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TREM2 regulates microglial cell activation in response to demyelination in vivo

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Abstract

Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2−/−) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2−/− microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2−/− microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage.

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Acknowledgments

The authors thank Drs. Gregory F. Wu, Jessica Williams and Erika D. Koval for critical discussions, advice and/or for reading the manuscript; Dr. Marco Colonna for providing TREM2−/− mice; Mike Ramsbottom for technical assistance. This work was supported by grants from Fondazione Italiana Sclerosi Multipla (FISM) [2009/R/33 to L.P.], the National Multiple Sclerosis Society (NMSS, JF 2144A2/1 to L.P.) and the Dana Foundation “Program in the Neuroimmunology and Brain Infections and Cancer” (to L.P.). C.C. is a FISM fellow (2012/B/1). Histological support came from NIH PO1 NS059560 Core B to RSK. L.P. is a Harry Weaver Neuroscience Scholar of the NMSS. A.H·C. was supported by the Manny and Rosalyn Rosenthal Dr. John L. Trotter Chair in Neuroimmunology from Barnes-Jewish Hospital Foundation. GTAC is supported by NCI Cancer Center Support Grant #P30 CA91842, ICTS/CTSA Grant# UL1 TR000448 from the National Center for Research Resources (NCRR), and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH.

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Authors and Affiliations

  1. Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St Louis, MO, 63110, USA

    Claudia Cantoni, Bryan Bollman, Robert Mikesell, Carla M. Yuede, Anne H. Cross & Laura Piccio

  2. CBM Scrl -Genomics, Area Science Park, Basovizza, Trieste, Italy

    Danilo Licastro

  3. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA

    Mingqiang Xie & Robert Schmidt

  4. Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy

    Daniela Galimberti

  5. Department of Medical Biosciences/Physiological Chemistry, Umeå University, 901 87, Umeå, Sweden

    Gunilla Olivecrona

  6. Department of Medicine, Washington University School of Medicine, St Louis, MO, USA

    Robyn S. Klein

  7. Immunology Research, Biogen Idec, 12 Cambridge Center, Cambridge, MA, 02142, USA

    Karel Otero

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  1. Claudia Cantoni
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Correspondence to Karel Otero or Laura Piccio.

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401_2015_1388_MOESM1_ESM.tif

Supplementary Fig. 1 Immuno-EM images indicating the presence of compacted or non-compacted myelin debris in WT and TREM2−/− mice at 3,000× (left column) and 15,000× (right column). Boxes indicate region of interest shown in higher magnification images on the right. Microglia were labeled with Iba and are marked with asterisks. WT mice at 4 weeks of cuprizone treatment contain small amounts of non-compacted myelin outside of microglia (white arrows) and inside microglia (black arrows). After 12 weeks of cuprizone treatment, the non-compacted myelin has been cleared, and remyelination can be seen by the presence of axons wrapped by compacted myelin (Ax). TREM2−/− mice at 4 weeks of treatment contain large amounts of non-compacted myelin outside of microglia (white arrows). After 12 weeks of treatment, TREM2−/− mice still contain significant amounts of non-compacted myelin outside of microglia (white arrows) and inside of microglia (black arrows). (TIFF 38348 kb)

401_2015_1388_MOESM2_ESM.tif

Supplementary Fig. 2 Defect in lipid metabolism in TREM2−/− mice. (a) Gene expression data for the 12 weeks on CPZ were uploaded to IPA for network analysis. Genes with a logarithmic fold change (TREM2−/− vs. WT mice) ≥ 1 and adjusted P value ≤ 0.05 were included in the analysis. The “Lipid Metabolism, Molecular Transport, Small Molecule Biochemistry” was the top network that was significantly altered in TREM2−/− compared to WT (score of 46) and it is presented in a. Red objects denote proteins that had increased gene expression, green objects denote proteins that had decreased gene expression in TREM2−/− compared to WT mice. Solid connecting lines imply direct relationship between proteins; dotted lines imply indirect interactions. (b) Analysis with the Ingenuity downstream effect analysis identified the cellular concentration of fatty acid as the biological function that is affected given the observed gene expression change. Red objects denote proteins with increased gene expression, green objects denote proteins with decreased gene expression in TREM2−/− vs. WT. Orange or yellow arrows denote when the change is consistent or inconsistent with the downstream effect, respectively. (c) LPL gene expression quantification by qRT-PCR in purified WT and TREM2−/− microglia from naïve mice (n = 3/group) or mice after 4 weeks on CPZ (from n = 6 WT and 8 TREM2−/− mice). (d) LPL protein expression quantification by IHC in the CC of naïve WT and TREM2−/− mice or after 4 weeks on CPZ (n = 4/group). Values are given as mean ± SD. * P ≤ 0.05; **P ≤ 0.001 using Mann–Whitney test (TIFF 23230 kb)

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Cantoni, C., Bollman, B., Licastro, D. et al. TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol 129, 429–447 (2015). https://doi.org/10.1007/s00401-015-1388-1

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