An immune response to the avascular lens following wounding of the cornea involves ciliary zonule fibrils

Abstract

The lens and central cornea are avascular. It was assumed that the adult lens had no source of immune cells and that the basement membrane capsule surrounding the lens was a barrier to immune cell migration. Yet, microfibril‐associated protein‐1 (MAGP1)‐rich ciliary zonules that originate from the vasculature‐rich ciliary body and extend along the surface of the lens capsule, form a potential conduit for immune cells to the lens. In response to cornea debridement wounding, we find increased expression of MAGP1 throughout the central corneal stroma. The immune cells that populate this typically avascular region after wounding closely associate with this MAGP1‐rich matrix. These results suggest that MAGP1‐rich microfibrils support immune cell migration post‐injury. Using this cornea wound model, we investigated whether there is an immune response to the lens following cornea injury involving the lens‐associated MAGP1‐rich ciliary zonules. Our results provide the first evidence that following corneal wounding immune cells are activated to travel along zonule fibers that extend anteriorly along the equatorial surface of the lens, from where they migrate across the anterior lens capsule. These results demonstrate that lens‐associated ciliary zonules are directly involved in the lens immune response and suggest the ciliary body as a source of immune cells to the avascular lens.

Resident immune cells of the avascular lens: Mediators of the injury and fibrotic response of the lens

“…In our studies with the developing chick embryo eye, which unlike mammalian embryo eyes has no lens‐associated tunica vasculosa that could serve as a vascular source of lens resident immune cells, we show that the ciliary zonules between the ciliary body and the lens are the likely path by which immune cells populate the lens during development. Since we previously show that immune cells that surveille the lens in response to corneal wounding are able to migrate across the lens basement membrane capsule, 21 we expect that immune cells use this same path to take residence in the lens during development. We also suggest that this is the pathway by which resident immune cells repopulate the lens in the adult as the vasculature of the tunica vasculosa of mammals is removed by apoptosis prior to birth 56 .…”

“…Whether injury activated resident immune cells integrated among the lens epithelium are responsible for contributing to the production of pro‐inflammatory factors and chemokines is not yet known. Lens resident immune cells provide a potential mechanism to recruit circulating innate immune cells to the lens as has been shown to occur in response to lens dysgenesis caused by conditional deletion of N‐cadherin, corneal wounding, and cataract surgery 20‐22 …”

Mutation of the TRPM3 cation channel underlies progressive cataract development and lens calcification associated with pro‐fibrotic and immune cell responses

“…68 Immune cells, known to populate the vascularized uveal tract of the eye, which includes the iris, ciliary body, and choroid, 73 have been proposed to surveille the lens by migrating across the ciliary zonules. 68,74 Further studies are underway to determine the ocular source and trafficking route of macrophage-like cells found in the Trpm3-MM mutant lens.…”

Immune responses to injury and their links to eye disease

“…Evidence of cooperative immune responses in the eye was also provided by studies revealing that surveillance of the lens by immune cells is induced in response to debridement wounding of the cornea [163]. In these studies, it was discovered that within one day of cornea wounding, immune cells sourced in the ciliary body are induced to travel along the ciliary zonules and populate the lens anterior surface from where they migrate across the lens capsule (Figure 3) [163].…”

“…The fact that the eye is considered an immune privileged site, and that the lens is avascular [160] and surrounded by a thick matrix capsule [161], had led investigators to presume that immune cells would not be associated with or recruited to wounded or dysgenic lenses, even though non-canonical mechanisms of immune cell recruitment had been discovered for other avascular regions of the eye [65,162]. It is only recently that it has been shown that there is surveillance of the lens by immune cells in response to eye injury, an adaptive immune response to lens degeneration, and a repair response by immune cells activated upon lens wounding [163][164][165]. These studies also provided evidence that the association of immune cells with the lens has negative outcomes, including a role for immune cells in lens fibrosis [164,165].…”