Microglial state dynamics in intracerebral hemorrhage: A systems-level integration from molecular networks to...

Intracerebral hemorrhage (ICH) induces secondary brain injury through a dynamic neuroimmune network rather than a single process of microglial "activation." After hemorrhage, resident microglia, infiltrating monocyte-derived macrophages, neutrophils, neurovascular-unit cells, and blood-derived injury signals, including thrombin, hemoglobin, heme, iron, DAMPs, complement, and lipid debris, jointly shape the evolving perihematomal immune microenvironment. The traditional M1/M2 polarization framework has provided historical heuristic value, but it is no longer sufficient as an organizing model for post-ICH myeloid biology. Accordingly, this review uses consensus-aligned terminology, including microglial states, state transitions, functional programs, transcriptional clusters, spatial niches, and myeloid-cell states, while retaining M1/M2 terminology only when discussing historical literature. Evidence from human perihematomal tissue, hematoma samples, rodent ICH models, single-cell and spatial transcriptomics, and mechanistic intervention studies indicates that post-ICH myeloid responses comprise heterogeneous inflammatory, metabolic-stress, lipid-handling, phagocytic-lysosomal, antigen-presentation, proliferative, and repair-associated programs. Here, we propose a systems-level framework defined as a conceptual synthesis and translational therapeutic framework, rather than a validated quantitative systems biology model. This framework integrates microglial state transitions, spatiotemporal mismatch, resident microglia-monocyte-derived macrophage distinction, neurovascular crosstalk, and therapeutic decision points. We further introduce the immunometabolic constraint as a working hypothesis: although inflammation, metabolism, phagocytosis, and hematoma clearance are each metabolically regulated, direct evidence for a quantifiable metabolic competition between inflammatory suppression and phagocytic enhancement in ICH remains lacking. Future studies require lineage-resolved, spatially informed, functionally validated, and biomarker-guided approaches.