Investigating the Role of Endosomal Toll-Like Receptors in Remyelination
Regulation of innate immunological self-tolerance, or the ability of cells to discern “self” from “non-self” has long been studied in the periphery in autoimmune disorders, especially in the context of nucleic acids (NA). Understanding of self-tolerance in the central nervous system (CNS), however, has not been thoroughly investigated despite expression of these NA-sensing TLRs by microglia, the primary phagocyte of the CNS. Published data from our lab highlights that microglia retain untranslated RNA transcripts from engulfed myelin for days after phagocytosis in vitro and in human multiple sclerosis patients. Based on these data, I hypothesized that these retained transcripts could aberrantly activate endosomal TLRs. I, thus, induced primary demyelination in UNC93B1 -/- mice, which lack functional NA-sensing TLRs, and observed that these mice remyelinate more efficiently than wildtype. These data suggest that signaling of NA-sensing TLRs suppresses remyelination during demyelinating disease. Several exciting questions have now arisen, which I will tackle in this proposal: 1) Is myelin phagocytosis causing aberrant endosomal TLR signaling? 2) Are microglia the primary cell type driving this response? 3) Does a specific NA-sensing TLR hinder remyelination? I hypothesize that TLR7 is aberrantly signaling in response to engulfed myelin RNAs in microglia and suppressing remyelination. To address these questions, I have acquired powerful in vivo molecular genetic tools to manipulate UNC93B1 and endosomal TLR function. I will first identify molecular pathways that are changed in microglia in vitro in response to chronic myelin phagocytosis and test whether these molecules are UNC93B1-dependent (Aim 1a). I will then determine if the UNC93B1 dependent effects that I observed on remyelination are microglia-specific (Aim 1b). Lastly, I will identify the endosomal TLR underlying these UNC93B1 effects (Aim 2). I am now in a strong position to molecularly dissect the role of NA sensing TLRs in remyelination during demyelinating disease, which has high long-term therapeutic potential.
