P154 PPAR-gamma is a negative feedback regulator of IRF7-dependent TLR/MYD88 signaling for type-I interferon (IFN) production and a crucial suppressor of type-I IFN responses in murine lupus

Abstract

Introduction Anti-viral immune responses involve the robust production of type-I interferon (IFN-α/β) in plasmacytoid dendritic cells (pDCs). This occurs through the virus-activated MyD88-independent pathway, or the TLR7, 9/MyD88 pathways, and is completely dependent on the transcription factor IRF7 [1] . How type-I IFN is negatively regulated with respect to IRF7 remains unknown.Here we report that peroxisome proliferator-activated receptor gamma (PPAR-γ) is a negative-feedback regulator of IRF7-dependent TLR signaling for type-I IFN production. Methods WT and PPAR-γ (+/−) mice were used for in vitro stimulation of pDCs with TLR agonists, or i.v delivery of TLR agonists. Levels of type-I IFN in culture supernatants were assessed by ELISA. Interactions between IRF7 and PPAR-γ were studied by FLAG-IRF7 immunoprecipitation and Western blot analysis for PPAR-γ. Pristane (0.5 ml) was injected into WT and PPAR-γ (+/−) C57BL/6 to develop lupus-like disease, or control PBS. Interferon responses in mice were assessed by RT-PCR and ELISAs for autoantibodies. Results Through TLR7, 9/MyD88 signaling in pDCs, type-I IFN induces the expression of PPAR-γ, which binds to the DNA-binding domain of IRF7, inhibiting IRF7 activation of type-I IFN genes. A critical role in vivo was confirmed in PPAR-γ (+/−) mice, which displayed enhanced TLR9-type-I IFN induction, compared to WT mice. Using the pristane-induced lupus model (TLR7/MyD88-type-IFN-dependent [2] ), disease in PPAR-γ (+/−) mice correlated with enhanced type-I IFN production/signaling, type-I IFN-dependent anti-nuclear antibody production and poor survival, compared to in WT mice. Pioglitazone (a PPAR-γ agonist) treatment inhibits murine lupus through a potent inhibitory effect on type-I IFN signaling. Conclusion Thus, the role of PPAR-γ in murine lupus, as a key regulator of type-I IFN production, provides a compelling argument for the therapeutic application of PPAR-γ agonists in human lupus, which is considered to be IFN-α-driven [3] , [4] , [5] .