Expression of Toll-like Receptor 4 and Its Associated Lipopolysaccharide Receptor Complex by Resident Antigen-Presenting Cells in the Human Uvea

Abstract

The present study demonstrates for the first time that resident APCs in the normal human uvea express TLR4 and its associated LPS receptor complex. This has significant implications for the understanding of normal ocular immunity as well as unraveling the potential role of Gram-negative bacteria in the pathogenesis of acute anterior uveitis (AAU).

Toll-like receptors in ocular immunity and the immunopathogenesis of inflammatory eye disease

“…31 In contrast with our findings, 28 however, Brito et al also reported TLR4 protein staining on the non-pigmented epithelial cells of the ciliary body and in the superficial layers of the retina. 31 We had also observed a similar pattern of staining when using paraffin embedded ocular sections (which were not observed in our studies using fresh frozen sections 28 ) and these were considered to be non-specific, as we observed an identical pattern of positive staining using the isotype matched negative control antibody (unpublished data).…”

“…We proposed that this may reflect the unique immunologically privileged nature of the eye. 28 Recently, Brito et al confirmed our findings with the detection of TLR4+ cells in the uveal stroma that were ''probably resident macrophages and DCs.'' 31 In contrast with our findings, 28 however, Brito et al also reported TLR4 protein staining on the non-pigmented epithelial cells of the ciliary body and in the superficial layers of the retina.…”

“…These TLR4+ APCs appeared to be strategically placed in perivascular and subepithelial locations within the uveal stroma and suggest that such uveal APCs endowed with the complete LPS receptor complex are optimally positioned to detect and respond to either blood borne or intraocular LPS of Gram negative bacteria. 28 This is analogous to the situation in the cornea where TLRs appear in a strategic location immediately below the point of likely microbial invasion. A similar network of resident APCs exists in the mouse uvea, 29 and we (unpublished data) and others 30 have found TLR4 mRNA expression in mouse eyes.…”

“…28 A relatively rich network of TLR4+ APCs were observed in the iris root and ciliary body, compared to that in the rest of the iris or choroid. These TLR4+ APCs appeared to be strategically placed in perivascular and subepithelial locations within the uveal stroma and suggest that such uveal APCs endowed with the complete LPS receptor complex are optimally positioned to detect and respond to either blood borne or intraocular LPS of Gram negative bacteria.…”

“…31 We had previously proposed that the preferential expression of TLR4 by the APCs within the uvea may suggest a novel mechanism for the initiating factors in the pathogenesis of AAU, which has a particular predilection for affecting this middle vascular layer of the eye. 28 LPS derived from Gram negative bacteria may trigger AAU by activating TLR4 on uveal APCs that are optimally positioned in perivascular locations to activate leucocyte recruitment, from the vasculature to the uvea, by activating the secretion of chemokines and the expression of vascular adhesion molecules.…”