Differential role of TASL and SLC15A4 in TLR responses to nucleic acids and lupus development

TASL 和 SLC15A4 在 TLR 对核酸反应和狼疮发展中的不同作用

• 批准号: 10583337
• 负责人: ROBERTO G BACCALA
• 金额: $ 28.8万
• 依托单位: SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-18 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10583337
• 关键词: Address; Affect; Antigen-Antibody Complex; Autoantibodies; Autoimmune Diseases; B-Lymphocytes; Binding; Complex; Data; Dendritic Cells; Development; Disease; Event; Family; Genes; Histidine; Human; Impairment; In Vitro; Inflammatory; Inflammatory Response; Interferon Type I; Interferons; Laboratories; Ligands; Lupus; Mediating; Mus; Mutation; Nucleic Acids; Organ; Pathogenesis; Pathogenicity; Peptides; Production; Receptor Activation; Receptor Signaling; Role; Signal Transduction; Systemic Lupus Erythematosus; T-Lymphocyte; TLR7 gene; Toll-like receptors; Transformed Cell Line; congenic; druggable target; genetic signature; in vivo; inhibitor; innate immune pathways; lupus-like; member; mouse model; novel; novel therapeutic intervention; pharmacologic; recruit; response; solute; systemic autoimmunity; therapeutically effective; tool

PROJECT SUMMARY Systemic lupus erythematosus (SLE) is characterized by hyperactivation of T cells, B cells and dendritic cells (DCs), production of autoantibodies to nucleic acid-associated and other self-molecules, and immune complex-mediated inflammatory damage in multiple organs. Mechanistic assessments in both mouse models and humans have implicated innate immune pathways of nucleic acid sensing in lupus pathogenesis, particularly Toll-like receptor (TLR) activation in B cells and plasmacytoid dendritic cells (pDCs), production of type I interferons, and expression of an interferon-inducible gene signature often correlating with disease activity. Additional studies including by our laboratory have shown that pathogenic TLR responses in systemic autoimmunity require the participation of the peptide/histidine transporter SLC15A4, suggesting that inhibition of this transporter may be an effective therapeutic approach. Very recent studies, however, suggested that SLC15A4 does not act as a transporter but rather as binding partner of TASL, which in turn facilitates TLR signaling. Thus, the focus of this proposal is to define mechanistically how SLC15A4 and TASL contribute to TLR activation. For this we will use a novel TASL- deficient mouse model that will allow to separate the SLC15A4 role as a transporter vs. its role as a platform that facilitates recruitment of TASL. Crucially, these studies will clarify if pharmacologic inhibition of the SLC15A4 transporter activity is an appropriate strategy, or if instead targeting TASL would be a better approach to reduce inflammatory responses in lupus and other autoimmune conditions.

项目概要 系统性红斑狼疮 (SLE) 的特点是 T 细胞、B 细胞和树突状细胞过度活化 细胞（DC）、针对核酸相关分子和其他自身分子的自身抗体的产生以及免疫 复合物介导的多个器官炎症损伤。两只小鼠的机械评估 模型和人类表明狼疮中核酸传感的先天免疫途径 发病机制，特别是 B 细胞和浆细胞样树突状细胞中 Toll 样受体 (TLR) 的激活 (pDC)、I 型干扰素的产生以及干扰素诱导基因特征的表达 与疾病活动相关。包括我们实验室在内的其他研究表明，致病性 系统性自身免疫中的 TLR 反应需要肽/组氨酸转运蛋白的参与 SLC15A4，表明抑制这种转运蛋白可能是一种有效的治疗方法。非常 然而，最近的研究表明，SLC15A4 并不充当转运蛋白，而是充当结合蛋白 TASL 的合作伙伴，进而促进 TLR 信号传导。因此，本提案的重点是定义 从机制上讲，SLC15A4 和 TASL 如何促进 TLR 激活。为此，我们将使用一种新颖的 TASL- 有缺陷的小鼠模型将允许将 SLC15A4 作为转运蛋白的角色与其作为平台的角色分开 这有利于 TASL 的招募。至关重要的是，这些研究将阐明药物抑制是否 SLC15A4 转运蛋白活性是一个合适的策略，或者如果以 TASL 为目标会更好 减少狼疮和其他自身免疫性疾病炎症反应的方法。