Macrophage Recruitment in Immune-Privileged Lens During Capsule Repair, Necrotic Fiber Removal and Fibrosis

Abstract

Emerging evidence of the presence of immune cells challenges the concept of the lens as an immune privileged organ, however, the underlying mechanism remains elusive. Here, we provide a direct mechanism supporting a role of macrophage recruitment in immuno-privileged lens during capsule rupture repair, fiber cell removal and fibrosis. Posterior lens capsule rupture was observed in a connexin (Cx) 50 and aquaporin 0 (AQP0) double knockout (dKO) mouse model. A ruptured posterior lens capsule resulted in lens fiber tissue extrusion into the vitreous cavity, forming a disorganized “tail-like” tissue at postnatal age of 15 days (P15). This “tail-like” tissue also contained hyaloid vessels, fibrotic tissue and macrophages. The regression of the hyaloid vessel system that contains macrophages was delayed. Moreover, fiber cell debris were detected inside the macrophages, suggesting phagocytic engulfment by macrophages. Additionally, necrotic fiber cells were surrounded by macrophages in the “tail-like” lens tissue. These macrophages were reduced after P30, and phenotypically distinct M2 macrophages were detected inside the lens, which coincided with an increase in necrotic fiber cells. By P90, the “tail-like” tissue completely disappeared, and the posterior capsule rupture was healed and replaced with thick fibrotic tissue. Furthermore, administration of colony stimulating factor 1 (CSF-1) activated polarization of macrophages to M2 and accelerated capsule repair, while inhibition of the CSF-1 receptor delayed the repair process. Taken together, these results suggest that necrotic fiber cells associated with lens posterior rupture lead to the recruitment of macrophages, which are delivered by the regression delayed hyaloid vessel system. M2 macrophages activated by CSF-1 mediate capsule rupture repair, fiber cell removal and development of fibrosis.