When Macrophages Heal and When They Scar: Timing in Corneal Fibrosis

Corneal fibrosis and scarring remain leading causes of vision impairment and blindness globally, particularly following trauma, infection, or surgical intervention. Macrophages, as central mediators of immune and repair responses, orchestrate key phases of corneal wound healing. Their functional states, ranging from pro-inflammatory to pro-resolving, are tightly regulated by environmental cues and timing. Following corneal injury, recruited macrophages undergo temporally distinct activation programs. Early inflammatory macrophage responses support debris clearance, pathogen defense, and initiation of stromal repair, whereas persistence of inflammatory and profibrotic macrophage signaling beyond the acute healing phase is associated with sustained TGF-β activity, fibroblast-to-myofibroblast differentiation, excessive extracellular matrix deposition, and stromal haze formation. Conversely, timely transition toward pro-resolving macrophage states promotes inflammation resolution, myofibroblast clearance, and restoration of corneal transparency. Recent single-cell transcriptomic profiling reveals substantial heterogeneity among macrophage populations in the cornea, highlighting the limitations of the oversimplified M1/M2 classification. This review aims to define how macrophage heterogeneity and temporal dynamics regulate corneal wound healing outcomes, with particular emphasis on the balance between fibrosis and regeneration, and to provide a conceptual framework relevant to both basic researchers and translational clinicians.