TLR7/8 activation in neutrophils impairs immune complex phagocytosis through shedding of FcgRIIA.
TLR7/8 activation in neutrophils impairs immune complex phagocytosis through shedding of FcgRIIA.
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DOI：
10.1084/jem.20161512
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发表时间：
2017-07-03
期刊：
影响因子：
--
通讯作者：
Elkon KB
中科院分区：
文献类型：
--
作者：
Lood C;Arve S;Ledbetter J;Elkon KB
blood等人发现中性粒细胞TLR7/8的活化使中性粒细胞从吞噬免疫复合物转变为NETosis。免疫复合物吞噬作用的减少与FcgRIIA部分蛋白水解裂解有关。Cleaved FcgRIIA在离体SLE中性粒细胞中发现。中性粒细胞在宿主防御中起关键作用。然而，中性粒细胞活化也与自身免疫性疾病有关，如系统性红斑狼疮（SLE），其中含有核酸的免疫复合物（IC）驱动炎症。toll样受体（TLR）信号在SLE ic和下游炎症中性粒细胞效应功能过程中的作用尚不清楚。我们观察到，TLR7/8激活导致FcgRIIA n端部分的糠蛋白依赖性蛋白水解裂解，将中性粒细胞从吞噬ic转向程序性坏死，即NETosis。tlr7 /8活化的中性粒细胞促进了浆细胞样树突状细胞和单核细胞上FcgRIIA的切割，导致ic的总体清除受损，补体C5a的生成增加。重要的是，来自SLE患者的体外衍生活化中性粒细胞显示出类似的FcgRIIA切割，这与疾病活性标志物和补体激活相关。旨在阻断TLR7/8激活的治疗方法预计会增加循环ic的吞噬，同时解除其炎症潜能。
Lood et al. find that neutrophil TLR7/8 activation shifts neutrophils from phagocytosis of immune complexes to NETosis. Reduced phagocytosis of immune complexes is associated with partial proteolytic cleavage of FcgRIIA. Cleaved FcgRIIA is found in SLE neutrophils ex vivo. Neutrophils play a crucial role in host defense. However, neutrophil activation is also linked to autoimmune diseases such as systemic lupus erythematosus (SLE), where nucleic acid–containing immune complexes (IC) drive inflammation. The role of Toll-like receptor (TLR) signaling in processing of SLE ICs and downstream inflammatory neutrophil effector functions is not known. We observed that TLR7/8 activation leads to a furin-dependent proteolytic cleavage of the N-terminal part of FcgRIIA, shifting neutrophils away from phagocytosis of ICs toward the programmed form of necrosis, NETosis. TLR7/8-activated neutrophils promoted cleavage of FcgRIIA on plasmacytoid dendritic cells and monocytes, resulting in impaired overall clearance of ICs and increased complement C5a generation. Importantly, ex vivo derived activated neutrophils from SLE patients demonstrated a similar cleavage of FcgRIIA that was correlated with markers of disease activity, as well as complement activation. Therapeutic approaches aimed at blocking TLR7/8 activation would be predicted to increase phagocytosis of circulating ICs, while disarming their inflammatory potential.
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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
影响因子：
56.9
作者：
Blander, JM;Medzhitov, R
通讯作者：
Medzhitov, R
影响因子：
4.5
作者：
Cunninghame Graham DS;Morris DL;Bhangale TR;Criswell LA;Syvänen AC;Rönnblom L;Behrens TW;Graham RR;Vyse TJ
通讯作者：
Vyse TJ
DOI：
10.1084/jem.20031237
发表时间：
2004-01-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Doyle SE;O'Connell RM;Miranda GA;Vaidya SA;Chow EK;Liu PT;Suzuki S;Suzuki N;Modlin RL;Yeh WC;Lane TF;Cheng G
通讯作者：
Cheng G
影响因子：
20.3
作者：
Chen, Kan;Nishi, Hiroshi;Mayadas, Tanya N.
通讯作者：
Mayadas, Tanya N.