Abstract：
Toxin- and drug-induced tubulointerstitial nephritis (TIN), characterized by interstitial infiltration of immune cells, frequently necessitates dialysis for patients due to irreversible fibrosis. However, agents modulating interstitial immune cells are lacking. Here, we addressed whether the housekeeping enzyme glutamyl-prolyl-transfer RNA synthetase 1 (EPRS1), responsible for attaching glutamic acid and proline to transfer RNA, modulates immune cell activity during TIN and whether its pharmacological inhibition abrogates fibrotic transformation. The immunological feature following TIN induction by means of an adenine-mixed diet was infiltration of EPRS1high T cells, particularly proliferating T and γδ T cells. The proliferation capacity of both CD4+ and CD8+ T cells, along with interleukin-17 production of γδ T cells, was higher in the kidneys of TIN-induced Eprs1+/+ mice than in the kidneys of TIN-induced Eprs1+/- mice. This discrepancy contributed to the fibrotic amelioration observed in kidneys of Eprs1+/- mice. TIN-induced fibrosis was also reduced in Rag1-/- mice adoptively transferred with Eprs1+/- T cells compared to the Rag1-/- mice transferred with Eprs1+/+ T cells. The use of an EPRS1-targeting small molecule inhibitor (bersiporocin) under clinical trials to evaluate its therapeutic potential against idiopathic pulmonary fibrosis alleviated immunofibrotic aggravation in TIN. EPRS1 expression was also observed in human kidney tissues and blood-derived T cells, and high expression was associated with worse patient outcomes. Thus, EPRS1 may emerge as a therapeutic target in toxin- and drug-induced TIN, modulating the proliferation and activity of infiltrated T cells.
摘要：
毒素和药物诱导的肾小管间质性肾炎（TIN），以免疫细胞的间质浸润为特征，由于不可逆的纤维化，患者经常需要透析。然而,缺乏调节间质免疫细胞的药物。这里,我们讨论了保房酶谷氨酰-氨酰-转移RNA合成酶1(EPRS1)，负责连接谷氨酸和脯氨酸以转移RNA，在TIN期间调节免疫细胞活性，以及其药理抑制作用是否消除纤维化转化。通过腺嘌呤混合饮食诱导TIN后的免疫学特征是EPRS1高T细胞的浸润，特别是增殖T和γδT细胞。CD4+和CD8+T细胞的增殖能力，随着白介素-17产生γδT细胞，TIN诱导的Eprs1/-小鼠的肾脏高于TIN诱导的Eprs1/-小鼠的肾脏。这种差异有助于在Eprs1+/-小鼠的肾脏中观察到的纤维化改善。与用Eprs1+/+T细胞转移的Rag1-/-小鼠相比,用Eprs1+/-T细胞过继转移的Rag1-/-小鼠中TIN诱导的纤维化也减少。在临床试验中使用EPRS1靶向小分子抑制剂（bersiporocin）评估其对特发性肺纤维化的治疗潜力，减轻TIN中的免疫纤维化加重。在人肾组织和血液来源的T细胞中也观察到EPRS1表达，高表达与患者预后较差相关。因此，EPRS1可能成为毒素和药物诱导的TIN的治疗靶标，调节浸润T细胞的增殖和活性。
