth
YTNFR
TNF-αYTNFR
glucose
glucose
glucose
glucose
glucose
glucose
e.g. muscle cell
glucose
no IR
GLUT1
GLUT4
Front. Endocrinol., 10 May 2013 | http://dx.doi.org/10.3389/fendo.2013.00052
Cross-talk between insulin and inflammatory signaling pathways
WARBURG
Selfish signal(TNF-α, IFN-γ, IL-6)
Insulin resistance
Systemic metabolic switchSelfish immune systemacute chronic
Insulin resistance is a way of immune cells to usurp energy/nutrients from the rest of the organism
Selfish immune systemimmune system (and brain) hierarchically above the rest of the organism in allocating energy/nutrition (they do not become insulin resistant)
Effective immune response requires energy
During acute stress, it is good to be selfish
Straub Arthritis Research & Therapy 2014
Insulin resistance is a way of immune cells to usurp energy/nutrients from the rest of the organism
Selfish immune systemimmune system (and brain) hierarchically above the rest of the organism in allocating energy/nutrition (they do not become insulin resistant)
Chronic activation is a pathological state
Chronic insulin resistance –> various diseases
Straub Arthritis Research & Therapy 2014
Systemic metabolic regulations during immune response in Drosophila
Parasitoid waspLeptopilina boulardi
…infecting larva of Drosophila melanogaster
MODEL:
Hml>GFP
MSN>GFP
Lamellocytedifferentiation
encapsulation and melanization
within 24 hours
within 48 hours
our white!
L2/L3 (~72 h) = 0 hpi
24 hpi
14C MACROMOLECULE DISTRIBUTION 14C TISSUE DISTRIBUTION
SYSTEMIC METABOLIC SWITCH
IMMUNE CELLS
D[U-14C]-glucose in diet
Immune cells increaseglycolysis (Warburg)
(Strasser and Dolezal, unpublished)
SYSTEMIC METABOLIC SWITCH
Infection slows down development
parasitoid egg
GLUCOSE
↑ aerobicglycolysis
pro-hemocyte
lamellocyte
proliferation
differentiation
encapsulationegg recognition
developing larval tissue
activation
systemic metabolic switch
nucleoside transporter
AMPK
adgf-a mutant
wild type
Extracellular adenosine • suppression of energy-consuming
processes• suppression of energy storage• energy release … hyperglycemia
(Dolezal, PLoS Biology 2005)
nucleoside transporter
AMPK
Extracellular adenosine • suppression of energy-consuming
processes• suppression of energy storage• energy release … hyperglycemia
adoR mutant
Blocking adenosine signaling by adoR mutation suppresses metabolic switch
Blocking adenosine signaling by adoR mutation suppresses metabolic switch
Lack of adenosine signaling-mediated systemic metabolic switch has consequences…
adoR mutant = low number of lamellocytes
(no problem with pathogen recognition, activation and lamellocyte differentiation, it is just less effective)
Adenosine signaling required for effective immune response
Trade-off between development and immunity
developing larval tissue
parasitoid egg
GLUCOSE
↑ aerobicglycolysis
AdoR
pro-hemocyte
lamellocyte
proliferation
differentiation
encapsulationegg recognition
activation
TRADE-OFF
Adenosine mediates systemic metabolic switch … where does it come from?
Srp expressed in all hematopoietic cellsand fat body
Equilibrative nucleoside transporters … ENT1, ENT2 and ENT3
Knockdown in various tissues by Gal4>UAS-RNAi:
No effect in fat body or circulating hemocytes
Knocking down ENT2 in prohemocytessuppresses immune response
Blocking adenosine transport from immune cells lowers number of lamellocytes
developing larval tissue
parasitoid egg
e-Ado ↑ aerobicglycolysis
AdoR
pro-hemocyte
lamellocyte
proliferation
differentiation
encapsulationegg recognition
SELFISH IMMUNE SYSTEM
activation
GLUCOSE
↓ ATP
↑ AMP
ADK
Ado
5’NT
AMPK anabolicprocesses
↓ ATP
↑ AMP
ADK
Ado
5’NT
AMPK
OXPHOS
anabolicprocesses
e-Ado
GLUCOSE
↑ ATP
AdoRHow?
Selfish signal
Immune cellselfish
Developing cellunselfish
Why Ado?
Adjusting systemic metabolism according to actual energy state of immune cells?
Pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6) act as selfish signals too … … measuring the extent of immune activation?
INFLAMMATION
damage ATP
Ado
↑Ado
local higher increase
systemic lower increase
↑Ado
ectoenzymes↓ATP↑AMP
Ado
FATIGUEdecreased overall
activity and metabolism
Glucose
Immunecell
WARBURG
Immune activation
5’NT
ENT
??
?
? Blood vessel
Adenosine – a selfish immunity signal even in mammalian system?
Dolezal – Oncotarget 2015