Microglial state dynamics in neuroinflammation: Mechanisms, transitions, and therapeutic frontiers

Microglia, the resident immune sentinels of the central nervous system (CNS), have emerged as central regulators of immune–neural interactions and homeostatic maintenance. Once believed to inhabit an immune-privileged environment, the CNS is now recognized as an immune-integrated system whose resilience depends on tightly regulated microglial functions. In their homeostatic state, microglia contribute to synaptic pruning, phagocytosis of debris, and trophic support. However, chronic or dysregulated activation transforms these cells into drivers of neuroinflammation and neural injury. Recent discoveries have underscored the remarkable heterogeneity of microglial phenotypes, spanning homeostatic, activated, and disease-associated states (DAM). This dynamic spectrum is orchestrated by complex transcriptional, epigenetic, and metabolic programs. While single-cell and spatial omics have begun revealing state-specific signatures, the molecular checkpoints that govern transitions among these functional states remain poorly defined. Understanding how microglia switch between adaptive and maladaptive responses represents a major challenge and opportunity in neuroimmunology.

This Research Topic aims to elucidate the molecular mechanisms driving microglial state transitions and to identify therapeutic strategies that precisely modulate these processes. Despite growing appreciation for the centrality of microglia in neuroinflammatory and neurodegenerative diseases, critical gaps remain in mapping the regulatory networks that determine their activation, resolution, and disease-associated trajectories. Key questions include how transcriptional and metabolic reprogramming underlie shifts between protective and pathological states, how microglial crosstalk with neurons and astrocytes shapes circuit outcomes, and which molecular nodes can be therapeutically manipulated to restore CNS homeostasis. Recent methodological advances—including high-dimensional single-cell profiling, spatial mapping, in vivo imaging, and computational modeling—offer unprecedented opportunities to capture the dynamic microglial landscape in health and disease. Integrating these approaches can reveal actionable targets for state-specific immunomodulation, informing strategies that preserve neuroprotection while resolving pathological inflammation.

This Research Topic will focus on mechanistic and translational studies exploring the regulation, function, and therapeutic targeting of microglial state transitions within neuroinflammatory contexts. It seeks contributions that span molecular mechanisms to system-level integration, emphasizing both discovery and application. To gather further insights into these boundaries, we welcome articles addressing, but not limited to, the following themes:

• Transcriptional and epigenetic regulation underlying microglial state transitions and heterogeneity

• Metabolic and signalling pathways coordinating activation, resolution, and disease-associated states

• Crosstalk between microglia and neural cells (neurons, astrocytes, synapses) in state-dependent contexts

• Molecular checkpoints and feedback loops that control state switching

• Integration of neuroimmune signalling with neural circuit function and behaviour

• Advanced methodologies—single-cell omics, spatial transcriptomics, in vivo imaging, and computational frameworks—for defining microglial states

We invite Original Research, Reviews, Mini-Reviews, and Perspectives that provide mechanistic insights into microglial regulation, methodological innovations enabling high-resolution state characterisation, or translational approaches targeting specific microglial states to improve neuroimmune health.

Please note that Dr. Himanshu Kathuria is affiliated with Nusmetics Pte. Ltd.