TREM2 regulates microglial cell activation in response to demyelination in vivo

Cantoni, Claudia; Bollman, Bryan; Licastro, Danilo; Xie, Meili; Mikesell, Robert; Schmidt, Robert E.; Yuede, Carla M.; Galimberti, Daniela; Olivecrona, Gunilla; Klein, Robyn S.; Cross, Anne H.; Otero, Karel; Piccio, Laura

doi:10.1007/s00401-015-1388-1

Cited by 235 publications

(273 citation statements)

References 85 publications

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“…TREM2 is expressed in innate immune cells (e.g. dendritic cells and macrophages) implicated in host defense [9] while in the CNS TREM2 is involved in microglia activation and phagocytosis in response to injury [7,42]. Consistently with this, our genetic analyses found an enrichment of pathways involved in virus endocytosis, transport and intracellular vesicular trafficking.…”

Section: Discussionsupporting

confidence: 79%

Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status

et al. 2016

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Low frequency coding variants in TREM2 are associated with increased Alzheimer disease (AD) risk, while loss of functions mutations in the gene lead to an autosomal recessive early-onset dementia, named Nasu-Hakola disease (NHD). TREM2 can be detected as a soluble protein in cerebrospinal fluid (CSF) and plasma, and its CSF levels are elevated in inflammatory CNS diseases. We measured solubleTREM2 (sTREM2) in the CSF of a large AD case-control dataset (n=180) and 40 TREM2 risk variant carriers to determine whether CSF sTREM2 levels are associated with AD status or mutation status. We also performed genetic studies to identify genetic variants associated with CSF sTREM2 levels. CSF, but not plasma, sTREM2 was highly correlated with CSF total tau and phosphorylated-tau levels (r=0.35, p<1×10-4; r=0.40, p<1×10-4 respectively), but not with CSF Aβ42. AD cases presented higher CSF sTREM2 levels than controls (P=0.01). Carriers of NHD-associated TREM2 variants presented significantly lower CSF sTREM2 levels, supporting the hypothesis that these mutations lead to reduced protein production/function (R136Q, D87N, Q33X or T66M; p=1×10-3). In contrast, CSF sTREM2 levels were significantly higher in R47H carriers compared to non-carriers (P=6×10-3), suggesting that this variant does not impact protein expression and increases AD risk through a different pathogenic mechanism than NHD variants. In GWAS analyses for CSF sTREM2 levels the most significant signal was located on the MS4A gene locus (P=5.45×10-07) corresponding to one of the SNPs reported to be associated with AD risk in this locus. Furthermore, SNPs involved in pathways related to virus cellular entry and vesicular trafficking were overrepresented, suggesting that CSF sTREM2 levels could be an informative phenotype for AD.

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Section: Discussionsupporting

confidence: 79%

Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status

et al. 2016

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“…However, recent work demonstrated that loss of Trem2 leads either to microglial degeneration in different diseases of the central nervous system [55,66,11], or conversely to protection [34]. Thus, the exact mechanisms underlying 5-HT 2B R-mediated regulation of microglial survival and the role of scavenger receptors in this response will have to be investigated in further studies.…”

Section: Discussionmentioning

confidence: 99%

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

et al. 2016

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Abstract:Microglia are the resident phagocytes of the central nervous system and have been implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). During neurodegeneration, microglial activation is accompanied by infiltration of circulating monocytes, leading to overall increased phagocytic activity and production of multiple inflammatory mediators in the spinal cord. Degenerative alterations in monocytes and microglia are commonly observed during neurodegenerative diseases, yet little is known concerning the mechanisms leading to their degeneration, or the consequences on disease progression. Here we observed that the serotonin 2B receptor (5-HT 2B ), a serotonin receptor expressed in microglia, is upregulated in the spinal cord of three different transgenic mouse models of ALS. In mutant SOD1 mice, this upregulation was restricted to cells positive for CD11b, a marker of mononuclear phagocytes. Ablation of 5-HT 2B receptor in transgenic ALS mice expressing mutant SOD1 resulted in increased degeneration of mononuclear phagocytes, as evidenced by fragmentation of Iba1-positive cellular processes. This was accompanied by decreased expression of key neuroinflammatory genes but also loss of expression of homeostatic microglial genes. Importantly, the dramatic effect of 5-HT 2B receptor ablation on mononuclear phagocytes was associated with acceleration of disease progression. To determine the translational relevance of these results, we studied polymorphisms in the human HTR2B gene, which encodes the 5-HT 2B receptor, in a large cohort of ALS patients. In this cohort, the C allele of SNP rs10199752 in HTR2B was associated with longer survival. Moreover, patients carrying one copy of the C allele of SNP rs10199752 showed increased 5-HT 2B mRNA in spinal cord and displayed less pronounced degeneration of mononuclear phagocytes than patients carrying two copies of the more common A allele. Thus functional 5-HT 2B receptors limit degeneration of spinal cord macrophages (most likely microglia), and slow disease progression in ALS. Targeting this receptor might be therapeutically useful.

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“…In the cuprizone-induced model of demyelinating disease, Trem2-deficient mice presented fewer activated microglia in the corpus callosum compared to wild-type mice; this corresponded to a defect in myelin clearance as well as to an increase in axonal pathology as evidenced from immunohistochemistry [146]. Remyelination after injury in Trem2 KO mice was also impaired, as was the microglial transcriptional response for genes involved in phagocytosis and lipid metabolism [55].…”

Section: Trem2 In Demyelination/remyelinationmentioning

confidence: 96%