AB0121 Resveratrol-enhanced autophagic flux reduces severity of experimental rheumatoid arthritis
Authors: J.A. Fernández-Rodríguez, M. Almonte-Becerril, O. Ramil-Gómez, S. Viñas-Diz, L. Hermida-Carballo, Á. Vela-Anero, Á. Concha, M. Camacho-Encina, F.J. Blanco, M.J. Lopez-Armada
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Previously, we have demonstrated that dietary supplementation with resveratrol (RSV) lowers synovial hyperplasia, chemokines and oxidative damage in an acute antigen-induced arthritis (AIA) model developed in rats, and that autophagic cell death and limiting angiogenic response were involved<sup>1</sup>. <h3>Objectives</h3> Here, we investigated the autophagic flux induced by RSV and its relation with serum interleukin (IL)−1β levels, since autophagy could regulate IL-1β via inflammasome. Moreover, C-reactive protein (CRP) and prostaglandin E<sub>2</sub> (PGE<sub>2</sub>), which are also closely linked to inflammation and correlated with disease activity, were also evaluated. <h3>Methods</h3> Animals were randomly divided into 3 groups: healthy, AIA, and RSV-treated AIA group. RSV (12,5 mg/kg/day) was given orally 8 weeks before AIA induction until sacrifice day (48 hour after intra-articular injection). Healthy and AIA animals were administered 100 µl of water. RSV effects on autophagy were evaluated by the expression of the autophagy proteins, microtubule-associated protein 1 light chain 3 (LC3), and Beclin1 (an autophagic-related protein which up-regulation is associated with increased autophagosome formation), and p62 (an autophagic adaptor protein whose accumulation is associated with autophagic degradation dysfunction), by confocal and immunohistochemistry, respectively. Specific enzyme-linked immunosorbent assay kits and cytokine magnetic milliplex were used to measure CRP and PGE<sub>2</sub> and IL-1β in serum samples, respectively. <h3>Results</h3> At the end of the study, RSV significantly reduced the serum levels of IL-1 β, CRP and PGE<sub>2</sub> (p≤0.01 for IL-1β and PCR, and p≤0.05 for PGE<sub>2</sub>). In relation to autophagy proteins, results showed that the expression of LC3 was greater in the AIA synovial membranes than in control synovial samples, in which the presence of vesicles was easily observed. Interestingly, the synovial tissues from the RSV group showed a significatively (p≤0.001) higher signal for LC3, compared with the AIA samples. As compared with healthy controls, AIA synovial membranes showed increased p62 expression, which was markedly inhibited by RSV treatment (p≤0.01). The protein level of Beclin 1 was higher in AIA synovial membranes than in healthy samples; however, RSV did not increase the signal of Beclin 1. Moreover, there was a significant correlation between p62 expression and serum IL-1β levels (p≤0.05 and r=0.617), PGE<sub>2</sub> (p≤0.01 and r=0. 604), and PCR (p≤0.001 and r=0.692). <h3>Conclusions</h3> These data suggest that resveratrol is capable of inducing the non-canonical (Beclin1 independent) autophagy pathway, and in consequence, modulates the cross-talk existence with inflammation in an acute AIA model, which could also ameliorate the severity of rheumatoid arthritis. <h3>Reference</h3> [1] Riveiro-Naveira R, Valcárcel N, Almonte M, Vaamonde C, Hermida L, López E, Blanco F, López-Armada MJ. Resveratrol lowers synovial hyperplasia, inflammatory markers and oxidative damage in an acute antigen-induced arthritis model. Rheumatology2016;55(10):1889–900. <h3>Disclosure of Interest</h3> None declared