Microglia activation triggers oligodendrocyte precursor cells apoptosis via HSP60

Abstract

Reactive microglia are present in lesions of myelin-associated white matter disorders resulting in injuries to oligodendrocyte precursor cells (OPCs). Therefore, protection of OPCs from injury due to excessive activation of microglia is important in treating these diseases. Heat shock protein 60 (HSP60) has been demonstrated to be released extracellularly in the failing heart upon stress or injury. However, the role of HSP60 in the central nervous system and whether it participates in the toxic effects of microglia on OPCs remains unclear. The present study used the co-culture, cell death assays, binding assays, immunochemistry, western blot and ELISA. HSP60 was demonstrated to be released extracellularly by LPS-activated microglia and to bind to OPCs, triggering OPC apoptosis. When pretreated with toll-like receptor (TLR) 4 blocking antibody, the viability of OPCs increased, while the expression of nuclear factor κB (NFκB), caspase 3 and the release of proinflammatory cytokines triggered by HSP60 decreased. These results suggest that HSP60 released by microglia may mediate OPC apoptosis through binding to TLR4 on the surface of OPCs and subsequently activating the TLR4-NFκB signaling pathway. HSP60 may, therefore, serve as a potential target for treatment of myelin-associated neurodegenerative diseases that are accompanied by microglia activation.

Heterogeneity of microglia and their differential roles in white matter pathology

“…In another study, LPS‐activated microglia secreted heat shock protein 60 (HSP60), a stress chaperone protein that has dual functions in cell apoptosis depending on specific conditions. These secreted HSP60 were found to bind to Toll‐like receptor (TLR) 4 of OPCs and initiated its apoptotic mechanism …”

“…These secreted HSP60 were found to bind to Toll-like receptor (TLR) 4 of OPCs and initiated its apoptotic mechanism. 86 On the other hand, recent studies have revealed protective roles of microglia during the remyelination phase. After myelin damage in MS model, a genome-wide gene expression analysis was performed for the microglia in corpus callosum during remyelination.…”

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

“…Despite that microglia are necessary for repairing the CNS in normal conditions, activated microglia suppress the processes of brain repair by inhibiting the differentiation of oligodendrocyte precursor cells into myelinating oligodendrocytes via distinct mechanisms including heat shock protein 60 production, NO‐dependent oxidative damage and TNF‐α signaling (Li, Zhang, et al, ; Pang et al, ). Following pathological alterations, extracellular adenosine triphosphate, a source of energy metabolism, produced by dead and injured neurons can in turn activate microglia via purinergic receptors (Liu & Wang, ).…”

Microglia heterogeneity along a spatio–temporal axis: More questions than answers

“…Depleting microglia reduces the number of OPCs in the corpus callosum and the extent of myelin formation, as seen in the marked reduction in expression of myelin-specific genes and proteins such as proteoliopid protein (PLP) and myelin basic protein (MBP; Hagemeyer et al, 2017). Microglial activation also triggers OPC apoptosis via HSP60 extracellular release and the TLR4-NFκβ signaling pathway (Li et al, 2017). These postnatal microglia are characterized by CD11c expression (and high production of Igf1) and are predominantly found in primary myelinating areas (Wlodarczyk et al, 2017).…”