Reprogramming Neuroinflammation After Stroke: A Coupled Network Model of Microglial Control

Ischaemic stroke induces a dynamic neuroimmune response in which microglia act as central regulators of both secondary injury and tissue repair. In the acute phase, microglial activation amplifies neuronal damage through inflammatory signalling and vascular dysfunction; over subsequent days, these cells undergo coordinated transcriptional and metabolic reprogramming toward reparative states. The repeated failure of immunomodulatory therapies in clinical translation, however, suggests that current approaches fundamentally mischaracterise the underlying biology. We propose that microglial state transitions are governed not by discrete linear pathways but by a coupled regulatory network integrating proteostatic clearance, receptor-mediated signalling, inflammasome activation, and intracellular metabolism. Within this network, impaired clearance of cellular debris sustains exposure to damage-associated molecular patterns, perpetuating inflammasome activity and a pro-inflammatory metabolic programme; conversely, restoration of clearance capacity shifts network equilibrium toward resolution and repair. Microglial phenotypes therefore emerge from dynamic shifts in network state rather than progression through fixed activation stages. This framework accounts for the limited efficacy of non-selective or temporally misaligned interventions and identifies the post-acute transitional phase as a window of maximal network plasticity. Aligning therapy with the temporal and functional dynamics of this network—guided by phase-specific biomarkers—provides a mechanistic basis for precision immunomodulation and improved clinical translation in ischaemic stroke.