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Cell regulation and signaling – 12.11.2015 České Budějovice
IMMUNOMETABOLISM
- Tomáš Doležal
Pattern recognition receptors of immune system
recognize pathogen-associated molecular patterns
Bacteria
Pathogen-associated
molecular pattern
Drosophila PGRP
Peptidoglycan-recognition protein
cytoplasm
nucleus
Pattern
recognition
receptor
TLRs
in mammals
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
IMMUNOLOGY
Bacteria
Pathogen-associated
molecular pattern
cytoplasm
nucleus
Pattern
recognition
receptor
RECOGNITION
Immune cell activation
METABOLIC SWITCH
- differentiation
essential
- proliferation and differentiation
immunomodulatory
Turning ON immune effector genes
Release of cytokines
Inflammatory response
PATHOGEN ELIMINATION
IMMUNOMETABOLISM
What is going on
inside the cell?
How does it affect
systemic metabolism?
Warburg effect – increased glycolysis even under aerobic conditions
Vander Heiden Science 2009
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
CD4+ T cells: in glucose-containing medium, both cytokine production and
proliferation were unaffected, even under complete OXPHOS suppression.
Tripmacher Eur. J. Immunol. 2008
Warburg used by immune cells
Verbist Seminars in Immunology 2012
Warburg used by immune cells
Dendritic cell
β-oxidation/OXPHOS
in resting DC
No proliferation, important for
survival while travelling to lymph
node and presenting to T cells.
Krawczyk BLOOD 2010
Pathogen recognition receptor (e.g. TLR) activation stimulates PI3K/Akt and HIF
Warburg effect
Front. Immunol., 30 January 2014 |
http://dx.doi.org/10.3389/fimmu.2014.00024
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 conditions
System/organ
Energy expenditure per day (kJ/day)
Total body basal metabolic rate
7,000
Total body metabolic rate with usual activity
10,000
Total 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
15,000
Total 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
2,100
Central nervous system metabolic rate
2,000
Muscle metabolic rate at rest
2,500
Muscle metabolic rate activated
2,500 to 10,000 and more
Spies Arthritis research & therapy 2012
Activated immune response is energetically costly
ENERGY
RELEASE
glucose

?
Negative feedback
REGULATION

nutrients
for pathogen

loss of energy
reserves (wasting)
Insulin signaling
Insulin
Insulin resistance
glucose
InR
IRS
translocation
glucose
JNK
PI3K/Akt
GluT
glycolysis
FOXO
FOXO
growth
Inflammation – pro-inflammatory cytokines released by immune cells
activation of immune response
TNF-α
IFN-γ
IL-6
Insulin signaling
Insulin
Insulin resistance
TNF-α
glucose
glucose
glucose
InR
IRS
TNF-α
GLUT4
translocation
glucose
glucose
TNFR
JNK
PI3K/Akt
glucose
GluT
glycolysis
FOXO
FOXO
GLUT1
growth
e.g. muscle cell
glucose
no IR
glucose
Cross-talk between insulin and inflammatory signaling pathways
Front. Endocrinol., 10 May 2013 |
http://dx.doi.org/10.3389/fendo.2013.00052
Selfish immune system
acute 
chronic 
Systemic metabolic switch
Insulin
resistance
Selfish signal
WARBURG
(TNF-α, IFN-γ, IL-6)
Insulin resistance is a way of immune cells to usurp
energy/nutrients from the rest of the organism
Selfish immune system
immune 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 system
immune 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
MODEL:
Parasitoid wasp
Leptopilina boulardi
…infecting larva of
Drosophila melanogaster
L2/L3 (~72 h) = 0 hpi
encapsulation and melanization
Hml>GFP
within 48 hours
Lamellocyte
differentiation
MSN>GFP
24 hpi within 24 hours
our white!
SYSTEMIC METABOLIC SWITCH
D[U-14C]-glucose in diet
14C
MACROMOLECULE DISTRIBUTION
14C
TISSUE DISTRIBUTION
IMMUNE
CELLS
Immune cells increase
glycolysis (Warburg)
(Strasser and Dolezal, unpublished)
SYSTEMIC METABOLIC SWITCH
Infection slows down development
encapsulation
egg recognition
parasitoid egg
activation
developing
larval tissue
pro-hemocyte proliferation
↑ aerobic
glycolysis
differentiation
lamellocyte
GLUCOSE
systemic metabolic switch
Extracellular adenosine
• suppression of energy-consuming
processes
• suppression of energy storage
• energy release … hyperglycemia
nucleoside
transporter
AMPK
wild type
adgf-a mutant
(Dolezal, PLoS Biology 2005)
Extracellular adenosine
adoR mutant
• suppression of energy-consuming
processes
• suppression of energy storage
• energy release … hyperglycemia
nucleoside
transporter
AMPK
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
encapsulation
egg recognition
parasitoid egg
activation
developing
larval tissue
pro-hemocyte proliferation
↑ aerobic
glycolysis
differentiation
lamellocyte
AdoR
GLUCOSE
TRADE-OFF
Adenosine mediates systemic metabolic switch … where does it come from?
Equilibrative nucleoside transporters … ENT1, ENT2 and ENT3
Knockdown in various tissues by Gal4>UAS-RNAi:
Srp expressed in all hematopoietic cells
and fat body
No effect in fat body or
circulating hemocytes
Knocking down ENT2 in prohemocytes
suppresses immune response
Blocking adenosine transport from immune cells lowers number of lamellocytes
encapsulation
egg recognition
parasitoid egg
activation
developing
larval tissue
e-Ado
pro-hemocyte proliferation
↑ aerobic
glycolysis
differentiation
lamellocyte
AdoR
GLUCOSE
SELFISH
IMMUNE SYSTEM
Why Ado?
Immune cell
selfish
Developing cell
unselfish
↓ ATP
↓ ATP
↑ ATP
ADK
ADK
↑ AMP
OXPHOS
AMPK
anabolic
processes
↑ AMP
AMPK
anabolic
processes
5’NT
5’NT
Ado
Ado
GLUCOSE
e-Ado
Selfish signal
AdoR
How?
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?
Adenosine – a selfish immunity signal even in mammalian system?
INFLAMMATION
Immune activation
ATP
damage
WARBURG
ectoenzymes
 Ado
↓ATP
↑AMP
?
Immune
5’NT
Ado cell
local
higher increase
 Glucose
↑Ado
systemic
lower increase
?
?
↑Ado
?
FATIGUE
decreased overall
activity and metabolism
Dolezal – Oncotarget 2015