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1From the Department of Ophthalmology and the 2Center for Global Health and Diseases, Case Western Reserve University, Cleveland, Ohio; the 3Medical Research Service, Louis Stokes VA Medical Center, Cleveland, Ohio; and the 4University of Massachusetts Medical School, Worcester, Massachusetts.
PURPOSE. Toll-like receptors (TLRs), which recognize microbial products, have an important role in the host innate immune response. The purpose of the present study was to determine whether activation of these receptors leads to development of keratitis and to assess the role of the common adaptor molecule myeloid differentiation factor-88 (MyD88).
METHODS. Corneal epithelium of C57BL/6, TLR2–/–, TLR9–/–, and MyD88–/– mice was abraded and treated with Pam3Cys, LPS, or CpG DNA, which bind TLR2, -4, and -9, respectively, and neutrophil recruitment to the corneal stroma, development of corneal haze, and chemokine production were measured.
RESULTS. Activation of TLR2 and -9 stimulated neutrophil recruitment to the corneal stroma of C57BL/6 mice, but not TLR2–/– or -9–/– mice, respectively. In marked contrast, neutrophil migration to the corneal stroma of MyD88–/– mice challenged with Pam3Cys, LPS, or CpG DNA was completely ablated. Activation of TLR2, -4, and -9 also caused a significant increase in corneal thickness and haze, indicative of disruption of corneal clarity; however, this response was ablated in MyD88–/– mice, which were not significantly different from untreated corneas. Production of CXC chemokines MIP-2 and KC, which mediate neutrophil recruitment to the corneal stroma, was elevated in the corneal epithelium and stroma of control, but not MyD88–/– mice.
CONCLUSIONS. Together, these findings demonstrate that the corneal epithelium has functional TLR2 and -9, and that TLR2, -4, and -9 signal through MyD88. This pathway is therefore likely to have an important role in the early events leading to microbial keratitis.
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