Monica J Carson (email@example.com) Microglia as a CNS-‐speciﬁc 9ssue macrophage: TREM2 dependent func9ons TREM2DAP12/TRYROBPTmem176bC1qA!!!!!"#$%&()*+&!,-./01-/.!23%41$5"# $#%&()*"+,)--.%"/0123456243078(524?0(84@A B0(84@A ,C0(84@A!#
Microglia are a distinct CNS-specific myeloid lineagebut the CNS is also served by infiltrating myeloid cellsB. IC LPS injectionCD45 àMG MPA. Untreated, no inflammationCD45 àFcRàMGFcRà1) CNS-resident MicrogliaMicroglia are:ü CD45lo to CD45intermediateü long-lived,ü largely self-replenishingü PU.1/IRF8 dependent lineage thatbegin populating the CNS duringembryonic developmentü Do not traffic to draining lymph nodes(at detectable rates)2) Peripheral monocytes /macrophagesthat acutely infiltrate the CNSThese cells are:ü CD45hiü short livedü rapidly replaced by bone marrowderived cells in the adultü Can traffic to draining lymph nodes
So what do we know about TREM2 and neuroinflammation:TREM2 up regulatedCuprizoneFacial AxotomyIn general, situations with increased celldamage, changes in neuronal activity and/orTNF lead to increased microglial expression ofTREM2Cell debris or TNF alone each are sufficient toincrease microglial expression of TREM2(Schmid et al. JNC 2002, 2009)Melchior et al. ASN NEURO 2010)Please note the gene:DAP12 = TYROBP = KARAP!!!!!"#$%&()*+&!,-./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