Resident tissue macrophages maintain intraocular pressure homeostasis

Intraocular pressure is tightly regulated by the conventional outflow tissues, preventing ocular hypertension that leads to neurodegeneration of the optic nerve, or glaucoma. Although macrophages reside throughout the conventional outflow tract, their role in regulating intraocular pressure remains unknown. Using macrophage lineage-tracing approaches, we uncovered a dual macrophage ontogeny with distinct spatial organization across the mouse lifespan. Long-lived resident tissue macrophages were concentrated in the trabecular meshwork and Schlemm's canal, whereas steady-state monocyte-derived macrophages were abundant around distal vessels. Specific depletion of resident tissue macrophages triggered increased intraocular pressure and outflow resistance, linked to aberrant extracellular matrix turnover in the resistance-generating tissues of the trabecular meshwork. In contrast, dysregulated physiology and tissue remodeling were not observed when monocyte-derived macrophages were depleted. Altogether, we show ontogeny- and tissue-specific macrophage functions within the outflow tract, uncovering the integral homeostatic role of resident tissue macrophages in resistance-generating tissues whose dysfunction is responsible for glaucoma.