Fas配体
炎症
肿瘤坏死因子α
CX3CL1型
趋化因子
免疫学
受体
关节炎
癌症研究
化学
细胞生物学
生物
细胞凋亡
趋化因子受体
程序性细胞死亡
生物化学
作者
Dongjin Jeong,Hye Sung Kim,Hye Young Kim,Min Jueng Kang,Hyeryeon Jung,Yumi Oh,Dong-Hyun Kim,Jaemoon Koh,Sung Yup Cho,Yoon Kyung Jeon,Eun Bong Lee,Seung‐Hyo Lee,Eui Cheol Shin,Ho Min Kim,Eugene C. Yi,Doo Hyun Chung
出处
期刊:eLife
[eLife Sciences Publications, Ltd.]
日期:2021-07-05
卷期号:10
被引量:4
摘要
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 ( Fasl gld/gld )- and soluble FasL ( Fasl Δs/Δs )-deficient mice, but not in Fas ( Fas lpr/lpr and Fas –/– )- or membrane FasL ( Fasl Δm/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.
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