Transcript akt model
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