Abstract
Purpose :
We have previously found that activation of the inflammatory cascade in mice treated with lipopolysaccharide (LPS) protects against retinal hypoxia and neovascularisation associated with oxygen induced retinopathy (OIR). We hypothesised that LPS treatment leads to upregulation of pro-inflammatory cytokines in ischaemic retina which is then protective against the ensuing hypoxia.
Methods :
To assess whether an increase in pro-inflammatory cytokine gene expression was seen in the ischaemic retina of LPS treated mice, transcriptional profiling using RNA sequencing was performed on central (vaso-obliterated) and peripheral (vascularised) retinal tissue, obtained from mice undergoing OIR treated with either LPS or phosphate buffered saline (PBS) . The cytokines found to be most upregulated were then injected intraocularly and intraperitoneally (IP) to assess their effect on OIR mice. Neovascularisation was assessed by measuring avascular area and area of neovascular tufts at P17. Hypoxia was assessed by measuring vessel tortuosity and EF5 hypoxia staining at P14.
Results :
The most apparent increases in cytokines as a result of LPS treatment compared to the PBS control in the central retina were IL1β (72 fold), CCR1 (16 fold), CCL5 (13 fold) and CCR2 (13 fold). Intraocular injection of IL1β at P12 in OIR mice significantly reduced hypoxia at P14 and reduced neovascularisation at P17. In comparison, intraocular injection of CCL5 at P12 failed to reduced hypoxia at P14. Intraperitoneal injection of IL1β at P12 in OIR mice also significantly reduced hypoxia at P14. The reduced OIR phenotype seen in IL1β treated mice is the same as that seen in LPS treated mice.
Conclusions :
IL1β is the main mediator of the protective effect LPS has on retinal hypoxia and neovascularisation associated with OIR. These findings are counterintuitive to the current literature and provide new insight into the role of IL1β on regulation of retinal oxygen demand. This novel approach of refined immunomodulation to reduce hypoxia has the potential to lead to novel therapies targeting hypoxia and preventing neovascularisation in ischaemic eye disease.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.