Spatial characterisation of TREM2 expression in actively demyelinating multiple sclerosis lesions supports its key roles in lipid metabolic pathways

Reactive macrophages and microglia are predominant myeloid cell types in demyelinating multiple sclerosis (MS) lesions in the central nervous system (CNS). Triggering receptor expressed on myeloid cells-2 (TREM2) promotes clearance of myelin debris, supporting remyelination in preclinical models. However, the relevance of TREM2 in people with MS is less understood. We evaluated TREM2 expression and function in autopsy CNS tissues from individuals with and without MS. Spatial transcriptomics and gene co-expression network analysis revealed TREM2 expression in chronic active MS lesioned white matter, where it was localised to glial cell rich clusters associated with lipid and cholesterol metabolism, cellular heat acclimation pathways, and regulation of oligodendrocyte precursor migration and differentiation. Immunofluorescence analysis confirmed that TREM2 was highly expressed in actively demyelinating MS white matter lesions (active lesion centres and chronic active lesion rims). In these areas, TREM2 was found in reactive microglia, perivascular macrophages, and infiltrating parenchymal macrophages. Similarities were observed between perilesional white matter (PLWM) and chronic active lesion rims, including presence of TREM2+ reactive microglia, which were rare in normal appearing white matter (NAWM). TREM2+ cells co-expressed microglia/macrophage markers Iba1, MHC class II, MS4A4A, CD68 and/or CD163, and PLIN2, a lipid storage marker. Almost all TREM2+ cells in active demyelinating white matter were also PLIN2+, while these cells were absent in NAWM. Abluminal TREM2+ PLIN2+ CD163+ vessel macrophages were particularly prominent in actively demyelinating MS white matter where they may play important roles in lipid metabolism and storage in the context of active demyelination. These findings highlight the involvement of TREM2 on both resident and infiltrating myeloid cell populations in response to the demyelinating insult within MS lesions that may directly or indirectly impact local oligodendrocyte myelination capacity and neuroprotection.