Lood Christian, Arve Sabine, Ledbetter Jeffrey, Elkon Keith B
Department of Medicine, Division of Rheumatology, University of Washington, Seattle, WA 98109
Department of Medicine, Division of Rheumatology, University of Washington, Seattle, WA 98109.
J Exp Med. 2017 Jul 3;214(7):2103-2119. doi: 10.1084/jem.20161512. Epub 2017 Jun 12.
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.
中性粒细胞在宿主防御中发挥着关键作用。然而，中性粒细胞的激活也与自身免疫性疾病相关，如系统性红斑狼疮（SLE），在该疾病中，含核酸的免疫复合物（IC）会引发炎症。Toll样受体（TLR）信号在SLE免疫复合物的处理及下游炎症性中性粒细胞效应功能中的作用尚不清楚。我们观察到，TLR7/8激活会导致FcgRIIA N端部分发生弗林蛋白酶依赖性蛋白水解切割，使中性粒细胞从吞噬免疫复合物转向程序性坏死形式，即中性粒细胞胞外诱捕网形成（NETosis）。TLR7/8激活的中性粒细胞促进浆细胞样树突状细胞和单核细胞上FcgRIIA的切割，导致免疫复合物的整体清除受损，并增加补体C5a的生成。重要的是，来自SLE患者的体外活化中性粒细胞表现出类似的FcgRIIA切割，这与疾病活动标志物以及补体激活相关。预计旨在阻断TLR7/8激活的治疗方法将增加循环免疫复合物的吞噬作用，同时消除其炎症潜能。
