Abstract
Macrophages are critical mediators of injury-associated corneal hemangiogenesis (HA) and lymphangiogenesis (LA). Yet, molecular regulators of the hem- and lymphangiogenic potential of corneal wound macrophages are poorly understood. Using two different mouse models of acute (perforating corneal incision injury) and chronic (corneal suture placement model) corneal injury, here we identified distinct functions of early- versus late-phase corneal wound macrophages in corneal HA and LA. Whereas early-phase wound macrophages are essential for initiation and progression of injury-mediated corneal HA and LA, late-phase wound macrophages control maintenance of established corneal lymphatic vessels, but not blood vessels. Furthermore, our findings reveal that the hem- and lymphangiogenic potential of corneal wound macrophages is controlled by the type of the corneal damage. Whereas perforating corneal incision injury induced primarily wound macrophages with lymphangiogenic potential, corneal suture placement provoked wound macrophages with both hem- and lymphangiogenic potential. Our findings highlight a previously unrecognized injury-context dependent role of early- versus late-phase corneal wound macrophages with potential clinical impact on therapy development for sight-threatening corneal neovascular diseases.
Highlights
The cornea as the front part and major refractive element of the eye, is physiologically avascular and alymphatic
The incision model, which is considered as an acute injury model, leads to transient and isolated LA without concurrent HA13, whereas the well-established model of corneal suture placement, which is considered as a chronic injury model, results in parallel growth of corneal blood vessels (BV) and LV25
In this study we demonstrated that macrophage infiltration and macrophage-mediated corneal angiogenesis follow different dynamics during diverse settings of corneal injury
Summary
The cornea as the front part and major refractive element of the eye, is physiologically avascular and alymphatic. In this study we aimed to analyze macrophage dynamics during the corneal inflammatory response after injury and to study the specific function of macrophages during corneal BV and LV initiation, progression, maintenance and regression using phase-restricted depletion of macrophages in subsequent phases after injury For this purpose, we made use of two corneal injury models in mice: a perforating corneal incision model and the well-established corneal suture model. The subsequent vessel regression is faster for LV than for BV, as LV are completely regressed by 6 months, while BV can be detected up to 8 months after suture removal[25] Comparing these different injury models allowed to analyze the function of macrophages in HA/LA in acute versus chronic injury responses. Both models (incision model and suture model) have previously been characterized in their vascular responses after injury[13,25], a characterization of the interrelationship between macrophage function and vascular growth at different time points after injury is lacking and was the aim of this study
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