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N. Gao, A. Kumar, J. Jyot, F. X. Yu; Flagellin-Induced Corneal Antimicrobial Peptide Production and Wound Repair Involve a Novel Nf-B-Independent and EGFR-Dependent Pathway. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3904.
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© ARVO (1962-2015); The Authors (2016-present)
The bacterial protein flagellin plays a major role in stimulating mucosal surface innate immune response to bacterial infection and uniquely induces profound cytoprotection against injury, chemicals, and radiation. This study sought to determine signaling pathways responsible for the flagellin-inducted inflammatory and cytoprotective effects on human corneal epithelial cells (HCECs).
Flagellin purified Pseudomonas aeruginosa PAK strain or live bacteria were used to challenge cultured HCECs. The activation of signaling pathways were assessed with Western blot and the secretion of cytokine/chemokine and the production of antimicrobial peptides (AMPs) were measured with ELISA and dot blot, respectively. Effects of flagellin on wound healing were assessed in cultured porcine corneas.
L94A (a site mutation in TLR5 binding region) flagellin and PAK expressing L94A flagellin were unable to stimulate NF-ΚB activation but was potent in eliciting EGFR signaling in a TGF-α related pathway in HCECs. Concomitant with the lack of NF-ΚB activation, L94A flagellin was ineffective in inducting IL-6 and IL-8 production in HCECs. Surprisingly, the secretion of two inducible AMPs, LL-37 and hBD2, was not affected by L94A mutation. Similar to wild-type flagellin, L94A induced epithelial wound closure in cultured porcine cornea through maintaining EGFR-mediated signaling.
1. Inflammatory response mediated by NF-ΚB can be uncoupled from epithelial innate defense machinery (i.e., AMP expression) and major epithelial proliferation/repair pathway mediated by EGFR and 2. Flagellin and its derivatives may have broad therapeutic applications in cytoprotection and in controlling infection in the cornea and other mucosal tissues.
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