Dual Role of Microglia: Neuroprotection and Neurotoxicity in Neurodegenerative Diseases

Article Impact Level: HIGH
Data Quality: STRONG
Summary of Neurobiology of Disease https://doi.org/10.1016/j.nbd.2025.107133  
Dr. Amir Ajoolabady  et al.

Points

Microglia are the principal innate immune cells of the central nervous system, mediating neuroinflammation and playing a dual role in brain pathology.
This dual role involves two distinct states: neuroprotection through suppression of pro-inflammatory signaling and neurotoxicity through the promotion of chronic inflammation.
The binary function of microglia is influenced by a complex network of internal and external molecular effectors that regulate the cell’s polarization state.
Particular focus is given to two key proteins, TREM2 and HMGB1, whose molecular mechanisms critically determine microglial fate and function in the brain.
Modulating pathways involving these proteins offers promising therapeutic opportunities to control neuroinflammation and advance novel treatments for neurodegenerative diseases.

Summary

This narrative review explores the complex and dual role of microglia—the principal innate immune cells of the central nervous system (CNS)—in mediating neuroinflammation across neurodegenerative and other brain disorders. Microglia exhibit two distinct functional states: a neuroprotective mode that promotes anti-inflammatory polarization and suppresses pro-inflammatory signaling, and a neurotoxic mode that amplifies chronic neuroinflammation through activation of pro-inflammatory pathways. This divergence is governed by a dynamic network of molecular effectors acting within and outside the cell.

The review emphasizes two critical regulatory proteins: Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) and High Mobility Group Box 1 (HMGB1). The mechanisms involving these proteins are central to determining microglial polarization and functional outcomes within the CNS microenvironment. Although specific quantitative data such as cell counts or hazard ratios are not included, the discussion provides mechanistic insight into how these pathways influence neuroinflammatory balance.

By analyzing the signaling pathways associated with TREM2 and HMGB1, the review identifies them as promising therapeutic targets for modulating microglial activity. Shifting microglia from a pro-inflammatory, neurotoxic phenotype toward an anti-inflammatory, neuroprotective state represents a key strategy for developing targeted treatments against neurodegenerative and other CNS diseases.

Link to the article: https://www.sciencedirect.com/science/article/pii/S096999612500350X?via%3Dihub

References

Ajoolabady, A., Kim, B., Abdulkhaliq, A. A., Ren, J., Bahijri, S., Tuomilehto, J., Borai, A., Khan, J., & Pratico, D. (2025). Dual role of microglia in neuroinflammation and neurodegenerative diseases. Neurobiology of Disease, 216, 107133. https://doi.org/10.1016/j.nbd.2025.107133