Microglial Immunoreceptor Tyrosine-Based Activation and Inhibition Motif Signaling in Neuroinflammation

Neural Regeneration, Institute of Reconstructive Neurobiology, University Hospital Bonn, University Bonn, 53127 Bonn, Germany.
International Journal of Alzheimer's Disease 06/2010; 2010(6). DOI: 10.4061/2010/587463
Source: PubMed


Elimination of extracellular aggregates and apoptotic neural membranes without inflammation is crucial for brain tissue homeostasis. In the mammalian central nervous system, essential molecules in this process are the Fc receptors and the DAP12-associated receptors which both trigger the microglial immunoreceptor tyrosine-based activation motif- (ITAM-) Syk-signaling cascade. Microglial triggering receptor expressed on myeloid cells-2 (TREM2), signal regulatory protein-beta1, and complement receptor-3 (CD11b/CD18) signal via the adaptor protein DAP12 and activate phagocytic activity of microglia. Microglial ITAM-signaling receptors are counter-regulated by immunoreceptor tyrosine-based inhibition motif- (ITIM-) signaling molecules such as sialic acid-binding immunoglobulin superfamily lectins (Siglecs). Siglecs can suppress the proinflammatory and phagocytic activity of microglia via ITIM signaling. Moreover, microglial neurotoxicity is alleviated via interaction of Siglec-11 with sialic acids on the neuronal glycocalyx. Thus, ITAM- and ITIM-signaling receptors modulate microglial phagocytosis and cytokine expression during neuroinflammatory processes. Their dysfunction could lead to impaired phagocytic clearance and neurodegeneration triggered by chronic inflammation.

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Available from: Bettina Linnartz-Gerlach
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    • "c o m / l o ca t e / n e u a g i n g number 605086), a rare disease characterized by painful bone cysts, psychotic symptoms, and progressive presenile dementia (Paloneva et al., 2002). Upon TYROBP stimulation, an ITAM-src kinasesignaling pathway is initiated leading to cellular activation via a range of downstream cascades (Linnartz et al., 2010) and among other possible functions, phagocytosis. Although the endogenous ligand of TREM2 remains unknown, TREM2 has been shown to recognize lipopolysaccharides in the cell wall of bacteria and, on activation, triggers the phagocytic uptake of bacteria and the release of reactive oxygen species (Daws et al., 2003; N'Diaye et al., 2009). "
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    ABSTRACT: Rare variants in TREM2 cause susceptibility to late-onset Alzheimer's disease. Here we use microarray-based expression data generated from 101 neuropathologically normal individuals and covering 10 brain regions, including the hippocampus, to understand TREM2 biology in human brain. Using network analysis, we detect a highly preserved TREM2-containing module in human brain, show that it relates to microglia, and demonstrate that TREM2 is a hub gene in 5 brain regions, including the hippocampus, suggesting that it can drive module function. Using enrichment analysis we show significant overrepresentation of genes implicated in the adaptive and innate immune system. Inspection of genes with the highest connectivity to TREM2 suggests that it plays a key role in mediating changes in the microglial cytoskeleton necessary not only for phagocytosis, but also migration. Most importantly, we show that the TREM2-containing module is significantly enriched for genes genetically implicated in Alzheimer's disease, multiple sclerosis, and motor neuron disease, implying that these diseases share common pathways centered on microglia and that among the genes identified are possible new disease-relevant genes.
    Full-text · Article · Jul 2013 · Neurobiology of aging
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    • "TREM2 is thus an anti-inflammatory receptor that at the same time promotes phagocytic activity. TREM2 is intracellularly coupled to the adapter protein DAP12 (see for review: Linnartz et al., 2010), and interestingly, loss of function mutations of either TREM2 or DAP12 lead to a rare chronic neurodegenerative disease known as Nasu–Hakola or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), an inherited autosomal recessive human disease characterized by early onset presenile dementia (Colonna, 2003). "
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    ABSTRACT: One long standing aspect of microglia biology was never questioned; their involvement in brain disease. Based on morphological changes (retracted processes and amoeboid shape) that inevitably occur in these cells in case of damage in the central nervous system, microglia in the diseased brain were called "activated." Because "activated" microglia were always found in direct neighborhood to dead or dying neuron, and since it is known now for more than 20 years that cultured microglia release numerous factors that are able to kill neurons, microglia "activation" was often seen as a neurotoxic process. From an evolutionary point of view, however, it is difficult to understand why an important, mostly post-mitotic and highly vulnerable organ like the brain would host numerous potential killers. This review is aimed to critically reconsider the term microglia neurotoxicity and to discuss experimental problems around microglia biology, that often have led to the conclusion that microglia are neurotoxic cells.
    Full-text · Article · May 2013 · Frontiers in Cellular Neuroscience
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    • "Post-ischemic phagocytosis of cell debris is crucial for resolving inflammation and reconstitution of tissue homeostasis. Triggering receptor expressed on myeloid cells-2 (TREM2) is a microglial receptor which delivers intracellular signals via the adaptor protein DAP12 [7], [8]. It has been shown to clear apoptotic material by phagocytosis within an anti-inflammatory milieu [9], [10]. "
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    ABSTRACT: Triggering receptor expressed on myeloid cells-2 (TREM2) is a microglial surface receptor involved in phagocytosis. Clearance of apoptotic debris after stroke represents an important mechanism to re-attain tissue homeostasis and thereby ensure functional recovery. The role of TREM2 following stroke is currently unclear. As an experimental stroke model, the middle cerebral artery of mice was occluded for 30 minutes with a range of reperfusion times (duration of reperfusion: 6 h/12 h/24 h/2 d/7 d/28 d). Quantitative PCR (qPCR) revealed a greatly increased transcription of TREM2 after stroke. We subsequently analyzed the expression of pro-inflammatory cytokines, chemokines and their receptors in TREM2-knockout (TREM2-KO) mice via qPCR. Microglial activation (CD68, Iba1) and CD3-positive T-cell invasion were analyzed via qPCR and immunohistochemistry. Functional consequences of TREM2 knockout were assessed by infarct volumetry. The acute inflammatory response (12 h reperfusion) was very similar between TREM2-KO mice and their littermate controls. However, in the sub-acute phase (7 d reperfusion) following stroke, TREM2-KO mice showed a decreased transcription of pro-inflammatory cytokines TNFα, IL-1α and IL-1β, associated with a reduced microglial activity (CD68, Iba1). Furthermore, TREM2-KO mice showed a reduced transcription of chemokines CCL2 (MCP1), CCL3 (MIP1α) and the chemokine receptor CX3CR1, followed by a diminished invasion of CD3-positive T-cells. No effect on the lesion size was observed. Although we initially expected an exaggerated pro-inflammatory response following ablation of TREM2, our data support a contradictory scenario that the sub-acute inflammatory reaction after stroke is attenuated in TREM2-KO mice. We therefore conclude that TREM2 appears to sustain a distinct inflammatory response after stroke.
    Full-text · Article · Jan 2013 · PLoS ONE
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