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.

全身性红斑狼疮（SLE）的患者经历光敏性，暴露于紫外线 （紫外线）经常驱动狼疮耀斑，除了引起皮肤外，还会引起关节疼痛和疲劳等症状 病变。但是，尽管将UVB接触到全身效应的机制尚不清楚，但I型IFNS 众所周知会扮演角色。我们以前的工作表明E3连接酶TRIM21是IFN的负调节剂 表达。有趣的是，我们观察到Trim21 - / - 小鼠反应DNA会出现自发皮肤病变 在皮肤中检测。这促使我们调查了trim21 - / - 小鼠是否对紫外线有效反应 驱动皮肤炎症。 TRIM21 - / - 小鼠比较响应UVB，会出现更严重的皮肤炎症 野生型，脾肿大和全身IFN的水平增强。关于TRIM21的目标 调节UVB诱导的响应我们已经确定了DDX41，这是一个相对研究的DNA传感器作为一个 潜在目标。我们假设TRIM21通过防止 由胞质DNA感应驱动的不受控制的全身IFN反应，例如在UVB皮肤中证明 模型，这可能对SLE的光敏性有影响。为了评估这一点，我们提出以下建议： 目标1：评估TRIM21在UVB引起的皮肤炎症中的作用及其对系统的贡献 更改。我们将定义哪些免疫细胞在TRIM21 - / - 小鼠中是全身性疾病的关键，以及如何刺痛 - IFN依赖和独立途径介导了从局部到系统的过渡驱动 在没有TRIM21的情况下响应UVB的炎症。 AIM 2：确定TRIM21和DDX41在对UVB响应中调节CGAS插曲信号传导中的作用。 我们将调查TRIM21和DDX41如何受到UVB下游的调节，并询问它们的损失如何改变 使用生物化学和蛋白质组学的组合，刺激性信号的组成，稳定性和功能。 AIM 3：定义TRIM21的损失如何贡献皮肤和全身性UVB驱动的IFN响应。 对SLE患者的PBMC和皮肤活检的分析将决定TRIM21如何有助于 SLE中的光敏性以及刺激在推动这些反应中的作用。 影响：该项目将确定Trim21在此中的这种机制 控制UVB驱动的系统性IFN响应，并询问更改的TRIM21调节途径是否可以 解释SLE中UVB暴露与狼疮耀斑风险增加之间的联系。