PPAR-alpha Agonist Fenofibrate Ameliorates Sjogren Syndrome-Like Dacryoadenitis by Modulating Th1/Th17 and Treg Cell Responses in NOD Mice

PURPOSE. To investigate the effects and mechanisms of fenofibrate, a synthetic ligand of peroxisome proliferator-activated receptor alpha (PPAR-alpha), on autoimmune dacryoadenitis in a mouse model of Sjogren syndrome (SS) dry eye.METHODS. Male nonobese diabetic (NOD) mice were fed chow with or without 0.03% fenofibrate for 8 weeks, and clinical scores were determined by assessing tear secretion, fluorescein, and hematoxylin and eosin staining. Intracellular IFN-gamma, IL-17, and Foxp3 in CD4+ T cells were measured by flow cytometry. The expressions of Th1, Th17, and Treg cell-related transcription factors and cytokines were detected by real-time PCR. The levels of PPAR-alpha and liver X receptor /3 (LXR-/3) were detected with real-time PCR and Western blotting.RESULTS. Fenofibrate efficiently diminished the lymphocytic inflammation in lacrimal glands (LGs), increased tear secretion, and decreased corneal fluorescein staining in NOD mice. Meanwhile, treatment of fenofibrate evidently reduced the proportion of Th1 and Th17 cells and increased the proportion of Treg cells in vivo and vitro, together with decreased expression of T-bet, IFN-gamma, ROR gamma t, and IL-17, as well as increased expres-sion of Foxp3 and TGF-/31 in LGs. Furthermore, fenofibrate significantly upregulated the expressions of PPAR-alpha and LXR-/3 at the protein and mRNA levels. CONCLUSIONS. Fenofibrate potently attenuated LG inflammation in a model of autoim-mune dry eye, and this effect might partially result from regulating Th1/Th17/Treg cell responses by activating PPAR-alpha/LXR-/3 signaling. These data suggest that fenofibrate may be a novel class of therapeutic agent for SS-associated dacryoadenitis.