Background and Purpose: In the context of inflammation and immunity, there are fragmented and observational studies relating to the pharmacological activity of Mangifera indica L. and its main active component mangiferin. We, therefore, aimed to evaluate the potential beneficial effects of this plant extract (MIE, 90% in mangiferin) in a mouse model of gouty arthritis, dissecting the cellular immune phenotypes and the biochemical mechanism/s beyond its activity. Experimental Approach: Gouty arthritis was induced by the intra-articular administration of MSU crystals (200 μg 20 μl-1). MIE (0.1-10 mg kg-1) or corresponding vehicle (DMSO/saline 1:3) were orally administrated concomitantly to MSU (time 0), 6 and 12 h after the stimulus. Thereafter, knee joint score and oedema were evaluated in addition to western blot analysis for several components of mPGES-1/PPARγ pathway. Moreover, the analysis of pro/anti-inflammatory cyto-chemokines coupled to the assessment of the cellular infiltrate’s phenotype was investigated. Key Results: Treatment with MIE revealed a dose-dependent reduction in joint inflammatory scores with maximal inhibition observed at 10 mg kg-1. MIE significantly reduced leukocyte infiltration and activation and the expression of different pro-inflammatory cyto-chemokines in inflamed tissues. Furthermore, biochemical analysis revealed that MIE modulated COX-2/mPGES-1 and mPGDS-1/PPARγ pathways. Flow cytometry analysis also highlighted a prominent modulation of infiltrating inflammatory monocytes (CD11b+ve/CD115+ve/LY6Chi), and (both infiltrated and circulating) Treg cells (CD4+ve/CD25+ve/FOXP3+ve) after MIE treatment. Conclusion and Implications: Collectively, the results of this study demonstrate a novel function of MIE to positively affect the local and systemic inflammatory/immunological perturbance in the onset and progression of gouty arthritis.

Background and Purpose: Recent biochemical and pharmacological studies have reported that in several tissues and cell types, microsomal prostaglandin E2 synthase (mPGES) and peroxisome proliferator-activated receptor-γ (PPAR-γ) expression are modulated by a variety of inflammatory factors and stimuli Considering that very little is known about the biological effects promoted by IL-17 in the context of mPGES-1/PPAR-γ modulation, we sought to investigate the contribution of this unique cytokine on these integrated pathways during the onset of inflammation. Experimental Approach: We evaluated PF 9184 (mPGES-1 antagonist) and Troglitazone (PPAR-γ agonist) activity utilising integrated in vitro and in vivo approaches. The dorsal air pouch model was employed, and inflammatory infiltrates were analysed by flow cytometry. Locally produced cyto-chemokines and prostaglandins were assessed using ELISA assays. Western blots were also employed to determine the activity of various enzymes involved in downstream signalling pathways. Key Results: PF 9184 and Troglitazone, in a time and dose-dependent manner, were shown to significantly modulate leukocyte infiltration, myeloperoxidase activity, and the expression of COX-2/mPGES-1, NF-кB/IкB-α and mPGDS-1/PPAR-γ induced by IL-17. Moreover, both compounds were found to modulate prostaglandins (PGE2, PGD2, and PGJ2) production, the expression of different pro-inflammatory cyto-chemokines and the recruitment of inflammatory monocytes in response to IL-17. Conclusions and Implications: Collectively, the data presented suggests that IL-17 may constitute a specific modulator of inflammatory monocytes during later phases of the inflammatory response. Therefore, the results of this study show, for the first time, that IL-17/mPGES-1/PPAR-γ “axis” could represent a potential therapeutic target for inflammatory-based and immune-mediated diseases.