中性粒细胞继发性坏死是介导组织损伤的关键因素之一，但其诱导SLE组织损伤的分子机制尚不十分清晰。1型经典树突状细胞（cDC1s）表面Clec9A特异性识别坏死细胞表面暴露的F-actin，内吞并提呈坏死细胞相关抗原。我们前期研究发现与对照组相比，SLE患者或模型小鼠皮肤、肺、肾脏组织中Clec9A+cDC1s数量显著升高，推测其可能是介导坏死中性粒细胞诱导组织损伤的关键靶点。本项目拟以SLE患者、小鼠模型及体外细胞实验证实cDC1s在坏死中性粒细胞诱导的SLE组织损伤中发挥的关键作用，并进一步探索坏死中性粒细胞释放DAMPs与自身抗体结合形成DAMPs-IgG-IC，共同活化cDC1s表面Clec9A-FcγR受体，促进坏死相关抗原交叉提呈及炎性细胞因子释放的分子机制。本研究将为干预坏死中性粒细胞激活的获得性免疫反应，作为SLE治疗的关键靶标提供理论基础及科学依据。

Secondary necrosis of neutrophils is one of key factors in the development of tissue damage, however, the molecular mechanism of tissue damage in SLE induced by which is not fully understood. Clec9A as a conventional type 1 dendritic cells (cDC1s)-restricted receptor specific for F-actin that is exposed by necrotic cells, mediates cDC1s phagocyte and presents necrosis-related antigens. Our previous work demnstrated that the numbers of Clec9A+ cDC1 were significantly elevated in skin, lung and kidney tissues of SLE patients and model mice than controls, suggesting that they may be key targets for tissue damage induced by necrotic neutrophils. This project is to be confirmed by study with SLE patients, model mice, and cells in vitro that the important role of Clec9A+ cDC1s in necrotic neutrophil-induced tissue damage of SLE. Then, we further explore the mechanism of co-stimulation of Clec9A-FcγR receptors on surface of cDC1 with DAMPs-IgG-IC, which was combinated with necrotic neutrophil and autoantibody, promotes cross-presentation of necrosis-related antigens and releases of inflammatory cytokines. This study will provide theoretical and scientific basis for the intervention of adaptive immune response activated by necrotic neutrophils as a key target of SLE treatment.