Negatively regulating TLR4/NF-κB signaling via PPARα in endotoxin-induced uveitis.
Toll-like receptor (TLR) signaling plays a fundamental role in the induction and progression of autoimmune disease. In the present study, we showed that lipopolysaccharide (LPS), a TLR4 ligand, functions as an antagonist of peroxisome proliferator-activated receptor alpha (PPARα), a nuclear transcription factor. Using endotoxin induced uveitis (EIU) as a model, we found that TLR was negatively regulated by PPARα. Our data revealed that treatment with the PPARα agonist fenofibrate dramatically prevented LPS-induced uveitis and inhibited TLR/ Nuclear factor-kappaB (NF-κB) signaling during inflammation. Evaluation of the severity of anterior uveitis further showed that PPARα agonist treatment significantly decreased inflammatory cell infiltration, total protein concentration, vessel density, inflammatory cytokine production, and clinical scores in the anterior section of the eye during EIU. Moreover, fenofibrate administration recovered retinal function and decreased the production of inflammatory cytokines, retinal vascular leukostasis, and inflammatory cell infiltration into the posterior section of the eyes during EIU. In vitro studies further showed that down-regulation or deletion of PPARα led to increased TLR4 levels and the activation of NF-κB signaling in RPE cells and also blocked the anti-inflammatory effects of fenofibrate. Furthermore, activation or up-regulation of PPARα decreased TLR4 levels and inhibited the NF-κB signaling pathway induced by LPS in RPE cells. In TLR4-expressing reporter cells, activation or up-regulation of PPARα partially inhibited the activation of NF-κB and also decreased TLR4 transcriptional activity. In conclusion, the activation of PPARα represents a novel therapeutic strategy for human uveitis, as PPARα negatively regulates TLR4 activity and therefore exerts anti-inflammatory actions.
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Wei
W
Shen
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, PR China.
Yang
Y
Gao
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, PR China.
Boyu
B
Lu
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, PR China.
Qingjiong
Q
Zhang
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA. Electronic address: yang-hu@omrf.org.
Yang
Y
Hu
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Electronic address: ying-chen@ouhsc.edu.
Ying
Y
Chen
D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004731:Endotoxins / Q000276:immunology*; D011345:Fenofibrate / Q000276:immunology / Q000378:metabolism; D018921:Leukostasis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D012172:Retinaldehyde / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology; D014605:Uveitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D016207:Cytokines; D004731:Endotoxins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047495:PPAR gamma; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D012172:Retinaldehyde; D011345:Fenofibrate
Endotoxin induced uveitis; LPS; PPARα; TLR4