Slit2 suppresses endotoxin-induced uveitis by inhibiting the PI3K/Akt/IKK/NF-κB pathway

Uveitis is a devastating intraocular inflammatory disease. The secreted leucine-rich repeat protein slit homologue 2 (Slit2) has been found to be an essential regulator of inflammation. This study aimed to analyse the anti-inflammatory effects and the underlying mechanisms of Slit2 in an endotoxin-induced uveitis (EIU) rat model. In this study, rats with EIU pretreated recombinant human Slit2 (rhSlit2) or a control vehicle by intravitreal injection. The clinical scores were graded under a slit lamp. The protein concentrations and total number of cells in the aqueous humour (AqH) were examined, and the retinal expression of various inflammatory mediators was detected. The levels of nuclear factor-kappa B (NF-κB), phosphorylated NF-κB, IkappaB-a (IκB-a), phosphorylated IκB-a, IKK, phosphorylated IKK, PI3Kp85, phosphorylated PI3Kp85, Akt and phosphorylated Akt were evaluated by western blotting. Treatment with rhSlit2 dramatically diminished the clinical scores of EIU, with significant decreases in inflammatory cell infiltration, protein concentrations, cellulose-like exudates, the production of ICAM-1, MCP-1, TNF-α and IL-6 in the AqH; and adhesion of leucocytes. The PI3K/Akt/IKK/NF-κB pathway was found to be activated in EIU. However, the pre-treatment of rhSlit2 significantly inhibited the production of ICAM-1, MCP-1, TNF-α, and IL-6, and inhibited leucocyte adhesion by modulating the PI3K/Akt/IKK/NF-κB pathway. In conclusion, the intravitreal injection of rhSlit2 alleviated EIU-related inflammation in Sprague-Dawley rats by reducing the proinflammatory cytokines and leucocyte adhesion; in particular, rhSlit2 may inhibit LPS-induced inflammation by inhibiting the activation of PI3K/Akt/IKK/NF-κB signalling pathway. Therefore, rhSlit2 shows significant potential for effectively alleviating immune inflammatory responses in vivo.