Purchase this article with an account.
F.X. Yu, A. Kumar, J. Zhang, Q. Li; Epithelium, via the Action of Tlrs, Coordinates Innate Immune Response to Infection in the Cornea . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4376.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
To study the role of epithelium, via the action of Toll–like receptors (TLRs), in coordinating corneal innate immune responses to bacterial and viral infection.
Cultured human corneal epithelial cells (HCECs) were challenged with live Staphylococcus (S.) aureus, Pseudomonas (P.) aeruginosa, Herpes simplex virus–1 (HSV–1), or TLR ligands. The activation of TLR mediated signaling pathways (NF–ΚB, P38, JNK, ERK, and PI3K) was assessed using a variety of approaches. Expression and production of proinflammatory cytokines, antimicrobial peptides, and molecules of TLR signaling pathways in response to pathogen challenge were assessed using RT–PCR, ELISA, and/or Western blotting. Neutralizing antibodies were used to determine the role of individual TLR in the recognition of pathogen.
Infection of HCECs with three common keratitis causing pathogens, S. aureus, P. aeruginosa, and HSV–1 resulted in robust expression and production of proinflammatory cytokines such as IL–8, IL–6, TNF–α, IL–1ß, as well as antimicrobial peptides ß–defensin–2. Intriguingly, HSV–1 infection of HCECs induced the expression of interferon–γ at the mRNA level and TLR7 at the protein levels, a viral recognizing TLR found primarily in immune cells. Corneal epithelium is unique in that it utilizes TLR2 to sense and respond to Gram–positive bacterial infection through recognition of lipoproteins, and TLR5 to sense and respond to Gram–negative bacterial infection through recognition of flagellin. HCECs do not recognize lipoteichoic acid and lipopolysaccharides; the unresponsiveness of HCECs to the most common bacterial virulent factors may represent a mechanism by which epithelial cells avoid unnecessary activation when in contact with the bacterial "endotoxin". Another mechanism for epithelium to avoid unnecessary activation was the expression of TLRs only in the inner cell layers of stratified epithelium of the cornea. Finally, exposure of HCECs to TLR ligands such as flagellin and bacterial lipoproteins resulted in HCEC "tolerance", as manifest by greatly decreased cytokine production and hypo–responsiveness to bacterial infection.
Strategically interposed between the environment and the ocular tissues, the corneal epithelium can modulate the host response by acting either as sensor to initiate and amplify pro–inflammatory reaction or as an insulator when it becomes tolerant to dampen inflammation and to restore homeostasis.
This PDF is available to Subscribers Only