Toll-like Receptors and the Eye

Abstract

The immune response to microbial pathogens relies on both innate and adaptive components.1 The innate or immediate response is mediated in large measure by leukocytes of the blood, such as neutrophils (PMNs) and macrophages, cells that phagocytose and kill the pathogens and that concurrently coordinate additional host responses by synthesis of a wide range of inflammatory mediators and cytokines.2 A primary challenge to the innate immune system is the ability to discriminate among a large number of potential pathogens from self, with the use of a restricted number of receptors. This discrimination is achieved by the evolution of a variety of receptors that recognize conserved motifs on pathogens called pathogen-associated molecular patterns (PAMPs). Toll-like receptors (TLRs), perhaps the best-characterized class of pattern-recognition receptors (PRRs)3,4 in mammalian species, play an important role in the recognition of components of pathogens and activation of innate immunity, which then leads to development of adaptive immune responses.5 In the eye, as in other parts of the body, the early response against invading pathogens is provided by innate immunity. It is now well established that the recognition of pathogens by the innate defense system is mediated through germ line–encoded PRRs,6,7 most notably, TLRs.4,8,9 A growing number of studies have shown that TLRs are expressed by a variety of tissues and cells of the eye and play an important role in ocular protection and defense against microbial infection.10–20 The TLR family of receptors links the extracellular compartment where contact and recognition of PAMPs occur and the intra-cellular compartment, where signaling cascades leading to cellular responses are initiated. Their extracellular domain contains leucine-rich repeats (LRRs), whereas the cytoplasmic domain shows a striking homology with that of the interleukin-1 receptor (IL-1R) and is referred to as the Toll/IL-1R (TIR) domain. The Toll/IL-1Rs play a critical role in host defense and inflammation.21 Ten TLRs have been identified in humans, whereas 13 can be found in the mouse genome.22 Individual TLRs recognize distinct microbial components or PAMPs.4 Recognition of PAMPs by TLRs induces the production of signals responsible for the activation of genes that are essential for an effective host defense, especially proinflammatory cytokine genes.8,23 One of the first mammalian receptors identified was TLR4.24,25 Figure 1 shows TLRs, their known ligands (or PAMPs), downstream signaling pathways, and their role in mediating innate responses in cells. TLR4 is the extensively studied PRR and has been shown to be capable of sensing lipopolysaccharide (LPS) and initiating responses.26 TLR2 has been shown to recognize a broad range of microbial components including bacterial and mycoplasma lipoproteins and yeast carbohydrates.27 TLR3 is necessary for the response to double-stranded RNA (dsRNA),28 TLR5 for the response to bacterial flagellin,29 TLR7 and -8 for the response to single-stranded RNA (ssRNA),30,31 and TLR9 for the response to the unmethylated CpG motifs found in both bacterial and viral DNA.32,33 There are no specific ligands identified for TLR1 and -6; however, they are known to form heterodimers with TLR2, dictating the specificity of TLR2 ligand recognition.34 Little is known about TLR10.35 Figure 1 TLR signaling and the role of epithelium in corneal innate defense. When cells are exposed to pathogens, TLRs such as TLR2, -4, and -5 at the cell surface recognize PAMPs such as lipoproteins, LPS, and flagellin, respectively. In contrast, nucleic acids ...