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）患者暴露于紫外光下，具有光敏性