Immunometabolism.pdf

Lactate+Nitric oxide(NO)Citrulline(export)Citrulline(import)IL-6,TNF,IL-1,IL-1OrnithineCCL18CCL22CCL24Lactate+IFN-Slc7a5Slc1a5Glut1FAsFAsMitochondrialbiogenesisThymic Treg developmentTORC1 on(Raptor)IL-2 signalingPostdevelopment TregTORC1 low/offIL-2 signalingAKT lowPTEN onPI3K lowGlycolysis lowAMPK onmTOR onAKT onPTEN lowPI3K onAMPK lowmTOR off=IgM+(B cells)Acetyl-CoACitrateGlucoseGlucoseTLRsIFNRsIL-6RIL-4/13RGlucoseGlucoseLactateGlucoseGlutamineGlutamineAmino acidsArginineIL-15RIL-2R/CD25GlucoseGlutamineTo biomassO2iNOSASS1+ASLArginineNO+CitrulineCitruline+AspFumarateAnapleroticTCA cycleGlutamineM2M1TeffTregTmemACTIVATEDB cellRESTING T/BHIF-1HIF-1HIF-1FoxP3c-MYCc-MYCIRF5NF-kBNF-BKLF6STAT1STAT1STAT3STAT6STAT6ARG1ARG1STAT3CD36PPARsKLF4LALLALGlucoseGlucoseArginineArginineUDP-GlcNAcTCAcycleNOcycleROS+GlutamineFAsCO2ATPTCAcycleCO2ATPCitrateSuccinateFAsCO2ATPTCAcycleTCAcycleATPTo biomassGlutamineGlucoseATPATPPPPNOOrnithineCCL18CCL22M2Lactate+Nitric oxide(NO)Citrulline(export)Citrulline(import)Amino acidsM1ACTIVATEDB cellRESTING T/BRESTING T/BTmemTregLactate+IFN-TeffAmino acidsTTCAcycleSnapShot:ImmunometabolismPeter J.Murray,1 Jeffrey Rathmell,2 and Edward Pearce31St.Jude Childrens Research Hospital,Memphis,TN 38105,USA;2Duke University Medical School,Durham,NC 27710,USA;3Washington University School of Medicine,St.Louis,MO 63110,USASee online version forlegend and references.190 Cell Metabolism 22,July 7,2015 2015 Elsevier Inc.DOI http:/dx.doi.org/10.1016/j.cmet.2015.06.014190.e1 Cell Metabolism 22,July 7,2015 2015 Elsevier Inc.DOI http:/dx.doi.org/10.1016/j.cmet.2015.06.014SnapShot:ImmunometabolismPeter J.Murray,1 Jeffrey Rathmell,2 and Edward Pearce31St.Jude Childrens Research Hospital,Memphis,TN 38105,USA 2Duke University Medical School,Durham,NC 27710,USA3Washington University School of Medicine,St.Louis,MO 63110,USAThe vast and fast-moving field of immunometabolism deciphers the contribution of biochemistry to immune cell development,fate,and behavior.An advantage of using the immune system to uncover fundamental aspects of intermediary metabolism lies in the fact that the majority of immune cell populations are(i)dispensable for normal organis-mal development(with the exception of tissue macrophages that populate,monitor,and modify most of the tissues of the body),(ii)can often be produced in large amounts or highly purified,(iii)are amenable to exquisitely specific genetic ablation strategies,and(iv)can be isolated and transferred between animals.A major theme of immunometabo-lism concerns distinctions between cells requiring rapid division cycles or activation,and cells destined for quiescent or surveillance roles.Characteristics of the former are closely related to oncogenically transformed malignant cells and embryonic stem cells,which import and burn massive amounts of glucose to generate biomass(Warburg-type metabolism).By contrast,the latter generally use fatty acid oxidation and the Krebs cycle to generate energy.Manipulating specific pathway components of immunometabolic cycles(TORC1,TORC2,PTEN,AMPK,PI3K)via genetic or pharmacological approaches is a useful tool to alter cell behavior and switch fates.Biochemical strategies help further uncover specific metabolic requirements for immune responses,globally,and address specific questions about how metabolites are made and metabolized.Lymphocytes and T CellsQuiescent lymphocytes rely primarily on fatty acid and glucose metabolism.T effectors(Teff)emerge from quiescence following activation by antigen through the T cell receptor and costimulation through an mTOR-dependent process that involves an increase in aerobic glycolysis(Warburg-type metabolism).Activated Teff cells undergo multiple cellular divisions and convert glucose and glutamine into biomass,require substantial supplies of amino acids imported from the local environment,and are dependent on TORC1,PI3K,and AKT.In terms of metabolic requirements,therefore,Teff cells are similar to oncogenically transformed cells.Glycolysis also allows the efficient translation of mRNAs encoding effector cytokines,such as IFN-,by preventing GAPDH moonlighting as an mRNA-binding protein.To persist for long periods as quiescent cells,memory T(Tmem)cells maintain healthy mitochondria by synthesizing and then oxidizing FA to support OXPHOS.CD8+cyto-toxic T cells treated with the TORC1 inhibitor rapamycin exhibit features of Tmem cells.TORC1 signaling is required for exit from quiescence.Regulatory T(Treg)cells are dependent on FoxP3,allowing highly specific genetic tests of Treg metabolic requirements.Mice lacking mTOR in all T cells have a phenotype similar to Treg,arguing that mTOR signaling counters the Treg phenotype.Similarly,AKT activation blocks Treg.However,ablation of Raptor(a component of TORC1)using FoxP3-Cre causes defects in Treg number and function.Treg development and function thus appear strongly dependent on specific metabolic cues at specific times:Treg expan-sion likely requires TORC1 and glycolysis,though this pathway must be suppressed for Treg to become fully functional.Further metabolic pathways impinging on Treg function include withdrawal of essential amino acids such as arginine,which is thought to help Teff convert to a more regulatory state.Activated B CellsOnce triggered to make antibodies,B cells are glycolytic and must construct an expanded endoplasmic reticulum to secrete antibodies.The metabolic requirements for antibody production and then return to the memory state are just being uncovered.Blocking mTOR in an ongoing B cell response biases antibody production to IgM,suggest-ing that metabolism is interlaced with antibody class.Macrophages M1 and M2M1 macrophages activated by pathogen products and type I IFNs are glycolytic and anti-microbial and have tissue-destructive potential.Most M1-like macrophages in inflammatory sites originate from bone marrow inflammatory monocytes and are thus replaceable without requiring self-renewal.A major product of M1 macrophages is NO,which requires the importation of arginine and oxygen.The product of the nitric oxide synthase reaction(mediated by iNOS)is citrulline and NO.Remarkably,citrulline is exported and then re-imported as needed to re-generate arginine and sustain NO production;this cycle forms part of the anaplerotic TCA cycle of M1 cells,which can also lead to poisoning of mitochondrial respiratory activity(in monocyte-derived dendritic cells).ARG1,induced by a complex TLR-dependent indirect mechanism,blocks this reaction by hydrolyzing arginine.In addition to NO,major products of M1 macrophages are cytokines,chemokines,metalloproteases,and the anti-microbial metabolite itaconate.The TCA cycle is fragmented in M1 macrophages,and this is associated with an accumulation of succinate,which has proinflammatory effects by stabilizing HIF1.In related dendritic cells,citrate derived from glucose is used to support increased fatty acid synthesis,which is essential for activation.M2 macrophages do not make NO and instead use ARG1 to hydrolyze massive amounts of imported arginine.While the products of this reaction are ornithine and urea,the main function of arginine consumption by M2 macrophages is to restrict supply to neighboring arginine auxotrophs:M2 macrophages are therefore immunoregulatory and can suppress Teff by blocking their supply of arginine.M2 macrophages use FA primarily derived from acquired triacyglycerols to support OXPHOS,have an intact TCA cycle,and make large amounts of glycosylated proteins,which require UDP-GlcNac from glucose.The metabolic status of the tissue macrophages that expand and seed growing organs in the early embryo(e.g.,microglia)remains unclear and may be dependent on the tissue context.However,like monocyte-derived macrophages,tissue macrophages can be M1 or M2 polarized,depending on the inflammatory microenvironment.ABBREVIATIONsARG1,arginase 1;ASL,argininosuccinate lyase;ASS1,argininosuccinate synthase 1;FA,fatty acid;GAPDH,glyceraldehyde 3-phosphate dehydrogenase;HIF1-,hypoxia-induc-ible factor 1-;IFN,interferon;IL,interleukin;KLF,Kruppel-like factor;NO,nitric oxide;iNOS,inducible NO synthase;LAL,lysosomal acid lipase;ROS,reactive oxygen species;TLR,Toll-like receptor;UDP-GlcNAc,uridine diphosphate N-acetylglucosamine.REfERENcEsKelly,B.,and ONeill,L.A.J.(2015).Cell Res.Published online June 5,2015.10.1038/cr.2015.68.MacIver,N.J.,Michalek,R.D.,and Rathmell,J.C.(2013).Annu.Rev.Immunol.31,259283.PubMedMurray,P.J.,Allen,J.E.,Biswas,S.K.,Fisher,E.A.,Gilroy,D.W.,Goerdt,S.,Gordon,S.,Hamilton,J.A.,Ivashkiv,L.B.,Lawrence,T.,et al.(2014).Immunity 41,1420.PubMedPearce,E.J.,and Everts,B.(2015).Nat.Rev.Immunol.15,1829.PubMedPearce,E.L.,and Pearce,E.J.(2013).Immunity 38,633643.PubMedPollizzi,K.N.,and Powell,J.D.(2015).Trends Immunol.36,1320.PubMedQualls,J.E.,Subramanian,C.,Rafi,W.,Smith,A.M.,Balouzian,L.,DeFreitas,A.A.,Shirey,K.A.,Reutterer,B.,Kernbauer,E.,Stockinger,S.,et al.(2012).Cell Host Microbe 12,313323.PubMedSiska,P.J.,and Rathmell,J.C.(2015).Trends Immunol.36,257264.PubMedWeinberg,S.E.,Sena,L.A.,and Chandel,N.S.(2015).Immunity 42,406417.PubMedZeng,H.,and Chi,H.(2015).Trends Immunol.36,312.PubMed