Regulation of microglial TMEM119 and P2RY12 immunoreactivity in multiple sclerosis white and grey matter lesions is dependent on their inflammatory environment

Abstract

Multiple Sclerosis (MS) is the most common cause of acquired neurological disability in young adults, pathologically characterized by leukocyte infiltration of the central nervous system, demyelination of the white and grey matter, and subsequent axonal loss. Microglia are proposed to play a role in MS lesion formation, however previous literature has not been able to distinguish infiltrated macrophages from microglia. Therefore, in this study we utilize the microglia-specific, homeostatic markers TMEM119 and P2RY12 to characterize their immunoreactivity in MS grey matter lesions in comparison to white matter lesions. Furthermore, we assessed the immunological status of the white and grey matter lesions, as well as the responsivity of human white and grey matter derived microglia to inflammatory mediators. We are the first to show that white and grey matter lesions in post-mortem human material differ in their immunoreactivity for the homeostatic microglia-specific markers TMEM119 and P2RY12. In particular, whereas immunoreactivity for TMEM119 and P2RY12 is decreased in the center of WMLs, immunoreactivity for both markers is not altered in GMLs. Based on data from post-mortem human microglia cultures, treated with IL-4 or IFNγ+LPS and on counts of CD3+ or CD20+ lymphocytes in lesions, we show that downregulation of TMEM119 and P2RY12 immunoreactivity in MS lesions corresponds with the presence of lymphocytes and lymphocyte-derived cytokines within the parenchyma but not in the meninges. Furthermore, the presence of TMEM119+ and partly P2RY12+ microglia in pre-active lesions as well as in the rim of active white and grey matter lesions, in addition to TMEM119+ and P2RY12+ rod-like microglia in subpial grey matter lesions suggest that blocking the entrance of lymphocytes into the CNS of MS patients may not interfere with all possible effects of TMEM119+ and P2RY12+ microglia in both white and grey matter MS lesions.

Distinct gene expression profiles in leukocortical demyelinated white and grey matter areas of Multiple Sclerosis patients

“…Similarly to IBA-1, we found that both WMLs and GMLs did not show a no significant differences in expression of homeostatic microglia markers such as TMEM119 and P2RY12 (Fig. 5a,b), although a tendency to downregulation of TMEM119 in the chronic active WM demyelinated area was present corresponding to what we reported before 24 . In addition, we observed no difference in expression in leukocortical lesions of two known microglial activation markers for MS lesions, CD74 and HLA-DR ( Fig.…”

“…By studying ITGAX at the immunohistochemical level (i.e. CD11c) we confirmed the selective regulation of CD11c in the GM area of leukocortical lesions and can thus be used as a potential new marker for a subset of microglia involved in the pathology of MS GMLs where there is no increase in HLA-DR expression at the gene and protein level 24 .…”

Human microglia upregulate cytokine signatures and accelerate maturation of neural networks

“…S1H, J, S2B). This expression pattern has been recently reported in early postnatal mouse brain, and shown to be associated with proliferative zones (13) and white matter (4,26,27). This cluster was found across all stages of development and all brain regions ( Fig 1D-E).…”

Patterns of Expression of Purinergic Receptor P2RY12, a Putative Marker for Non-Activated Microglia, in Aged and Alzheimer’s Disease Brains

“…P2RY12-expressing microglia in astrocytomas were increased in low-grade but reduced in high-grade tumors [31]. Immunohistochemistry of human brain sections from multiple sclerosis cases confirmed loss of P2RY12 microglial immunoreactivity in areas associated with enhanced inflammation [22,30,32,33]. Another study in 2 AD cases showed that microglia positive for P2RY12 did not express TREM-2 [34].…”