Abstract
Rat endotoxin-induced uveitis (EIU) is a well-established model of human uveitis. In this model, intravitreal injection of resolvin D1 (RvD1, 10–100–1000 ng/kg) 1 hour after subcutaneous treatment of Sprague-Dawley rats with lipopolysaccharide (LPS, 200 μg/rat) significantly prevented the development of uveitis into the eye. RvD1 dose-dependently increased the expression of sirtuin-1 (SIRT1) within the eye, while it decreased the expression of acetyl-p53 and acetyl-FOXO1. These effects were accompanied by local downregulation of some microRNAs related to the expression and activity of SIRT1. These were miR-195-5p, miR-200a-3p, miR-34a-5p, and miR-145-5p. An increase of manganese superoxide dismutase and decrease of caspase 3 were evident after RvD1 treatment. In another set of experiments, the protective effects of RvD1 (1000 ng/kg) were partly abolished by the pretreatment of the rats with EX527 (10 mg/kg/day, i.p.), a specific inhibitor of SIRT1 activity, for 7 days prior to the induction of EIU in rats. Similarly, the effects of RvD1 (1000 ng/kg) on the SIRT1 protein expression were abolished by Boc2, N-t-butoxycarbonyl-PLPLP, a specific formyl-peptide receptor type 2/lipoxin A receptor antagonist. Therefore, an interplay of the SIRT1 activity on the RvD1 mediated resolution of EIU is argued.
Highlights
Endotoxin-induced uveitis (EIU) in rats is an experimental model of human uveitis
EX527 treatment (10 mg/kg, i.p. injected daily for 7 days) prior to LPS + resolvin D1 (RvD1) significantly reduced the fall in clinical score induced by RvD1
Previous work in our laboratory has shown that intravitreal RvD1 has a proresolutive role against endotoxic induced uveitis in rats, via modulation of the immune-inflammatory process in the eye [12]
Summary
Endotoxin-induced uveitis (EIU) in rats is an experimental model of human uveitis. In this model, uveitis is induced by systemic injection of LPS, develops after 24 h, and has involvement of both eyes with acute anterior inflammation, disruption of the blood-ocular barrier, and accumulation of cellular inflammatory mediators [1]. Studies from our group [12] have shown that exogenous resolvin D1 (RvD1), a lipid derived protein that promotes the resolution of the inflammatory response back to a noninflamed state [13,14,15,16], reduces uveitis by improving the immuneinflammatory profile of the external and median tunics of the eye and by stimulating the resolution of the inflammation Bearing in mind this evidence, the aim of the present study was to investigate whether there is interplay between the protein RvD1 and the protein SIRT1 in the eye protection against EIU. The effects of a specific inhibitor of SIRT1 activity and a specific RvD1 receptor antagonist were, respectively, investigated on the RvD1 response and on the local expression of SIRT1
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