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    13alzforum carson 13alzforum carson Presentation Transcript

    • Monica  J  Carson  (monica.carson@microglia.org)  Microglia  as  a  CNS-­‐specific  9ssue  macrophage:    TREM2  dependent  func9ons  TREM2DAP12/TRYROBPTmem176bC1qA!!!!!"#$%&()*+&!,-./01-/.!23%41$5"# $#%&()*"+,)--.%"/0123456243078(524?0(84@A B0(84@A ,C0(84@A!#
    • Microglia are a distinct CNS-specific myeloid lineagebut the CNS is also served by infiltrating myeloid cellsB. IC LPS injectionCD45 àMG MPA. Untreated, no inflammationCD45 àFcRàMGFcRà1)  CNS-resident MicrogliaMicroglia are:ü  CD45lo to CD45intermediateü  long-lived,ü  largely self-replenishingü  PU.1/IRF8 dependent lineage thatbegin populating the CNS duringembryonic developmentü  Do not traffic to draining lymph nodes(at detectable rates)2)  Peripheral monocytes /macrophagesthat acutely infiltrate the CNSThese cells are:ü  CD45hiü  short livedü  rapidly replaced by bone marrowderived cells in the adultü  Can traffic to draining lymph nodes
    • Trem1  Trem2   Macrophage  Trem2  Trem1  Microglia  Bkgrd  Bkgrd  mg100101102103104FL2-HMJC050212.039 11.8MJC050212.030 11.4MJC050212.021 15.7MJC050212.012 11.2live no boxesMJC050212.011Event Count: 27279100101102103104FL4-H100101102103104FL1-HCD45 àFcRàC. IP LPS injectionMPMG
    • So what do we know about TREM2 and neuroinflammation:TREM2 up regulatedCuprizoneFacial AxotomyIn general, situations with increased celldamage, changes in neuronal activity and/orTNF lead to increased microglial expression ofTREM2Cell debris or TNF alone each are sufficient toincrease microglial expression of TREM2(Schmid et al. JNC 2002, 2009)Melchior et al. ASN NEURO 2010)Please note the gene:DAP12 = TYROBP = KARAP!!!!!"#$%&()*+&!,-./01-/.!23%41$5"# $#%&()*"+,)--.%"/0123456243078(524%&()%((,9:;< < <= = =!0000>000!0000>0000!0000>000!0000>0000!0000>0000!000>?0(84@A B0(84@A ,C0(84@A!#!"#"$"%"&"!"#"$"%"&"(")*+,-." /")*+,-." 0")*+,-."*# Trem2Blue=non-transgenic wild-type; Red=APP23 transgenic
    • :Why focus on TREM2 in AD Associated Neuroinflammation?Because  Trem2  is  a  receptor  that:    1)  10-­‐50  fold  higher  on  microglia  than  on  blood-­‐derived  macrophages  2)  In  the  murine  CNS  is  only  expressed  by  microglia  (no  TREM2  in  PU.1  KO’s  lacking  microglia)    3)  Inhibits  signaling  of  some  pro-­‐inflammatory  receptors  (TLR4)  4)  Increases  phagocytosis  of  cell  debris  and  amyloid  by  microglia        5)  promotes  9ssue  repair  following  injury  and    inflammatory  insults  (Overexpression  &  an9body  blocking  studies)  6)  TREM2  binding  ac9vity  (puta9ve  TREM2  ligands)  expressed  by  microglia,  CNS-­‐infiltra9ng  macrophages,  ac9vated  glia  and  stressed  &  apopto9c  neurons  and  glia  Loss of functional TREM2 signalingleads to early onset cognitive dementia(20’s) & death by the 40-50’s:Nasu-Hakola DiseaseTempting to speculate that normal age-related decrease in TREM2 levelscontributes to age-related susceptibilityfor AD(Thrash et al. 2009)!""!"!!"#!"$!"%!"#$%&(&)(&*+),&)-,.*/0$1*2(3"&4B:TREM2PD23mo.PD21PD7Bkgrd5*$6*738!""!"!!"#!"$!"%!""!"!!"#!"$!"%!&()*+,-./*09:;<9:==>A.
    • Microglia are the tissue macrophage of the brain….So, what are the roles and functions of the typical tissue macrophage?Is the recent AD-associated mutation in TREM2 ligand binding domain, loss of function or alteredrecognition of ligands leading to dysregulated TREM2 dependent microglial activation?PhagocytosisAntigen-presentationTo T cells: activate,retain direct effectorfunctionsTrafficking to lymph nodesTissue homeostasisTissue repairPathogen defenseMicroglia not detected totraffick to cervical lymphnodesMicroglia: yesTREM2 regulatedMicroglia: Yes:TREM2 regulatedMicroglia: Yes viainnate and adaptiveimmunityTREM2 regulatedMicroglia: Yes,But as inhibitory/tolerogenic APCsTREM2 regulated in vitroMicroglia: Yes, veryactive innate immunityand oxidative pathwaysTREM2 regulated
    • TREM2 immunoreactivity: a caution!!!!!"#$%&()*+&!,-./01-/.!23%41$5"# $#%&()*"+,)--.%"/0123456243078(524< < <= = =!0000>000!0000>0000!0000>000!0000>0000!0000>0000!000>?0(84@A B0(84@A ,C0(84@A!#Microglia also produce soluble “decoy” form of receptor!Therefore reports of TREM2 immunoreactivity on non-microglia might reflect detectionof the soluble variant of TREM2 binding these TREM2 ligands on neurons, glia andperivascular macrophagesUnpublished results, Schmid et al. 2002, Hamerman et al 2006,Piccio et al. 2008, Hsieh et al.2009TREM2 binding activity (putativeligand expression) is detected onreactive astrocytes, infiltratingmacrophages (high levels) andstressed and/or apoptotic neurons,reactive and apoptotic glia
    • NINDSUCR Div of Biomed Sci PIC grantUCR Chancellor’s Strategic InitiativeDana FoundationBiogen Idec, MerckDOD; CRCCTammy KielianCaroline WhitacreEmma WilsonKathryn JonesVirginia SandersMarco ColonnaHarald NeumanJenny TingCarson LabTiffany ButtsDeirdre S. DavisAlfredo HernandezBenoit MelchiorYoshinori OtaniShweta PuntambekarVictoria SenechalChristoph D. SchmidJ. Cameron ThrashIryna M. EthellTina BilousovaSlawomir SloniwskiPeter HickmottDevin BinderMike HsuMicroglia and Macrophages in braindevelopment and neuroinflammation