Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea; Laboratory of Immune Regulation in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
Min Jueng Kang
Department of Molecular Medicine and Biopharmaceutical Sciences, School of Convergence Science, Seoul, Republic of Korea; Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea
Department of Molecular Medicine and Biopharmaceutical Sciences, School of Convergence Science, Seoul, Republic of Korea; Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea
Yumi Oh
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea
Graduate School of Medical Science and Engineering, Korean Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
Eugene C Yi
Department of Molecular Medicine and Biopharmaceutical Sciences, School of Convergence Science, Seoul, Republic of Korea; Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea
Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea; Laboratory of Immune Regulation in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
To date, no study has demonstrated that soluble Fas ligand (sFasL)-mediated inflammation is regulated via interaction with Fas in vivo. We found that FasL interacts specifically with tumor necrosis factor receptor superfamily (TNFRSF)10B, also known as death receptor (DR)5. Autoantibody-induced arthritis (AIA) was attenuated in FasL (Faslgld/gld)- and soluble FasL (FaslΔs/Δs)-deficient mice, but not in Fas (Faslpr/lpr and Fas–/–)- or membrane FasL (FaslΔm/Δm)-deficient mice, suggesting sFasL promotes inflammation by binding to a Fas-independent receptor. Affinity purification mass spectrometry analysis using human (h) fibroblast-like synovial cells (FLSCs) identified DR5 as one of several proteins that could be the elusive Fas-independent FasL receptor. Subsequent cellular and biochemical analyses revealed that DR5 interacted specifically with recombinant FasL–Fc protein, although the strength of this interaction was approximately 60-fold lower than the affinity between TRAIL and DR5. A microarray assay using joint tissues from mice with arthritis implied that the chemokine CX3CL1 may play an important downstream role of the interaction. The interaction enhanced Cx3cl1 transcription and increased sCX3CL1 production in FLSCs, possibly in an NF-κB-dependent manner. Moreover, the sFasL–DR5 interaction-mediated CX3CL1–CX3CR1 axis initiated and amplified inflammation by enhancing inflammatory cell influx and aggravating inflammation via secondary chemokine production. Blockade of FasL or CX3CR1 attenuated AIA. Therefore, the sFasL–DR5 interaction promotes inflammation and is a potential therapeutic target.
