Genetic models of cleavage-reduced and soluble TREM2 reveal distinct effects on myelination and microglia function in the cuprizone model.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a cell-surface immunoreceptor expressed on microglia, osteoclasts, dendritic cells and macrophages. Heterozygous loss-of-function mutations in TREM2, including mutations enhancing shedding form the cell surface, have been associated with myelin/neuronal loss and neuroinflammation in neurodegenerative diseases, such as Alzheimer`s disease and Frontotemporal Dementia. Using the cuprizone model, we investigated the involvement of soluble and cleavage-reduced TREM2 on central myelination processes in cleavage-reduced (TREM2-IPD), soluble-only (TREM2-sol), knockout (TREM2-KO) and wild-type (WT) mice. The TREM2-sol mouse is a new model with selective elimination of plasma membrane TREM2 and a reduced expression of soluble TREM2. In the acute cuprizone model demyelination and remyelination events were reflected by a T2-weighted signal intensity change in magnetic resonance imaging (MRI), most prominently in the external capsule (EC). In contrast to WT and TREM2-IPD, TREM2-sol and TREM2-KO showed an additional increase in MRI signal during the recovery phase. Histological analyses of TREM2-IPD animals revealed no recovery of neuroinflammation as well as of the lysosomal marker LAMP-1 and displayed enhanced cytokine/chemokine levels in the brain. TREM2-sol and, to a much lesser extent, TREM2-KO, however, despite presenting reduced levels of some cytokines/chemokines, showed persistent microgliosis and astrocytosis during recovery, with both homeostatic (TMEM119) as well as activated (LAMP-1) microglia markers increased. This was accompanied, specifically in the EC, by no myelin recovery, with appearance of myelin debris and axonal pathology, while oligodendrocytes recovered. In the chronic model consisting of 12-week cuprizone administration followed by 3-week recovery TREM2-IPD displayed sustained microgliosis and enhanced remyelination in the recovery phase. Taken together, our data suggest that sustained microglia activation led to increased remyelination, whereas microglia without plasma membrane TREM2 and only soluble TREM2 had reduced phagocytic activity despite efficient lysosomal function, as observed in bone marrow-derived macrophages, leading to a dysfunctional phenotype with improper myelin debris removal, lack of remyelination and axonal pathology following cuprizone intoxication.

Beckmann N ，Neuhaus A ，Zurbruegg S ，Volkmer P ，Patino C ，Joller S ，Feuerbach D ，Doelemeyer A ，Schweizer T ，Rudin S ，Neumann U ，Berth R ，Frieauff W ，Gasparini F ，Shimshek DR ... -  《Journal of Neuroinflammation》

Brain region-specific enhancement of remyelination and prevention of demyelination by the CSF1R kinase inhibitor BLZ945.

Beckmann N ，Giorgetti E ，Neuhaus A ，Zurbruegg S ，Accart N ，Smith P ，Perdoux J ，Perrot L ，Nash M ，Desrayaud S ，Wipfli P ，Frieauff W ，Shimshek DR ... -  《Acta Neuropathologica Communications》

TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis.

Cignarella F ，Filipello F ，Bollman B ，Cantoni C ，Locca A ，Mikesell R ，Manis M ，Ibrahim A ，Deng L ，Benitez BA ，Cruchaga C ，Licastro D ，Mihindukulasuriya K ，Harari O ，Buckland M ，Holtzman DM ，Rosenthal A ，Schwabe T ，Tassi I ，Piccio L ... -  《-》

TREM2 regulates microglial cell activation in response to demyelination in vivo.

Cantoni C ，Bollman B ，Licastro D ，Xie M ，Mikesell R ，Schmidt R ，Yuede CM ，Galimberti D ，Olivecrona G ，Klein RS ，Cross AH ，Otero K ，Piccio L ... -  《-》

Astrocyte-targeted production of interleukin-6 reduces astroglial and microglial activation in the cuprizone demyelination model: Implications for myelin clearance and oligodendrocyte maturation.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. Interleukin (IL)-6 is a pleiotropic cytokine with a potential role in MS. Here we used transgenic mice with astrocyte-targeted production of IL-6 (GFAP-IL6Tg) to study the effect of IL-6 in the cuprizone-induced demyelination paradigm, which is an experimental model of de- and re-myelination, both hallmarks of MS. Our results demonstrated that cuprizone-treated GFAP-IL6Tg mice showed a significant reduction in astroglial and especially microglial activation/accumulation in the corpus callosum in comparison with the corresponding cuprizone-treated wild type (WT). Production of a key microglial attracting chemokine CXCL10, as well as CXCL1 and CCL4 was lower in cuprizone-treated GFAP-IL6Tg mice compared with cuprizone-treated WT. Reduced microglial cell accumulation was associated with inefficient removal of degraded myelin and axonal protection in cuprizone-treated GFAP-IL6Tg mice, compared with WT mice at the peak of demyelination. In addition, transgenic production of IL-6 did not alter initial oligodendrocyte (OL) apoptosis and oligodendrocyte precursor cell recruitment to the lesion site, but it impaired early OL differentiation, possibly due to impaired removal of degraded myelin. Indeed, a microglial receptor involved in myelin phagocytosis, TREM2, as well as the phagolysosomal protein CD68 were lower in cuprizone-treated GFAP-IL6Tg compared with WT mice. Our results show for the first time that astrocyte-targeted production of IL-6 may play a role in modulating experimental demyelination induced by cuprizone. Further understanding of the IL-6-mediated molecular mechanisms involved in the regulation of demyelination is needed, and may have implications for the development of future therapeutic strategies for the treatment of MS. GLIA 2016;64:2104-2119.

Petković F ，Campbell IL ，Gonzalez B ，Castellano B ... -  《-》