VISTA regulates type I interferon response to ultraviolet light

VISTA 调节 I 型干扰素对紫外线的反应

• 批准号: 10286517
• 负责人: Sladjana Skopelja-Gardner
• 金额: $ 38.4万
• 依托单位: DARTMOUTH-HITCHCOCK CLINIC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286517
• 关键词: Acute; Address; Affect; Agonist; Automobile Driving; Biology; Biopsy; Blood; Blood Cells; Burn injury; Cells; Coupled; Data; Disease; Exposure to; Flare; Gene Expression Profile; Human; Immune response; Immunoglobulins; In Vitro; Individual; Inflammatory Response; Integral Membrane Protein; Interferon Type I; Interferon-beta; Interferons; Kidney; Kinetics; Knock-in Mouse; Knockout Mice; Knowledge; Lead; Lupus; Molecular; Monoclonal Antibodies; Mouse Strains; Mus; Myeloid Cells; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Photosensitivity; Production; Publishing; Regulation; Resources; Risk; Role; Skin; Skin Tissue; Source; Stimulus; Suppressor-Effector T-Lymphocytes; Systemic Lupus Erythematosus; Systemic disease; T-Cell Activation; Testing; Therapeutic; Time; UV Radiation Exposure; Ultraviolet Rays; base; conditional knockout; experience; in vivo; inhibiting antibody; keratinocyte; lupus cutaneous; lupus-like; monocyte; mouse model; multiplexed imaging; novel; prevent; response; skin disorder; success; therapeutic evaluation; ultraviolet

Project Summary Sensitivity to UV light affects ~80% of lupus patients and can exacerbate local skin disease and lead to systemic disease flares. The molecular pathways predisposing lupus patients to photosensitivity and the mechanisms driving the inflammatory responses to UV light are poorly understood. We showed that a single exposure to UV light leads to a rapid type I interferon (IFN- I) response in human and murine skin in vivo. That UV light is a potent stimulus of the IFN-I response is particularly relevant as lupus patients (~75%) have a high IFN-I signature in both the skin tissue and the peripheral blood cells, indicative of worse disease. Therefore, there is a critical need to discover what regulates the IFN-I production in response to UV light and in lupus skin. Recent studies showed that deficiency in VISTA result in lupus-like skin disease and accelerate systemic disease in lupus mouse models. The observed pathologies were accompanied by an increase in the IFN-I signature, suggesting VISTA can modulate the IFN-I response. Indeed, we demonstrated that an agonistic anti-VISTA antibody inhibits the IFN-I response in human monocytes. While findings that the transcriptional profile of cells from lupus patients resembles that of murine VISTA-/- cells suggest an important role for VISTA in lupus pathogenesis, how VISTA modulates the IFN-I response in lupus skin and in response to UV light is unknown. Here, we hypothesize that VISTA negatively regulates the IFN-I response to UV light and that VISTA activity in keratinocytes modulates the baseline and UV-triggered IFN-I production. To test these hypotheses, we will pursue the following specific aims: In Aim 1, we will define how VISTA regulates local and systemic IFN-I response to UV light in vivo. We predict that the IFN-I response to UV light in the skin and blood of VISTA-/- mice will be of greater magnitude and/or duration, compared to VISTA-sufficient controls. We will examine the therapeutic potential of targeting VISTA to modulate the IFN-I response to UV light using an agonistic anti-human VISTA monoclonal antibody in humanized VISTA knock-in mice. In Aim 2, we will characterize UV-light triggered IFN-I production by keratinocytes and define keratinocyte VISTA function. The cellular source and class of IFN-I in UV light exposed skin is unknown as is the function of VISTA expressed by keratinocytes. Given the rapid IFN-b production in the skin after UV exposure, we will investigate the contribution of keratinocytes as the likely source of IFN-Is in UV light-exposed skin of normal and lupus mouse strains. We will also define the keratinocyte-specific VISTA function in vivo in VISTA conditional knockout mice and in primary lupus keratinocytes.

项目摘要 对紫外光的敏感性会影响约80％的狼疮患者，并加剧局部皮肤病和 导致全身性疾病耀斑。分子途径使狼疮患者倾向于 光敏性和推动对紫外线的炎症反应的机制较差 理解。我们表明，一次暴露于紫外线会导致I型I类干扰素（IFN- i）体内人类和鼠皮的反应。紫外线是IFN-I的有效刺激 反应尤其重要，因为狼疮患者（约75％）在两者中都具有高IFN-I签名 皮肤组织和外周血细胞，表明疾病恶化。因此，有一个关键 需要发现是什么因响应紫外线和狼疮皮肤而调节IFN-I产生。 最近的研究表明，远景缺乏会导致狼疮样皮肤病和加速 狼疮小鼠模型中的全身性疾病。观察到的病理伴随着 IFN-I特征的增加，表明Vista可以调节IFN-I响应。确实，我们 证明一种激动抗Vista抗体抑制了人类的IFN-I反应 单核细胞。同时发现来自狼疮患者的细胞的转录特征相似 鼠的远景 - / - 细胞的表明，远景在狼疮发病机理中的重要作用，如何 Vista调节狼疮皮肤中的IFN-I反应，并响应紫外线。这里， 我们假设远景对IFN-I对紫外线的反应负面调节，该远景 角质形成细胞中的活性调节基线和紫外线触发的IFN-I产生。测试这些 假设，我们将追求以下具体目标：在AIM 1中，我们将定义如何远景 调节体内对紫外线的局部和全身性IFN-I反应。我们预测IFN-I响应 紫外线和远景的血液 - / - 小鼠的血液将更大和/或持续时间， 与远景充足的控件相比。我们将检查靶向的治疗潜力 使用激动剂的抗人类远景来调节IFN-I对紫外线的反应 人性化远景敲入小鼠中的单克隆抗体。在AIM 2中，我们将描述紫外线 通过角质形成细胞触发了IFN-I产生，并定义了角质形成细胞远景功能。细胞 紫外线裸露的皮肤中的IFN-I的来源和类别未知，远景的功能也是 由角质形成细胞表达。鉴于紫外线暴露后皮肤中的IFN-B产生迅速，我们 将研究角质形成细胞作为紫外线暴露的IFN-IS的贡献 正常和狼疮小鼠菌株的皮肤。我们还将定义角质形成细胞特定的远景 在远景有条件敲除小鼠和原代角质形成细胞中的体内功能。

项目成果

Spatial characterization of interface dermatitis in cutaneous lupus reveals novel chemokine ligand-receptor pairs that drive disease.

皮肤狼疮界面皮炎的空间特征揭示了驱动疾病的新型趋化因子配体-受体对。

• DOI: 10.1101/2024.01.05.574422
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Shakiba,Saeed;Haddadi,Nazgol-Sadat;Afshari,Khashayar;Lubov,JanetE;Raef,HayaS;Li,Robert;Yildiz-Altay,Ümmügülsüm;Daga,Mridushi;Refat,MaggiAhmed;Kim,Evangeline;deLaflin,JohannaGalindo;Akabane,Andressa;Sherman,Shany;MacDonald,E
• 通讯作者: MacDonald,E