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Microglia extracellular traps (MiETs) in Neurodegeneration: Mechanisms, Evidence Gaps, and Untapped Therapeutic
1Department of Bioscience and Bioengineering, Indian Institute of Technology, Jodhpur, India.
Abstract:
Microglia are the resident myeloid cells of the central nervous system, they play essential roles in neural tissue homeostasis, including synaptic pruning, clearance of debris and protein aggregates, and regulation of neuroinflammatory processes. In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, microglial activation and chronic glial-driven inflammation contribute substantially to neuronal dysfunction and loss. Beyond these well-characterised functions, recent evidence indicates that microglia can release chromatin-based extracellular traps (microglia extracellular traps, or MiETs), similar to the neutrophil extracellular traps (NETs) observed in peripheral immunity. Microglia ETs are induced by stimuli such as dopamine and microbial infection, dependent or independent of NADPH oxidase/ROS pathways and histone citrullination. This chapter provides a detailed examination of MiET formation, triggers, intracellular signalling, and structural components, as well as contribution to neurodegenerative pathology. Potential mechanisms include amplification of neuroinflammation via extracellular histones and proteases, disruption of the blood-brain barrier and extracellular matrix, synaptic damage, and possible facilitation of spread of misfolded protein aggregates. We situate MiET formation within the broader microglial functional repertoire (phagocytosis, cytokine production, synaptic stripping) and focus on how ET-dominant responses may compromise homeostatic or neuroprotective roles. The chapter reviews evidence from disease models, highlights key gaps and discusses translational implications. Targeting MiET formation or promoting the clearance of MiETs represents promising, yet unexplored, therapeutic avenues in neurodegenerative disease. By focusing on MiETs, this work expands the conceptual framework for microglial pathogenicity and invites future mechanistic and translational research.
Insights
Microglia release chromatin extracellular traps (MiETs) that contribute to neuroinflammation and neuronal damage in neurodegenerative diseases. Targeting MiETs offers a novel therapeutic strategy for conditions like Alzheimer's and Parkinson's disease.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are crucial for central nervous system homeostasis.
- Dysfunctional microglia and neuroinflammation drive neurodegenerative diseases.
- Emerging evidence shows microglia form extracellular traps (MiETs).
Purpose of the Study:
- To examine microglia extracellular trap (MiET) formation, triggers, and role in neurodegeneration.
- To understand how MiETs contribute to neuroinflammatory processes.
- To explore MiETs as potential therapeutic targets.
Main Methods:
- Review of existing literature on MiETs.
- Analysis of signaling pathways and structural components of MiETs.
- Examination of evidence from neurodegenerative disease models.
Main Results:
- MiETs are induced by stimuli like dopamine and infection.
- MiETs can amplify neuroinflammation via extracellular histones and proteases.
- MiETs contribute to blood-brain barrier disruption, synaptic damage, and protein aggregate spread.
Conclusions:
- MiET formation represents a pathogenic microglial response.
- Targeting MiETs presents a promising therapeutic avenue for neurodegenerative diseases.
- Further research is needed to elucidate MiET mechanisms and therapeutic potential.
