Abstract
Purpose :
The prevalence of autoimmune diseases has steadily increased in developed countries in the past decade, with annual health care costs at $100 billion. Current treatment for autoimmune uveitis is systemic immune suppression, which often causes opportunistic infections and secondary glaucoma. We previously showed that lipoxin A4 (LXA4) exerts protective effects during uveitis pathogenesis by limiting inflammation and disease progression of experimental autoimmune uveitis (EAU). We investigated whether LXA4 is an effective treatment and endogenous protective circuit of EAU in C57B6/J and B10RIII mouse strains and set out to define the mechanism of action and cellular targets for the LXA4 circuit.
Methods :
Autoimmune uveitis was induced in both C57B6/J and B10RIII mice to assess the role of LXA4 during uveitis pathogenesis. Expression of 5-lipoxygenase (5-LOX), 12/15-lipoxygenase (12/15-LOX) and LXA4 receptor gene expression was assessed in the eye and lymph nodes to determine the role of LXA4 circuit during healthy homeostasis and EAU. Endogenous LXA4 formation in tissues and isolated effector cells was measured by liquid chromatography- tandem mass spectrometry (LC-MS/MS). Immune cell infiltration, identification and EAU pathogenesis was assessed by flow cytometry, immunohistochemistry and clinical scoring of the fundus and retinal morphology.
Results :
5-LOX and 12/15-LOX are dramatically upregulated in the choroid and retina respectively, and LXA4 receptor expression was cell-type specific indicating novel site- and cell-specific actions of the LXA4 circuit in the eye and lymph nodes. Endogenous formation of LXA4 was dramatically abrogated in the draining lymph nodes by a factor of 4 (n=6) during peak inflammation, which correlated with autoimmune disease progression and development. More importantly, treatment with LXA4 prevented EAU development in both C57B6/J and B10RIII mice.
Conclusions :
Findings suggest that the LXA4 circuit in the eye and lymph nodes is essential in maintaining healthy homeostasis and balanced T-cell activation, and is a key factor for the limiting the progression and development of EAU. This endogenous protective and immune regulatory circuit can be amplified therapeutically and thus is a target of interest for treating ocular autoimmune diseases.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.