Toll-like receptors in ocular surface disease

Abstract

The ability of the ocular surface to mount an immune response is in part attributed to a family of proteins called toll-like receptors (TLRs). The latter are evolutionary conserved receptors that recognize and respond to various microbes and endogenous ligands. In addition to their recognition function, TLR activation triggers a complex signal transduction cascade that induces the production of inflammatory cytokines and co-stimulatory molecules, thus initiating innate and adaptive immunity. Toll-like receptor expression at the ocular surface is modulated during infection (e.g. Herpes simplex, bacterial keratitis and fungal keratitis) as well as during various inflammatory conditions (allergic conjunctivitis and dry-eye syndrome). Here recent findings regarding TLR expression and their involvement in various ocular surface diseases are discussed.

Figure 1

Simplified Overview of TLR Signaling. Cell surface TLR2, 4 and 5 recognize bacterial PAMPs lipoproteins, LPS and flagellin respectively, whereas intracellular TLR3, 7/8, and 9 recognize microbial dsRNA, ssRNA and unmethlylated CpG motifs respectively from either replicating or infecting viruses or bacteria in the endosome of the cell. The activation of TLRs initiates a MyD88-dependent (all TLRs except TLR3) or TRIF-dependent (TLR3 and TLR4) pathway. The MyD88-dependent pathway utilizes adapter molecule TIRAP (except TLR7, 8 and 9) leading to IRAK-4 and IRAK-1 recruitment, activated IRAK-4 phosphorylates IRAK-1 which ultimately leads to the activation of transcription factors AP-1, NFκB and IRF-5. TLR3 and TLR4 signal via a MyD88-independent pathway that is mediated via the adaptor protein, TRIF, which leads to the activation of transcription factors IRF-3 and IRF-7 that induce the expression of type I IFN genes.

Figure 2

Expression of TLRs at the Ocular Surface. (A) This summary is based on published data from multiple sources discussed in the text for human tissue sections and primary cultured cells. AC: anterior chamber, neg: negligible expression. (B) TLR 5 expression. TLR5 (green) is localized to basal and wing epithelial cells in normal human corneas (top image).The isotype control antibody revealed no background staining (bottom image). DAPI was used to stain nuclei (blue).