Abstract：
Psoriasis is a chronic inflammatory skin disease connected with immune dysregulation. Macrophages are key inflammatory cells in psoriasis but the specific mechanism of their activation is not fully understood. Neutrophil extracellular traps (NETs) have been shown to regulate macrophage function. Here, we found that NET deposition was increased in psoriasis lesions. Peptidylarginine deaminase 4 (PAD4, a key enzyme for NET formation) deficiency attenuated skin lesions and inflammation in an imiquimod-induced psoriatic mouse model. Furthermore, the STING signaling pathway was markedly activated in psoriasis and abolished by PAD4 deficiency. PAD4-deficient mice treated with the STING agonist DMXAA exhibited more severe symptoms and inflammation than control mice. Mechanistically, the STING inhibitor C-176 inhibited NET-induced macrophage inflammation and further inhibited the proliferation of HaCaT cells. Our findings suggest an important role of NETs in the pathogenesis of psoriasis, and activation of macrophage STING/NF-κB signaling pathway might involve in NETs related psoriasis.
摘要：
银屑病是一种与免疫失调有关的慢性炎症性皮肤病。巨噬细胞是银屑病的关键炎性细胞,但其活化的具体机制尚不完全清楚。中性粒细胞胞外诱捕网(NETs)已被证明可调节巨噬细胞功能。这里,我们发现牛皮癣皮损中网络沉积增加。在咪喹莫特诱导的牛皮癣小鼠模型中，肽基精氨酸脱氨酶4（PAD4，NET形成的关键酶）缺乏减轻了皮肤损伤和炎症。此外，STING信号通路在银屑病中被显著激活，并因PAD4缺乏而被废除。用STING激动剂DMXAA治疗的PAD4缺陷型小鼠表现出比对照小鼠更严重的症状和炎症。机械上,STING抑制剂C-176抑制NET诱导的巨噬细胞炎症，并进一步抑制HaCaT细胞的增殖。我们的发现提示NETs在银屑病的发病机制中的重要作用,巨噬细胞STING/NF-κB信号通路的激活可能参与了NETs相关的银屑病。
