Negatively regulating TLR4/NF-κB signaling via PPARα in endotoxin-induced uveitis

Abstract

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.

Role of the lipid-regulated NF-κB/IL-6/STAT3 axis in alpha-naphthyl isothiocyanate-induced liver injury

“…Due to the inhibitory effect of PPARα activation on NF-κB activation (Jeon et al 2014; Shen et al 2014), the role of PPARα in the treatment of ANIT-induced toxicity was investigated. Pretreatment with the PPAR α agonist Wy-14,643 for 24 h before ANIT treatment resulted in the total protection toward ANIT-induced liver toxicity, as indicated by normal ALT and AST levels, and liver histology (Fig.…”

Pathogenic Role of microRNA-21 in Diabetic Retinopathy Through Downregulation of PPARα

“…For instance, a PPARα agonist inhibited thrombin-induced endothelin-1 biosynthesis in human vascular endothelial cells (41). In RPE cells, upregulation of PPARα decreased Toll-like receptor 4 (TLR4) levels and inhibited the nuclear factor-κB signaling pathway induced by lipopolysaccharide (42). …”

Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14+ Monocytes

“…Downregulation of IRAK-1 protein was reported in models of LPS tolerance (57), and loss of IRAK-1 is reported in tolerogenic DCs (66). The concept of antagonist ligands modulating TLR4 function was investigated in models of autoimmune arthritis (67), myocardial ischemia (68), and endotoxin-induced uveitis (69). Spontaneous models of colitis in mice using TLR4 knockouts revealed disease exacerbation that was dependent on TLR4 signals and IL-10 (70).…”