Background. Exposure of systemic lupus erythematosus (SLE) patients to ultraviolet light B (UVB) triggers local and systemic inflammation, with cytosolic DNA sensing and induction of type I interferons (IFNs) known to play a role. We previously identified TRIM21 as a negative regulator of DNA sensing and IFN expression. Here we explore the role of TRIM21 in regulating local and systemic responses following UVB exposure. Methods. WT (C57BL/6) and Trim21-/- mice were irradiated with UVB (100mJ/cm2) daily for 1 and 3 weeks, and UVB-induced inflammation in skin, blood, and spleen were analyzed by qPCR, histology, RNA sequencing and flow cytometry. Mechanistic studies were performed in bone marrow-derived macrophages (BMDMs) and mouse skin fibroblasts (MDF) from WT and Trim21-/- mice, and TRIM21-/- THP-1 cells. Results. Infiltration of inflammatory cells and induction of type I IFN developed in UVB-exposed areas in both sets of mice, however Trim21-/- mice developed splenomegaly, enhanced total IgG levels and IFN-stimulated genes (ISG) in the blood and spleen. Enhanced basal and UVB-dependent Ifnb1 expression was observed in Trim21-/- BMDMs and MDFs, which was dependent on the cytosolic DNA sensing cGAS-STING pathway. Mechanistically, we found both degradation of DDX41 and STING levels were impaired in stimulated Trim21-/- BMDMs. Conclusion: Taken together, our results indicate that TRIM21 protects against IFN induction at local and systemic levels through restricting STING signaling. Our finding that reduced levels of TRIM21 are observed in SLE patients with cutaneous involvement indicates a potential role for TRIM21 in guarding against systemic flare in SLE patients.

中文翻译：

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TRIM21 的缺失通过调节 DNA 传感途径驱动 UVB 诱导的全身炎症

背景。系统性红斑狼疮 (SLE) 患者暴露于紫外线 B (UVB) 下会引发局部和全身炎症，其中细胞质 DNA 传感和 I 型干扰素 (IFN) 的诱导发挥了作用。我们之前确定 TRIM21 是 DNA 传感和 IFN 表达的负调节因子。在这里，我们探讨 TRIM21 在调节 UVB 暴露后局部和全身反应中的作用。方法。 WT (C57BL/6) 和 Trim21-/- 小鼠每天接受 UVB (100mJ/cm2) 照射，持续 1 周和 3 周，并通过 qPCR、组织学、RNA 测序和分析来分析 UVB 诱导的皮肤、血液和脾脏炎症。流式细胞仪。在来自 WT 和 Trim21-/- 小鼠的骨髓源性巨噬细胞 (BMDM) 和小鼠皮肤成纤维细胞 (MDF) 以及 TRIM21-/- THP-1 细胞中进行了机制研究。结果。两组小鼠的 UVB 暴露区域均出现炎症细胞浸润和 I 型干扰素诱导，但 Trim21-/- 小鼠出现脾肿大、血液和脾脏中总 IgG 水平和干扰素刺激基因 (ISG) 增加。在 Trim21-/- BMDM 和 MDF 中观察到基础和 UVB 依赖性 Ifnb1 表达增强，这依赖于胞质 DNA 传感 cGAS-STING 途径。从机制上讲，我们发现受刺激的 Trim21-/- BMDM 中 DDX41 和 STING 水平的降解均受到损害。结论：总而言之，我们的结果表明 TRIM21 通过限制 STING 信号传导，在局部和全身水平上防止 IFN 诱导。我们发现，在皮肤受累的 SLE 患者中观察到 TRIM21 水平降低，这表明 TRIM21 在预防 SLE 患者全身发作方面具有潜在作用。