Wu Jing-Yiing, Lee Guan-Lin, Chueh Yu-Fan, Kuo Cheng-Chin, Hsu Yu-Juei, Wu Kenneth K
Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.
Department of Bioscience Technology, Chung Yuan Christian University, Taoyuan, Taiwan.
J Innate Immun. 2025;17(1):78-94. doi: 10.1159/000543275. Epub 2025 Jan 7.
5-Methoxytryptophan (5-MTP) is a cellular metabolite with anti-inflammatory properties. Several recent reports indicate that 5-MTP protects against post-injury tissue fibrosis. It was unclear how 5-MTP controls tissue fibrosis. We postulated that 5-MTP attenuates renal interstitial fibrosis by blocking toll-like receptor 2 (TLR2) and transforming growth factor β (TGFβ) signaling pathways.
In vivo experiments were carried out in a well-established unilateral ureteral obstruction (UUO) model in wild-type (WT) and tlr2-/- mice. The effect of 5-MTP on renal fibrosis was evaluated by pretreatment of WT UUO mice with intraperitoneal administration of 5-MTP. To determine whether 5-MTP attenuates fibrosis by inhibiting TLR2 and TGFβ signaling pathways, we evaluated the effect of 5-MTP on TLR2-induced fibroblast phenotypic switch in NRK-49F fibroblasts and TLR2 and TGFβ signaling pathways in human proximal tubular epithelial cells (HPTECs) and RAW264.7 macrophages stimulated with Pam3CSK4 (Pam3) or TGFβ1.
UUO-induced renal fibrosis was abrogated in tlr2-/- mice consistent with a crucial role of TLR2 in UUO-induced renal fibrosis. UUO-induced macrophage infiltration and pro-fibrotic cytokine production in renal tissues were suppressed by tlr2 knockout. 5-MTP administration attenuated renal tissue fibrosis accompanied by reduction of macrophage infiltration and IL-6 and TGFβ levels. 5-MTP inhibits TLR2 upregulation and blocks TLR2-MyD88-TRAF6 signaling pathway in macrophages. Furthermore, 5-MTP blocked Pam3- and TGFβ1-induced phenotypic switch of NRK-49F to myofibroblasts and inhibited Pam3- and TGFβ1-induced signaling pathways in HPTECs and RAW264.7 cells.
5-MTP is effective in protecting against UUO-induced renal interstitial fibrosis by blocking TLR2 and TGFβ signaling pathways.
5-Methoxytryptophan (5-MTP) is a cellular metabolite with anti-inflammatory properties. Several recent reports indicate that 5-MTP protects against post-injury tissue fibrosis. It was unclear how 5-MTP controls tissue fibrosis. We postulated that 5-MTP attenuates renal interstitial fibrosis by blocking toll-like receptor 2 (TLR2) and transforming growth factor β (TGFβ) signaling pathways.
In vivo experiments were carried out in a well-established unilateral ureteral obstruction (UUO) model in wild-type (WT) and tlr2-/- mice. The effect of 5-MTP on renal fibrosis was evaluated by pretreatment of WT UUO mice with intraperitoneal administration of 5-MTP. To determine whether 5-MTP attenuates fibrosis by inhibiting TLR2 and TGFβ signaling pathways, we evaluated the effect of 5-MTP on TLR2-induced fibroblast phenotypic switch in NRK-49F fibroblasts and TLR2 and TGFβ signaling pathways in human proximal tubular epithelial cells (HPTECs) and RAW264.7 macrophages stimulated with Pam3CSK4 (Pam3) or TGFβ1.
UUO-induced renal fibrosis was abrogated in tlr2-/- mice consistent with a crucial role of TLR2 in UUO-induced renal fibrosis. UUO-induced macrophage infiltration and pro-fibrotic cytokine production in renal tissues were suppressed by tlr2 knockout. 5-MTP administration attenuated renal tissue fibrosis accompanied by reduction of macrophage infiltration and IL-6 and TGFβ levels. 5-MTP inhibits TLR2 upregulation and blocks TLR2-MyD88-TRAF6 signaling pathway in macrophages. Furthermore, 5-MTP blocked Pam3- and TGFβ1-induced phenotypic switch of NRK-49F to myofibroblasts and inhibited Pam3- and TGFβ1-induced signaling pathways in HPTECs and RAW264.7 cells.
5-MTP is effective in protecting against UUO-induced renal interstitial fibrosis by blocking TLR2 and TGFβ signaling pathways.
5-甲氧基色氨酸（5-MTP）是一种具有抗炎特性的细胞代谢产物。最近的几份报告表明，5-MTP可预防损伤后组织纤维化。目前尚不清楚5-MTP如何控制组织纤维化。我们推测5-MTP通过阻断Toll样受体2（TLR2）和转化生长因子β（TGFβ）信号通路来减轻肾间质纤维化。
在野生型（WT）和tlr2基因敲除小鼠中建立的单侧输尿管梗阻（UUO）模型上进行体内实验。通过对野生型UUO小鼠腹腔注射5-MTP进行预处理，评估5-MTP对肾纤维化的影响。为了确定5-MTP是否通过抑制TLR2和TGFβ信号通路减轻纤维化，我们评估了5-MTP对用Pam3CSK4（Pam3）或TGFβ1刺激的NRK-49F成纤维细胞中TLR2诱导的成纤维细胞表型转换以及人近端肾小管上皮细胞（HPTECs）和RAW264.7巨噬细胞中TLR2和TGFβ信号通路的影响。
在tlr2基因敲除小鼠中，UUO诱导的肾纤维化被消除，这与TLR2在UUO诱导的肾纤维化中的关键作用一致。tlr2基因敲除抑制了UUO诱导的肾组织巨噬细胞浸润和促纤维化细胞因子的产生。给予5-MTP可减轻肾组织纤维化，同时减少巨噬细胞浸润以及IL-6和TGFβ水平。5-MTP抑制巨噬细胞中TLR2的上调并阻断TLR2-MyD88-TRAF6信号通路。此外，5-MTP阻断了Pam3和TGFβ1诱导的NRK-49F向肌成纤维细胞的表型转换，并抑制了Pam3和TGFβ1诱导的HPTECs和RAW264.7细胞中的信号通路。
5-MTP通过阻断TLR2和TGFβ信号通路，有效预防UUO诱导的肾间质纤维化。
5-甲氧基色氨酸（5-MTP）是一种具有抗炎特性的细胞代谢产物。最近的几份报告表明，5-MTP可预防损伤后组织纤维化。目前尚不清楚5-MTP如何控制组织纤维化。我们推测5-MTP通过阻断Toll样受体2（TLR2）和转化生长因子β（TGFβ）信号通路来减轻肾间质纤维化。
在野生型（WT）和tlr2基因敲除小鼠中建立的单侧输尿管梗阻（UUO）模型上进行体内实验。通过对野生型UUO小鼠腹腔注射5-MTP进行预处理，评估5-MTP对肾纤维化的影响。为了确定5-MTP是否通过抑制TLR2和TGFβ信号通路减轻纤维化，我们评估了5-MTP对用Pam3CSK4（Pam3）或TGFβ1刺激的NRK-49F成纤维细胞中TLR2诱导的成纤维细胞表型转换以及人近端肾小管上皮细胞（HPTECs）和RAW264.7巨噬细胞中TLR2和TGFβ信号通路的影响。
在tlr2基因敲除小鼠中，UUO诱导的肾纤维化被消除，这与TLR2在UUO诱导的肾纤维化中的关键作用一致。tlr2基因敲除抑制了UUO诱导的肾组织巨噬细胞浸润和促纤维化细胞因子的产生。给予5-MTP可减轻肾组织纤维化，同时减少巨噬细胞浸润以及IL-6和TGFβ水平。5-MTP抑制巨噬细胞中TLR2的上调并阻断TLR2-MyD88-TRAF6信号通路。此外，5-MTP阻断了Pam3和TGFβ1诱导的NRK-49F向肌成纤维细胞的表型转换，并抑制了Pam3和TGFβ1诱导的HPTECs和RAW264.7细胞中的信号通路。
5-MTP通过阻断TLR2和TGFβ信号通路，有效预防UUO诱导的肾间质纤维化。
