Microglia-derived TNFa induces apoptosis in neural precursor cells via transcriptional activation of the Bcl-2 family member Puma

Cell Death and Disease, 2013 · DOI: 10.1038/cddis.2013.59 · Published: March 14, 2013

Simple Explanation

Neuroinflammation, a feature of neurological conditions, can harm neural precursor cells (NPCs), limiting regeneration. This study shows that tumor necrosis factor alpha (TNFa) from activated microglia triggers apoptosis in mouse NPCs. Microglia-derived TNFa induces NPC apoptosis through a mitochondrial pathway, regulated by the Bcl-2 family protein Bax. The BH3-only protein Puma is induced in NPCs via an NF-κB-dependent mechanism. NPC apoptosis induced by activated microglia-derived TNFa is reduced in Puma-deficient NPCs. Puma-deficient NPCs show increased survival after transplantation into the injured spinal cord, suggesting Puma induction is required for NPC death.

Study Duration

Not specified

Participants

Mouse neural precursor cells in vitro and in vivo

Evidence Level

Not specified

Key Findings

1
TNFa produced by LPS-activated microglia is necessary and sufficient to trigger apoptosis in mouse NPCs in vitro.
2
Microglia-derived TNFa induces the expression of the BH3-only family member Puma in NPCs via an NF-κB-dependent mechanism.
3
NPC apoptosis induced by activated microglia-derived TNFa is attenuated in Puma-deficient NPCs, indicating that Puma induction is required for NPC death.

Research Summary

This study investigates the mechanisms by which neuroinflammatory processes induce neural precursor cell (NPC) death, focusing on the role of microglia and tumor necrosis factor α (TNFα). The research demonstrates that TNFα produced by activated microglia induces NPC apoptosis via a mitochondrial pathway regulated by the Bcl-2 family protein Bax, with the BH3-only protein Puma playing a critical role. The findings highlight a key signaling pathway involving NF-κB-dependent transcriptional induction of Puma, which regulates NPC survival during neuroinflammatory responses both in vitro and in the injured nervous system in vivo.

Practical Implications

Therapeutic Target Identification

The identification of the TNFα/NF-κB/Puma pathway offers potential therapeutic targets for promoting regeneration and repair in neurological conditions.

Improving Cell Transplantation

Understanding Puma's role in NPC death can lead to strategies for enhancing the survival of transplanted cells in inflammatory environments, such as the injured spinal cord.

Modulating Microglial Activity

Interventions aimed at modulating microglial activation and reducing TNFα production could mitigate NPC apoptosis and promote neurogenesis.

Study Limitations

1
The study primarily uses a mouse microglia cell line (EOC-20), which may not fully represent the complexity of microglia in vivo.
2
The in vivo experiments focus on spinal cord injury; the generalizability of the findings to other neurological conditions needs further investigation.
3
The study identifies Puma as a key regulator, but other factors and pathways may also contribute to neuroinflammation-induced NPC apoptosis.

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