Acute TREM2 Blockade Impairs Remyelination by Reducing MAFB-High Microglia

We investigated the role of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in myelin regeneration in the brain. TREM2 is a receptor found on microglia, which are crucial for clearing myelin debris and promoting remyelination. Previous studies in a mouse model of demyelination induced by the copper-chelating agent Cuprizone (CPZ) have shown that stimulation of TREM2 with a monoclonal antibody reduces demyelination, while deleting the Trem2 gene in mice impairs remyelination. Here we blocked TREM2 function acutely with an antibody during both the demyelination and remyelination phases and analyzed the impact of the antibody on myelination and gene expression in single cells. We found that blocking TREM2 depleted a specific population of microglia characterized by high expression of the transcription factor MAFB during remyelination. These MAFB-high microglia were crucial for myelin repair, and their depletion led to impairment of myelinating oligodendrocytes. Importantly, we identified MAFB+ microglia in acute and acute-chronic brain lesions from individuals with multiple sclerosis (MS), but not in inactive lesions. We conclude that TREM2 is essential for maintaining a population of MAFB-high microglia that are critical for myelin repair. This finding has important implications for understanding demyelinating diseases like MS and suggests that stimulating TREM2 could be a potential therapeutic strategy. Overall design: To characterize the role of TREM2 blockade in the CNS during de- and re-myelination, eight-week-old male wild-type (WT) mice were divided into 5 experimental groups. A) Untreated: fed regular chow for 5 weeks. B) CPZ + control (Ctrl) IgG2a: fed 0.2% CPZ diet for 5 weeks to induce demyelination and injected intraperitoneally (i.p.) with Ctrl IgG2a during demyelination. C) CPZ + anti-TREM2: fed 0.2% CPZ diet and injected i.p. with anti-TREM2 during demyelination. D) Remyelination + Ctrl IgG2a: fed 0.2% CPZ diet initially, then returned to regular chow for 2 weeks to allow remyelination, and injected i.p. with Ctrl IgG2a during remyelination. E) Remyelination + anti-TREM2: fed 0.2% CPZ diet initially, then returned to regular chow for 2 weeks, and injected i.p. with anti-TREM2 during remyelination.