13alzforum carson
TRANSCRIPT
Monica J Carson ([email protected])
Microglia as a CNS-‐specific 9ssue macrophage: TREM2 dependent func9ons
TREM2
DAP12/ TRYROBP
Tmem176b
C1qA
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*# Trem2
Tmem176bD#
Blue=non-transgenic wild-type; Red=APP23 transgenic
Microglia are a distinct CNS-specific myeloid lineage but the CNS is also served by infiltrating myeloid cells
B. IC LPS injection
CD45 à
MG MP
A. Untreated, no inflammation
CD45 à
FcR
à
MG
FcR
à
1) CNS-resident Microglia Microglia are: ü CD45lo to CD45intermediate ü long-lived, ü largely self-replenishing ü PU.1/IRF8 dependent lineage that
begin populating the CNS during embryonic development
ü Do not traffic to draining lymph nodes (at detectable rates)
2) Peripheral monocytes /macrophages
that acutely infiltrate the CNS These cells are: ü CD45hi ü short lived ü rapidly replaced by bone marrow
derived cells in the adult ü Can traffic to draining lymph nodes
Trem1
Trem2 Macrophage
Trem2 Trem1
Microglia
Bkgrd
Bkgrd
mg
100 101 102 103 104
FL2-H
MJC050212.039 11.8MJC050212.030 11.4MJC050212.021 15.7MJC050212.012 11.2
live no boxesMJC050212.011Event Count: 27279
100 101 102 103 104
FL4-H
100
101
102
103
104
FL1-H
CD45 à
FcR
à
C. IP LPS injection MP
MG
So what do we know about TREM2 and neuroinflammation:
TREM2 up regulated
Cuprizone
Facial Axotomy In general, situations with increased cell
damage, changes in neuronal activity and/or TNF lead to increased microglial expression of
TREM2
Cell debris or TNF alone each are sufficient to increase microglial expression of TREM2
(Schmid et al. JNC 2002, 2009) Melchior et al. ASN NEURO 2010)
Please note the gene:
DAP12 = TYROBP = KARAP
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*# Trem2
Tmem176bD#
Blue=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 signaling leads to early onset cognitive dementia
(20’s) & death by the 40-50’s: Nasu-Hakola Disease
Tempting to speculate that normal age-
related decrease in TREM2 levels contributes to age-related susceptibility
for AD (Thrash et al. 2009)
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B: TREM2
PD2
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PD21
PD7
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PD21
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D: PD-L1
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F: MHC Class II
PD2
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G: CD40
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H. B7.2
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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 altered recognition of ligands leading to dysregulated TREM2 dependent microglial activation?
Phagocytosis
Antigen-presentation To T cells: activate, retain direct effector functions
Trafficking to lymph nodes
Tissue homeostasis
Tissue repair
Pathogen defense
Microglia not detected to traffick to cervical lymph
nodes
Microglia: yes TREM2 regulated
Microglia: Yes: TREM2 regulated
Microglia: Yes via innate and adaptive
immunity TREM2 regulated
Microglia: Yes, But as inhibitory/tolerogenic APCs
TREM2 regulated in vitro
Microglia: Yes, very active innate immunity and oxidative pathways
TREM2 regulated
TREM2 immunoreactivity: a caution
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*# Trem2
Tmem176bD#
Blue=non-transgenic wild-type; Red=APP23 transgenic
Microglia also produce soluble “decoy” form of receptor! Therefore reports of TREM2 immunoreactivity on non-microglia might reflect detection of the soluble variant of TREM2 binding these TREM2 ligands on neurons, glia and
perivascular macrophages Unpublished results, Schmid et al. 2002, Hamerman et al 2006,
Piccio et al. 2008, Hsieh et al.2009
TREM2 binding activity (putative ligand expression) is detected on reactive astrocytes, infiltrating macrophages (high levels) and stressed and/or apoptotic neurons, reactive and apoptotic glia
NINDS UCR Div of Biomed Sci PIC grant
UCR Chancellor’s Strategic Initiative Dana Foundation
Biogen Idec, Merck DOD; CRCC
Tammy Kielian
Caroline Whitacre
Emma Wilson
Kathryn Jones Virginia Sanders
Marco Colonna
Harald Neuman
Jenny Ting
Carson Lab Tiffany Butts
Deirdre S. Davis Alfredo Hernandez
Benoit Melchior Yoshinori Otani
Shweta Puntambekar Victoria Senechal
Christoph D. Schmid J. Cameron Thrash
Iryna M. Ethell Tina Bilousova Slawomir Sloniwski Peter Hickmott Devin Binder Mike Hsu
Microglia and Macrophages in brain development and neuroinflammation