TRIM21 as a regulator of UVB- and cytosolic DNA-driven IFN responses in lupus

TRIM21 作为狼疮中 UVB 和胞质 DNA 驱动的 IFN 反应的调节剂

• 批准号: 10707577
• 负责人: Caroline Jefferies
• 金额: $ 36.74万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10707577
• 关键词: Address; Antiviral Response; Arthralgia; Autoantigens; Automobile Driving; Biochemical; Biochemistry; Biology; Biopsy; Blood; Cells; Coculture Techniques; Complementary DNA; Complex; Cutaneous; Cutaneous Involvement; DNA; DNA Damage; Detection; Disease; Ensure; Exposure to; Factor Analysis; Fatigue; Flare; Gatekeeping; Gene Expression; Gene Proteins; Genetic; Goals; Immune; Immune response; Individual; Inflammation; Inflammatory; Interferon Type I; Interferons; Kidney; Lesion; Link; Lupus; Mediating; Modeling; Molecular; Mus; Oxidative Stress; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Photosensitivity; Play; Production; Proteomics; RNA; Regulation; Risk; Role; Sampling; Severity of illness; Signal Transduction; Skin; Spleen; Splenomegaly; Stimulator of Interferon Genes; Sting Injury; Symptoms; Systemic Lupus Erythematosus; Systemic disease; Tissue imaging; Translating; UV Radiation Exposure; UV induced; UV induced DNA damage; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; Work; cell type; conditional knockout; experience; genetic signature; human disease; mouse model; prevent; protein expression; response; sensor; skin lesion; systemic autoimmunity; systemic inflammatory response; ubiquitin-protein ligase; ultraviolet

Patients with systemic lupus erythematosus (SLE) experience photosensitivity, with exposure to ultraviolet light (UV) often driving lupus flares, triggering symptoms like joint pain and fatigue, in addition to causing cutaneous lesions. However, although the mechanism(s) linking UVB exposure to systemic effects are unclear, type I IFNs are known to play a role. Our previous work has shown that the E3 ligase TRIM21 is a negative regulator of IFN expression. Interestingly we observed that Trim21-/- mice develop spontaneous skin lesions in response to DNA detection in the skin. This prompted us to investigate whether Trim21-/- mice were hyperresponsive to UV in driving skin inflammation. Trim21-/- mice develop more severe skin inflammation in response to UVB compared to wild type, as well as splenomegaly and enhanced levels of systemic IFNs. Regarding targets for TRIM21 in regulating UVB-induced responses we have identified DDX41, a relatively under studied DNA sensor as a potential target. We hypothesize that TRIM21 acts as a gatekeeper against systemic disease by preventing uncontrolled systemic IFN responses driven by cytosolic DNA sensing, such as demonstrated in the UVB skin model and that this may have implications for photosensitivity in SLE. To evaluate this, we propose the following: Aim 1: Assess the role of TRIM21 in UVB-induced skin inflammation and how it contributes to systemic changes. We will define what immune cells are key to systemic disease in the Trim21-/- mice and how STING- and IFN-dependent and independent pathways mediate the drive the transition from local to systemic inflammation in response to UVB in the absence of TRIM21. Aim 2: Determine the role of TRIM21 and DDX41 in regulating cGAS-STING signaling in response to UVB. We will investigate how TRIM21 and DDX41 is regulated downstream of UVB and ask how their loss alters the composition, stability and function of the STING signalsome using a combination of biochemistry and proteomics. Aim 3: Define how loss of TRIM21 contributes both cutaneous and systemic UVB-driven IFN responses. Analysis of PBMCs and skin biopsies from SLE patients will determine how TRIM21 may contribute to photosensitivity in SLE and the role of STING in driving these responses. Impact: This project will determine the mechanisms underlying this hitherto unknown role of TRIM21 in controlling UVB-driven systemic IFN responses and ask whether altered TRIM21-regulated pathways can explain the link between UVB exposure and increased risk of lupus flare in SLE.

系统性红斑狼疮 (SLE) 患者暴露于紫外线后会出现光敏反应 （紫外线）除了引起皮肤损伤外，还经常导致狼疮发作，引发关节疼痛和疲劳等症状 病变。然而，尽管 UVB 暴露与全身效应之间的联系机制尚不清楚，但 I 型干扰素 已知发挥作用。我们之前的工作表明E3连接酶TRIM21是IFN的负调节因子 表达。有趣的是，我们观察到 Trim21-/- 小鼠响应 DNA 出现自发性皮肤损伤 皮肤中的检测。这促使我们研究 Trim21-/- 小鼠是否对紫外线过度反应 导致皮肤发炎。与 Trim21-/- 小鼠相比，Trim21-/- 小鼠因 UVB 反应而出现更严重的皮肤炎症 野生型，以及脾肿大和全身干扰素水平升高。关于 TRIM21 的目标 我们已经确定了 DDX41，这是一种研究相对较少的 DNA 传感器，可调节 UVB 诱导的反应 潜在目标。我们假设 TRIM21 通过预防来充当系统性疾病的守门人 由胞质 DNA 传感驱动的不受控制的全身 IFN 反应，如 UVB 皮肤中所证实的 模型，这可能对 SLE 的光敏性产生影响。为了评估这一点，我们提出以下建议： 目标 1：评估 TRIM21 在 UVB 诱导的皮肤炎症中的作用以及它如何促进全身性炎症 变化。我们将定义哪些免疫细胞是 Trim21-/- 小鼠全身性疾病的关键，以及如何进行 STING- IFN 依赖性和独立途径介导驱动从局部到全身的转变 TRIM21 缺失时 UVB 引起的炎症反应。 目标 2：确定 TRIM21 和 DDX41 在响应 UVB 调节 cGAS-STING 信号传导中的作用。 我们将研究 TRIM21 和 DDX41 如何在 UVB 下游进行调节，并询问它们的损失如何改变 结合生物化学和蛋白质组学研究 STING 信号体的组成、稳定性和功能。 目标 3：定义 TRIM21 的缺失如何影响皮肤和全身 UVB 驱动的 IFN 反应。 对 SLE 患者的 PBMC 和皮肤活检的分析将确定 TRIM21 如何有助于 SLE 中的光敏感性以及 STING 在驱动这些反应中的作用。 影响：该项目将确定 TRIM21 迄今为止未知的作用背后的机制 控制 UVB 驱动的系统性 IFN 反应，并询问改变 TRIM21 调节的途径是否可以 解释 UVB 暴露与 SLE 狼疮发作风险增加之间的联系。