TLR3 Ligand Poly(I:C) Exerts Distinct Actions in Synovial Fibroblasts When Delivered by Extracellular Vesicles.
TLR3 Ligand Poly(I:C) Exerts Distinct Actions in Synovial Fibroblasts When Delivered by Extracellular Vesicles.
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DOI：
10.3389/fimmu.2018.00028
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发表时间：
2018
影响因子：
7.3
通讯作者：
Gay S
中科院分区：
文献类型：
--
作者：
Frank-Bertoncelj M;Pisetsky DS;Kolling C;Michel BA;Gay RE;Jüngel A;Gay S
细胞外囊泡（EV）可以调节细胞对TLR连接的反应;相反，TLR配体如双链RNA（dsRNA）可以促进EV的释放并影响EV货物的组成和功能。类风湿性关节炎（RA）患者的炎症滑膜关节富含EV和细胞外RNA，坏死的滑膜液细胞释放的RNA可激活RA患者滑膜成纤维细胞（SF）中的TLR 3信号。由于EV主要发生在RA的滑膜关节中，并可能有助于发病机制，我们质疑EV是否可以与dsRNA（一种TLR 3配体）相互作用，并改变其在关节炎中的作用。我们已经使用作为模型的RA SF的影响，从单核细胞U937细胞和外周血单核细胞的EV释放后，刺激与聚（I：C），合成的类似物的dsRNA。我们表明，EV释放未受刺激的细胞和Poly（I：C）刺激的U937细胞[Poly（I：C）EV]大小不同，但结合相似量的膜联蛋白V，并在囊泡膜上表达相当水平的MAC-1（dsRNA的受体）。具体地，Poly（I：C）EV含有Poly（I：C）或与Poly（I：C）缔合，并且至少部分地保护Poly（I：C）免于RNA酶III降解。Poly（I：C）EV将Poly（I：C）穿梭于SF，并再现SF对Poly（I：C）直接刺激的促炎和抗病毒基因应答。然而，Poly（I：C）EV阻止了SF中死亡受体诱导的凋亡，从而逆转了Poly（I：C）的促凋亡性质。这些促生存作用与阳离子脂质体递送的Poly（I：C）的高毒性形成鲜明对比，并且可能反映了通过EV递送Poly（I：C）的途径或EV中分子货物对Poly（I：C）作用的微调。EV可以保护细胞外dsRNA并允许dsRNA对SF发挥抗凋亡作用的证明突出了EV在关节炎中放大dsRNA致病性的潜力，而不仅仅是炎症（通过同时增强侵入性滑膜基质的扩张）。
Extracellular vesicles (EV) can modulate the responses of cells to toll-like receptor (TLR) ligation; conversely, TLR ligands such as double-stranded RNA (dsRNA) can enhance the release of EV and influence of the composition and functions of EV cargos. Inflamed synovial joints in rheumatoid arthritis (RA) are rich in EV and extracellular RNA; besides, RNA released from necrotic synovial fluid cells can activate the TLR3 signaling in synovial fibroblasts (SFs) from patients with RA. Since EV occur prominently in synovial joints in RA and may contribute to the pathogenesis, we questioned whether EV can interact with dsRNA, a TLR3 ligand, and modify its actions in arthritis. We have used as model the effects on RA SFs, of EV released from monocyte U937 cells and peripheral blood mononuclear cells upon stimulation with Poly(I:C), a synthetic analog of dsRNA. We show that EV released from unstimulated cells and Poly(I:C)-stimulated U937 cells [Poly(I:C) EV] differ in size but bind similar amounts of Annexin V and express comparable levels of MAC-1, the receptor for dsRNA, on the vesicular membranes. Specifically, Poly(I:C) EV contain or associate with Poly(I:C) and at least partially protect Poly(I:C) from RNAse III degradation. Poly(I:C) EV shuttle Poly(I:C) to SFs and reproduce the proinflammatory and antiviral gene responses of SFs to direct stimulation with Poly(I:C). Poly(I:C) EV, however, halt the death receptor-induced apoptosis in SFs, thereby inverting the proapoptotic nature of Poly(I:C). These prosurvival effects sharply contrast with the high toxicity of cationic liposome-delivered Poly(I:C) and may reflect the route of Poly(I:C) delivery via EV or the fine-tuning of Poly(I:C) actions by molecular cargo in EV. The demonstration that EV may safeguard extracellular dsRNA and allow dsRNA to exert antiapoptotic effects on SFs highlights the potential of EV to amplify the pathogenicity of dsRNA in arthritis beyond inflammation (by concurrently enhancing the expansion of the invasive synovial stroma).
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影响因子：
16
作者：
Crescitelli R;Lässer C;Szabó TG;Kittel A;Eldh M;Dianzani I;Buzás EI;Lötvall J
通讯作者：
Lötvall J
影响因子：
4.6
作者：
Damo M;Wilson DS;Simeoni E;Hubbell JA
通讯作者：
Hubbell JA
影响因子：
14.8
作者：
Jones DS;Jenney AP;Swantek JL;Burke JM;Lauffenburger DA;Sorger PK
通讯作者：
Sorger PK
影响因子：
11.1
作者：
Cloutier, Nathalie;Tan, Sisareuth;Boudreau, Luc H.;Cramb, Catriona;Subbaiah, Roopashree;Lahey, Lauren;Albert, Alexandra;Shnayder, Ruslan;Gobezie, Reuben;Nigrovic, Peter A.;Farndale, Richard W.;Robinson, William H.;Brisson, Alain;Lee, David M.;Boilard, Eric
通讯作者：
Boilard, Eric
影响因子：
4.4
作者：
Itoh, Kiyoharu;Watanabe, Ayako;Matsumoto, Misako
通讯作者：
Matsumoto, Misako