Aryl hydrocarbon receptor dependent anti-inflammation and neuroprotective effects of tryptophan metabolites on retinal ischemia/reperfusion injury.
Aryl hydrocarbon receptor dependent anti-inflammation and neuroprotective effects of tryptophan metabolites on retinal ischemia/reperfusion injury.
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DOI：
10.1038/s41419-023-05616-3
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发表时间：
2023-02-08
影响因子：
9
通讯作者：
Sun, Hao
中科院分区：
文献类型：
--
作者：
Yang, Yijie;Wang, Ning;Xu, Li;Liu, Yixin;Huang, Lulu;Gu, Mengyang;Wu, Yue;Guo, Wenyi;Sun, Hao
青光眼是世界上以进行性视网膜神经变性为特征的不可逆性失明的主要原因，视网膜局部炎症与视网膜神经节细胞(RGC)的持续性丢失有关。为了探讨芳香烃受体(AhR)及其激动剂色氨酸代谢产物是否参与青光眼的发生发展，我们采集了非青光眼对照组和青光眼患者的血清和视网膜。结果显示，青光眼患者血清色氨酸代谢发生改变，视网膜AhR表达减少。我们还发现，腹腔注射色氨酸代谢产物2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic酸甲酯可下调视网膜局部炎症反应，并通过激活AhR来保护视网膜缺血再灌注(IR)损伤中的视网膜节细胞凋亡。我们进一步揭示ITE可以抑制BV2小胶质细胞的炎症反应，并减轻小胶质细胞条件培养液对RGCs的神经毒性。最后，我们阐明了ITE抑制ERK和NFκB依赖的小胶质细胞炎症的可能机制。综上所述，这些发现提示色氨酸代谢和视网膜AhR信号在调节小胶质细胞介导的青光眼局部炎症中起着关键作用，并为青光眼的治疗提供了一条针对因色氨酸代谢紊乱而导致的固有改变的AhR信号的新途径。
Glaucoma is the major cause of irreversible blindness in the world characterized by progressive retinal neurodegeneration, in which local inflammation in retina is involved in persistent loss of retinal ganglion cells (RGCs). In order to explore whether aryl hydrocarbon receptor (AhR) and its agonists tryptophan metabolites are involved in the development of glaucoma, we collected serum and retinas from non-glaucoma controls and patients with glaucoma. Results showed altered serum tryptophan metabolism and reduced retinal AhR expression in glaucoma patients. We also showed intraperitoneally injection of tryptophan metabolite 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) down-regulated retinal local inflammation and protected RGC apoptosis from retinal ischemia/reperfusion (IR) injury via AhR activation. We further revealed that ITE could inhibit inflammation in BV2 microglia and alleviate the neurotoxicity of microglial conditioned medium to RGCs under IR. Finally, we illustrated the possible mechanism that ITE limited ERK and NFκB dependent microglial inflammation. In summary, these findings suggest the critical role of tryptophan metabolism and retinal AhR signaling in modulating local inflammation mediated by microglia in glaucoma, and provide a novel avenue to targeting the intrinsically altered AhR signaling resulted from disturbed tryptophan metabolism for glaucoma treatment.
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影响因子：
9.3
作者：
Harder JM;Williams PA;Braine CE;Yang HS;Thomas JM;Foxworth NE;John SWM;Howell GR
通讯作者：
Howell GR
影响因子：
5.3
作者：
Nourbakhsh B;Bhargava P;Tremlett H;Hart J;Graves J;Waubant E
通讯作者：
Waubant E
DOI：
10.1007/s13167-021-00260-3
发表时间：
2021-12
期刊：
The EPMA journal
影响因子：
--
作者：
Li S;Qiu Y;Yu J;Shao M;Li Y;Cao W;Sun X
通讯作者：
Sun X
影响因子：
9.3
作者：
Grotegut P;Perumal N;Kuehn S;Smit A;Dick HB;Grus FH;Joachim SC
通讯作者：
Joachim SC
影响因子：
5.2
作者：
Harari OA;Liao JK
通讯作者：
Liao JK