The microglial lineage: from molecular states to context-dependent functions

Microglial states are now being cataloged far faster than their associated cellular functions can be tested, widening the gap between molecular description and causal understanding of tissue impact. The gap becomes especially apparent as microglial biology moves beyond the rodent central nervous system (CNS). Peripheral nervous system (PNS) microglia, identified in human and other large-vertebrate ganglia, share major molecular features with CNS microglia and contribute to neuronal growth, yet their adult maintenance and responses to injury and disease remain unresolved. TREM2 exposes a second limit of state-based interpretation. The receptor supports recurring cellular processes, including myeloid fitness, lesion-associated accumulation and cargo handling, but their tissue consequences vary with the substrate, model and disease stage. This review separates population identity, molecular state, cellular function and tissue outcome, and outlines an experimental path that combines state-informed genetic screens, direct functional assays, multicellular human models and temporally controlled in vivo validation to connect molecular discovery with context-dependent function.