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.

项目摘要 系统性红斑狼疮（SLE）以T细胞、B细胞和树突状细胞过度活化为特征 细胞（DC），产生针对核酸相关和其他自身分子的自身抗体，以及免疫 复合物介导的多器官炎症损伤。两种小鼠中的机制评估 模型和人类已经暗示了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的Toll样受体（TLR）活化 （pDC）、I型干扰素的产生以及干扰素诱导基因特征的表达通常 与疾病活动相关。包括我们实验室在内的其他研究表明， 全身性自身免疫中的TLR应答需要肽/组氨酸转运蛋白的参与 SLC 15 A4，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，SLC 15 A4不作为转运蛋白，而是作为结合蛋白， TASL的伙伴，这反过来又促进TLR信号传导。因此，本提案的重点是界定 因此，我们可以从机制上解释SLC 15 A4和TASL如何促进TLR活化。为此，我们将使用一个新的TASL- 缺陷型小鼠模型，其将允许分离SLC 15 A4作为转运蛋白的作用与其作为平台的作用 这有助于招募TASL。至关重要的是，这些研究将阐明， SLC 15 A4转运蛋白活性是一种适当的策略，或者如果靶向TASL， 减少狼疮和其他自身免疫性疾病中炎症反应的方法。