The hierarchy of pro-inflammatory cytokines in ocular inflammation

Abstract

Purpose : The concept of tissue dependent cytokine hierarchy has been demonstrated in a number of diseases but it has not been investigated in ophthalmic diseases. Here we evaluated the functional hierarchy of IL-1b, IL-6, IL-17A and TNF in the induction of ocular inflammation.

Methods : We delivered AAV vectors expressing IL-1β, IL-6, IL-17A, or TNF intravitreally in naïve C57/BL6 mice and compared and contrasted the inflammatory effects in the eye 5 weeks after AAV-mediated gene transfer. We also used an in vitro human system to test the effect of cytokines on barrier function.

Results : We found that IL-1b had the highest ability to initiate ocular inflammation. The continuous overexpression of IL-1b resulted in a significant upregulation of additional pro-inflammatory mediators in the eye. Using SLO and OCT imaging techniques we showed that a low dose of AAVIL-1β was sufficient and was as pathogenic as a high dose of TNF in inducing vascular leakage, retinal degeneration and cellular infiltration. Furthermore, only a marginal increase in IL-1b was enough to cause cellular infiltration thus confirming the highly pathogenic nature of IL-1b in the eye. Contrary to our expectation, IL-6 or IL-17A had minimal or no effect in the eye. To examine the clinical relevance of our findings we used an impedance assay to show that IL-1β alone or TNF alone was able to cause primary human retinal endothelial cell barrier dysfunction in vitro. Again, IL-6 alone or IL-17A alone had no effect on barrier function however, in the presence of IL-1b or TNF, IL-17A but not IL-6 may provide additive pro-inflammatory effects.

Conclusions : Our studies demonstrate the existence of a functional hierarchy of pro-inflammatory cytokines in the eye and we show that IL-1b is the most pathogenic when it is continuously expressed in the eye.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.