Abstract
Purpose :
We investigated the expression and the function of IL17 signaling pathway in C57BL/6 mouse corneas in response to Pseudomonas (P.) aeruginosa infection.
Methods :
The expression of IL17 isoforms and their receptors in mouse corneas was determined by PCR, Western blot, Immunostaining and/or Elisa. IL17A-IL17A receptors signaling was downregulated by neutralizing antibodies, their effects on the severity of P. aeruginosa keratitis and cytokine expression were assessed using clinical scoring, bacterial counting, PMN infiltration and realtime PCR. IL17 Down stream genes changes were evaluated by cytokine array.
Results :
P. aeruginosa-infection induced the expression of IL17A, IL17RA, IL17RC, IL17C in mouse corneas. The expression of IL23, an upstream cytokine and MCPIP-1, a known downstream effector, was also upregulated. Targeting IL17A or IL17A specific receptor IL17RC with neutralizing antibodies resulted in a great decrease in the severity of P. aeruginosa keratitis, including a decrease in bacterial burden and PMN infiltration. IL17A signaling blockages also significantly reduced the expression of the pro-inflammatory cytokines IL24, IL-6, L-1β in the mouse whole cornea, and increase the expression of anti-inflammatory cytokines IL-1RA, IL-10 in the epithelium. The subconjunctival injection of recombinant mouse IL17A exacerbated P. aeruginosa mediated tissue destruction. Cytokine array revealed that the expression of Osteoprotegerin (OPG) was regulated by IL17A. OPG Neutralization also resulted in decrease in the severity of P. aeruginosa keratitis.
Conclusions :
IL17A plays a detrimental role in the pathogenesis of P. aeruginosa keratitis. Blocking IL17A is a potential therapeutic strategy for controlling the outcome of P. aeruginosa keratitis at the early stage of corneal infection.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.