Microglial states revisited: from homeostasis to disease

Microglia, the resident macrophages of the CNS parenchyma, are recognized as highly plastic, transcriptionally diverse cells whose phenotypes are moulded by development, region, sex, age, genotype and environment. Advances in single-cell and single-nucleus transcriptomics, chromatin accessibility profiling, and spatial multi-omics have negated binary frameworks of 'resting versus activated' or 'M1 (pro-inflammatory) versus M2 (anti-inflammatory)' and revealed a multidimensional state space that supports brain development, homeostasis and adaptive responses to perturbation. Building on the foundational concepts of the microglial sensome, homeostatic and disease-associated signatures, microglia exhibit transcriptomic state transitions in neurodegeneration, demyelination, infection and systemic inflammation. Moreover, a mechanistic framework for more 'hidden' microglial states has emerged, in which latent programmes that appear homeostatic at baseline are revealed by challenges and are instructed through innate immune training or tolerance. We argue that these covert reprogrammed states, which are shaped by ageing, genotype, sex, location and prior exposures such as sepsis or viral infection, help explain interindividual variability in disease trajectories. We conclude by outlining priorities for unifying state annotation across species and modalities, and for translating state-resolved insights into biomarkers and interventions.