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

项目总结 系统性红斑狼疮(SLE)的特征是T细胞、B细胞和树突状细胞的过度激活 细胞(DC)，产生与核酸相关的自身抗体和其他自身分子，以及免疫 复合体介导的多器官炎症损伤。两只小鼠的机械性评估 模型和人类在狼疮中涉及到核酸感应的先天免疫途径 B细胞和浆细胞样树突状细胞Toll样受体(TLR)活化的发病机制 (PDC)、I型干扰素的产生和干扰素诱导基因信号的表达通常 与疾病活动相关的。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/组氨酸转运体的参与 SLC15A4，提示抑制该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不是作为转运蛋白，而是作为结合蛋白 TASL的合作伙伴，TASL反过来促进TLR信令。因此，这项提案的重点是界定 SLC15A4和TASL在TLR激活中的作用机制。为此，我们将使用一种新颖的TASL- 有缺陷的小鼠模型，允许将SLC15A4作为运输者的角色与其作为平台的角色分开 这为招募塔斯勒提供了便利。重要的是，这些研究将澄清是否药物抑制 SLC15A4转运体活动是一个合适的策略，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的炎症反应的方法。

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.