Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Clin Immunol. 2024 Sep;266:110308. doi: 10.1016/j.clim.2024.110308. Epub 2024 Jul 11.
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.
银屑病是一种与免疫失调有关的慢性炎症性皮肤病。巨噬细胞是银屑病中的关键炎症细胞，但它们的激活的具体机制尚不完全清楚。中性粒细胞胞外诱捕网（NETs）已被证明可以调节巨噬细胞功能。在这里，我们发现银屑病皮损中 NET 沉积增加。肽基精氨酸脱氨酶 4（PAD4，NET 形成的关键酶）缺乏可减轻咪喹莫特诱导的银屑病小鼠模型中的皮肤损伤和炎症。此外，STING 信号通路在银屑病中明显激活，并被 PAD4 缺乏所消除。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。在机制上，STING 抑制剂 C-176 抑制了 NET 诱导的巨噬细胞炎症，并进一步抑制了 HaCaT 细胞的增殖。我们的研究结果表明 NETs 在银屑病发病机制中起重要作用，而巨噬细胞 STING/NF-κB 信号通路的激活可能与 NETs 相关的银屑病有关。
