Abstract
The cornea must maintain homeostasis, enabling rapid response to injury and microbial insult, to protect the eye from insult and infection. Toll-like receptors (TLRs) are critical to this innate immune response through the recognition and response to pathogens. Myeloid differentiation primary response (MyD88) is a key signaling molecule necessary for Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R)-mediated immune defense and has been shown to be necessary for corneal defense during infection. Here, we examined the intrinsic role of TLR signaling in ocular surface tissues by determining baseline levels of inflammatory mediators, the response to mechanical stimuli, and corneal infection in MyD88-deficient mice (MyD88-/-). In addition, cytokine, chemokine, and matrix metalloproteinase (MMP) expression was determined in ocular surface cells exposed to a panel of TLR agonists. Compared to wild-type (WT) animals, MyD88-/- mice expressed lower MMP-9 levels in the cornea and conjunctiva. Corneal IL-1α, TNFα, and conjunctival IL-1α, IL-2, IL-6, and IL-9 levels were also significantly reduced. Additionally, CXCL1 and RANTES expression was lower in both MyD88-/- tissues compared to WT and IL-1R-/- mice. Interestingly, MyD88-/- mice had lower corneal sensitivities (1.01±0.31 gm/mm2) than both WT (0.59±0.16 gm/mm2) and IL-1R-/- (0.52±0.08 gm/mm2). Following Pseudomonas aeruginosa challenge, MyD88-/- mice had better clinical scores (0.5±0.0) compared to IL-1R-/- (1.5±0.6) and WT (2.3±0.3) animals, but had significantly more corneal bacterial isolates. However, no signs of infection were detected in inoculated uninjured corneas from either MyD88 or IL-1R-deficient mice. This work furthers our understanding of the importance of TLR signaling in corneal defense and immune homeostasis, showing that a lack of MyD88 may compromise the baseline innate response to insult.
Highlights
The corneal and conjunctival epithelium form the anterior covering of the eye and provide the first line of defense against damage and injury, as well as protection against invading pathogens
In vitro and in vivo studies demonstrate the importance of Toll-like receptors (TLRs) activation in the initiation and propagation of inflammation, through production of immune-regulating mediators that aid in ocular surface innate defense
As our aim was to evaluate the expression of these mediators in ocular surface tissues and their dependence on TLR signaling, we first sought to analyze the effect of TLR signaling in vitro on matrix metalloproteinase (MMP) (Fig 1) and cytokine (Fig 2) expression in various corneal and conjunctival cells
Summary
The corneal and conjunctival epithelium form the anterior covering of the eye and provide the first line of defense against damage and injury, as well as protection against invading pathogens. One of the primary functions of these tissues is to provide a barrier, preventing infection and physical damage to the rest of the eye. Toll-like receptors (TLRs) are pattern-recognition receptors that mediate innate immunity through recognition of pathogen-associated molecular patterns (PAMPs) on microbial ligands and endogenous damage-associated molecular patterns (DAMPs) [1,2,3]. Activation of TLRs results in the production of cytokines, chemokines, and other mediators which signal to neighboring cells, recruit immune cells to the site of activation, trigger extracellular matrix changes, and stimulate an adaptive immune response against infection. TLRs stimulate antimicrobial peptide production, which mediate pathogen killing, modulate immune signals, and play a role in wound healing [4,5,6]
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