Profiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation

Clusters of ramified HLA-DR+ cells, known as microglia nodules, are associated with brain pathology. Here we investigated if microglia nodules in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) are different from microglia nodules in white matter (WM) in stroke and whether they may relate to the start of demyelinating MS lesions. We studied the relation between microglia nodules and pathological severity in an MS autopsy cohort (n=167), and we compared frequency, size, and gene expression of microglia nodules in MS (n=7) and stroke (n=7). MS donors with microglia nodules (64%) had a higher lesion load and a higher proportion of active lesions compared to donors without microglia nodules (36%). We found altered expression of genes in microglia nodules in MS compared to stroke, including genes previously shown to be upregulated in MS lesions. Genes associated with lipid metabolism, presence and proliferation of T and B cells, production of and response to immunoglobulins and cytokines (specifically TNF and IFN), activation of the complement cascade, and metabolic stress were upregulated. Using immunohistochemistry, we confirmed that in MS, more than in stroke, microglia nodules are associated with membrane attack complexes, have phagocytosed oxidized phospholipids, and have a tubular mitochondrial network reflecting increased metabolic activity. Furthermore, in MS, some nodules encapsulated partially demyelinated axons. Taken together, we propose that activation of some microglia nodules in MS by pro-inflammatory cytokines and immunoglobulins in combination with phagocytosis of oxidized phospholipids may lead to a volatile phenotype prone to form MS lesions.