Transcript Profiles of Microglia/Macrophage Cells at the Borders of Chronic Active and Subpial Gray Matter Lesions in Multiple Sclerosis

Microglia/macrophages line the border of demyelinated lesions in both cerebral white matter and cortex in multiple sclerosis brains. Microglia/macrophages associated with chronic white-matter lesions are thought to be responsible for slow lesion expansion and disability progression in progressive multiple sclerosis whereas those lining gray matter lesions are less studied. Profiling these microglia/macrophages could help to focus therapies on genes or pathways specific to lesion expansion and disease progression. We compared the morphology and transcript profiles of microglia/macrophages associated with borders of white matter (WM line) and subpial gray matter lesions (GM line) using laser capture microscopy. We performed RNAseq on isolated cells followed by immunocytochemistry to determine distribution of translational products of transcripts increased in WM line. Cells in WM line appear activated with shorter processes and larger cell bodies, whereas those in GM Line appear more homeostatic with smaller cell bodies and multiple thin processes. Transcript profiling revealed 176 genes in WM lines and 111 genes in GM lines as differentially expressed. Transcripts associated with immune activation and iron homeostasis were increased in WM line whereas genes belonging to canonical Wnt signaling pathway were increased in GM line. We propose that mechanisms of demyelination and dynamics of lesion expansion are responsible for differential transcript expression in WM lines and GM lines, and posit that increased expression of Fc epsilon receptor, spleen tyrosine kinase, and Bruton’s tyrosine kinase play a key role in regulating microglia/macrophage function at the border of chronic active white matter lesions.