Neutrophil-derived microvesicles enter cartilage and protect the joint in inflammatory arthritis.
Neutrophil-derived microvesicles enter cartilage and protect the joint in inflammatory arthritis.
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DOI：
10.1126/scitranslmed.aac5608
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发表时间：
2015-11-25
影响因子：
17.1
通讯作者：
Perretti M
中科院分区：
文献类型：
--
作者：
Headland SE;Jones HR;Norling LV;Kim A;Souza PR;Corsiero E;Gil CD;Nerviani A;Dell'Accio F;Pitzalis C;Oliani SM;Jan LY;Perretti M
微囊泡（Microvesicles，MV）是一种新的细胞间通讯机制，通过将细胞内的脂质和蛋白质成分转移到靶细胞，但其在疾病中的作用目前还未得到研究。我们发现，与配对血浆相比，来自类风湿性关节炎患者的滑液中的嗜中性粒细胞衍生的MV的浓度增加。滑膜MV过表达前分解，抗炎蛋白膜联蛋白A1（AnxA 1）。缺乏TMEM 16 F（一种微泡形成所需的脂质扰乱酶）的小鼠在遭受炎性关节炎时表现出加剧的软骨损伤。为了确定MV在炎性关节炎中的功能，为了基于MV的治疗的可能性，我们检查了免疫细胞衍生的MV在啮齿动物模型和人原代软骨细胞中的作用。在体外，外源性AnxA 1 + MV激活软骨细胞中的合成代谢基因表达，导致细胞外基质积累和软骨保护，通过减少应激适应性稳态介质白细胞介素-8和前列腺素E2。在体内，关节内注射AnxA 1 + MV减轻了炎症性关节炎引起的软骨降解。关节炎小鼠接受过继转移的整个中性粒细胞显示丰富的MV软骨基质内，并透露，MV，但不是中性粒细胞本身，可以穿透软骨。机制研究支持MV相关AnxA 1与其受体FPR 2（甲酰肽受体2）/ALX相互作用的模型，增加软骨细胞转化生长因子-b的产生，最终导致软骨保护。我们设想，MV，无论是直接或装载治疗剂，可以利用作为一种独特的治疗策略，在与软骨变性相关的疾病的保护。
Microvesicles (MVs) are emerging as a new mechanism of intercellular communication by transferring cellular lipid and protein components to target cells, yet their function in disease is only now being explored. We found that neutrophil-derived MVs were increased in concentration in synovial fluid from rheumatoid arthritis patients compared to paired plasma. Synovial MVs overexpressed the proresolving, anti-inflammatory protein annexin A1 (AnxA1). Mice deficient in TMEM16F, a lipid scramblase required for microvesiculation, exhibited exacerbated cartilage damage when subjected to inflammatory arthritis. To determine the function of MVs in inflammatory arthritis, toward the possibility of MV-based therapeutics, we examined the role of immune cell–derived MVs in rodent models and in human primary chondrocytes. In vitro, exogenous neutrophil-derived AnxA1+ MVs activated anabolic gene expression in chondrocytes, leading to extracellular matrix accumulation and cartilage protection through the reduction in stress-adaptive homeostatic mediators interleukin-8 and prostaglandin E2. In vivo, intra-articular injection of AnxA1+ MV lessened cartilage degradation caused by inflammatory arthritis. Arthritic mice receiving adoptive transfer of whole neutrophils displayed abundant MVs within cartilage matrix and revealed that MVs, but not neutrophils themselves, can penetrate cartilage. Mechanistic studies support a model whereby MV-associated AnxA1 interacts with its receptor FPR2 (formyl peptide receptor 2)/ALX, increasing transforming growth factor–b production by chondrocytes, ultimately leading to cartilage protection. We envisage that MVs, either directly or loaded with therapeutics, can be harnessed as a unique therapeutic strategy for protection in diseases associated with cartilage degeneration.
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影响因子：
32.4
作者：
Campbell EL;Bruyninckx WJ;Kelly CJ;Glover LE;McNamee EN;Bowers BE;Bayless AJ;Scully M;Saeedi BJ;Golden-Mason L;Ehrentraut SF;Curtis VF;Burgess A;Garvey JF;Sorensen A;Nemenoff R;Jedlicka P;Taylor CT;Kominsky DJ;Colgan SP
通讯作者：
Colgan SP
DOI：
10.1038/mtna.2011.2
发表时间：
2012-02-07
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
通讯作者：
--
影响因子：
11.4
作者：
KEFFER, J;PROBERT, L;KOLLIAS, G
通讯作者：
KOLLIAS, G
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：
4.6
作者：
Headland SE;Jones HR;D'Sa AS;Perretti M;Norling LV
通讯作者：
Norling LV