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Microglia activation triggers oligodendrocyte precursor cells apoptosis via HSP60
Yunhong Li1, Rui Zhang1, Xiaolin Hou2
1Ningxia Key Laboratory of Cerebrocranial Diseases, Basic Medical College of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China.
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.
Insights
Heat shock protein 60 (HSP60) released by activated microglia induces oligodendrocyte precursor cell (OPC) death. Blocking toll-like receptor 4 (TLR4) protects OPCs, suggesting HSP60-TLR4 signaling as a therapeutic target for white matter disorders.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Reactive microglia are implicated in myelin-associated white matter disorders, causing injury to oligodendrocyte precursor cells (OPCs).
- Extracellular heat shock protein 60 (HSP60) is released during cellular stress, but its role in the central nervous system, particularly in microglia-mediated OPC injury, is unknown.
Purpose of the Study:
- To investigate the role of extracellular HSP60 released by microglia in oligodendrocyte precursor cell (OPC) apoptosis.
- To elucidate the underlying molecular mechanisms, including the involvement of toll-like receptor 4 (TLR4) and the NFκB pathway.
Main Methods:
- Co-culture systems, cell death assays, binding assays, immunochemistry, western blot, and ELISA were employed.
- The study utilized lipopolysaccharide (LPS)-activated microglia and oligodendrocyte precursor cells (OPCs).
- Toll-like receptor (TLR) 4 blocking antibody was used to assess its protective effects.
Main Results:
- LPS-activated microglia released extracellular HSP60, which bound to OPCs and induced apoptosis.
- Pretreatment with a TLR4 blocking antibody increased OPC viability.
- Blocking TLR4 reduced HSP60-induced expression of NFκB, caspase 3, and proinflammatory cytokines.
Conclusions:
- Microglia-released HSP60 mediates oligodendrocyte precursor cell (OPC) apoptosis via binding to TLR4 and activating the TLR4-NFκB signaling pathway.
- HSP60 represents a potential therapeutic target for treating myelin-associated neurodegenerative diseases characterized by microglia activation.
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