Microglial activation is a prominent feature of numerous neuropathologies including Alzheimer's disease, multiple sclerosis and stroke. As the tissue macrophage of the CNS, microglia have the potential to regulate and be regulated by cells of the CNS and by CNS-infiltrating immune cells. The exquisite sensitivity of microglia to these signals, coupled with their ability to develop a broad range of effector functions allows the CNS to tailor microglial function for specific physiological needs. As yet the mechanisms by which the CNS and the immune system regulate microglial function are incompletely defined. We have recently discovered that subsets of microglia in the healthy murine CNS constitutively express Triggering Receptors Expressed on Myeloid cells-2 (TREM-2), illustrating microglial heterogeneity not only between brain regions, but also even within a single brain region. While microglial expression of TREM-2 is repressed by LPS, expression was dramatically upregulated in transgenic mice overexpressing beta-amyloid but only in those cells immediately surrounding amyloid plaques. Conversely, while unactivated microglia do not express TREM-1, LPS-activated microglia do. Functionally, these receptors have the potential to regulate critical states of microglial activation and differentiation in potentially opposing directions. Our preliminary studies suggest microglia express additional and perhaps CNS-specific forms of these receptors. Some of these forms may have the potential to serve as """"""""decoy"""""""" receptors for the as yet unknown ligand(s) for these receptors. Here we propose 1) to clone, identify and generate antisera specific for each form, in order to characterize TREM expression in healthy and inflamed CNS; 2) dissect the potential intracellular signaling pathways triggered by these receptors; and 3) define the functional consequences of TREM expression by microglia. Our analysis will focus on signals and outcomes relevant for bacterial signals, CNS autoimmunity, and Alzheimer's disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045735-05
Application #
7022269
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Utz, Ursula
Project Start
2003-04-01
Project End
2008-02-28
Budget Start
2006-03-01
Budget End
2008-02-28
Support Year
5
Fiscal Year
2006
Total Cost
$278,303
Indirect Cost
Name
University of California Riverside
Department
Type
Schools of Medicine
DUNS #
627797426
City
Riverside
State
CA
Country
United States
Zip Code
92521
Ploix, Corinne C; Noor, Shahani; Crane, Janelle et al. (2011) CNS-derived CCL21 is both sufficient to drive homeostatic CD4+ T cell proliferation and necessary for efficient CD4+ T cell migration into the CNS parenchyma following Toxoplasma gondii infection. Brain Behav Immun 25:883-96
Puntambekar, Shweta S; Davis, Deirdre S; Hawel 3rd, Leo et al. (2011) LPS-induced CCL2 expression and macrophage influx into the murine central nervous system is polyamine-dependent. Brain Behav Immun 25:629-39
Melchior, Benoit; Garcia, Angie E; Hsiung, Bor-Kai et al. (2010) Dual induction of TREM2 and tolerance-related transcript, Tmem176b, in amyloid transgenic mice: implications for vaccine-based therapies for Alzheimer's disease. ASN Neuro 2:e00037
Schmid, Christoph D; Melchior, Benoit; Masek, Kokoechat et al. (2009) Differential gene expression in LPS/IFNgamma activated microglia and macrophages: in vitro versus in vivo. J Neurochem 109 Suppl 1:117-25
Thrash, J Cameron; Torbett, Bruce E; Carson, Monica J (2009) Developmental regulation of TREM2 and DAP12 expression in the murine CNS: implications for Nasu-Hakola disease. Neurochem Res 34:38-45
Carson, Monica J; Crane, Janelle; Xie, Alison X (2008) Modeling CNS microglia: the quest to identify predictive models. Drug Discov Today Dis Models 5:19-25
Carson, Monica J; Lo, David D (2007) Perspective is everything: an irreverent discussion of CNS-immune system interactions as viewed from different scientific traditions. Brain Behav Immun 21:367-73
Papenfuss, Tracey L; Thrash, J Cameron; Danielson, Patricia E et al. (2007) Induction of Golli-MBP expression in CNS macrophages during acute LPS-induced CNS inflammation and experimental autoimmune encephalomyelitis (EAE). ScientificWorldJournal 7:112-20
Carson, Monica J; Bilousova, Tina V; Puntambekar, Shweta S et al. (2007) A rose by any other name? The potential consequences of microglial heterogeneity during CNS health and disease. Neurotherapeutics 4:571-9
Plant, Sheila R; Iocca, Heather A; Wang, Ying et al. (2007) Lymphotoxin beta receptor (Lt betaR): dual roles in demyelination and remyelination and successful therapeutic intervention using Lt betaR-Ig protein. J Neurosci 27:7429-37

Showing the most recent 10 out of 14 publications