Both IDO1 and TDO contribute to the malignancy of gliomas via the Kyn–AhR–AQP4 signaling pathway

Indoleamine 2,3-dioxygenase 1(IDO1),indoleamine 2,3-dioxygenase 2(IDO2),and tryptophan 2,3-dioxygenase(TDO)initiate the first step of the kynurenine pathway(KP),leading to the transformation of L-tryptophan(Trp)into L-kynurenine(Kyn)and other downstream metabolites.Kyn is known as an endogenous ligand of the aryl hydrocarbon receptor(AhR).Activation of AhR through TDO-derived Kyn is a novel mechanism to support tumor growth in gliomas.However,the role of IDO1 and IDO2 in this mechanism is still unknown.Herein,by using clinical samples,we found that the expression and activity of IDO1 and/or TDO(IDO1/TDO)rather than IDO2 were positively correlated with the pathologic grades of gliomas.The expression of IDO1/TDO rather than IDO2 was positively correlated with the Ki67 index and overall survival.The expression of IDO1/TDO was positively correlated with the expression of aquaporin 4(AQP4),implying the potential involvement of IDO1/TDO in glioma cell motility.Mechanistically,we found that IDO1/TDO accounted for the release of Kyn,which activated AhR to promote cell motility via the Kyn–AhR–AQP4 signaling pathway in U87MG glioma cells.RY103,an IDO1/TDO dual inhibitor,could block the IDO1/TDO–Kyn–AhR–AQP4 signaling pathway and exert anti-glioma effects in GL261 orthotopic glioma mice.Together,our results showed that the IDO1/TDO–Kyn–AhR–AQP4 signaling pathway is a new mechanism underlying the malignancy of gliomas,and suggest that both IDO1 and TDO might be valuable therapeutic targets for gliomas.

Correction:Both IDO1 and TDO contribute to the malignancy of gliomas via the Kyn-AhR-AQP4 signaling pathway

In the process of collating the raw data,the authors noticed the inadvertent mistakes in Fig.4h&6g that need to be corrected.The correct data are provided as follows.The key findings of the article are not affected by the corrections.We apologize for the inadvertent mistakes.The authors mistakenly placed the wrong representative image showing the invasion ability of U87MG cells in the IFN-γ+1-MT group.The correct version of Fig.4h is shown above.

Amyloidβneurotoxicity is IDO1–Kyn–AhR dependent and blocked by IDO1 inhibitor

Dear Editor,Alzheimer’s disease(AD),the most common neurodegenerative disorder and a leading cause of dementia is characterized by progressive memory deficits,cognitive impairment and personality changes.The accumulation of extracellular amyloid beta(Aβ)plaques consisted by Aβpeptide and intracellular neurofibrillary tangles(NFTs)composed by misfolded hyperphosphorylated tau are main pathological hallmarks of AD,which ultimately lead to the dysfunction and loss of synapses and the eventual death of neuron.Neuroinflammation plays a causal role in AD pathogenesis.While the mechanism underlying neuroinflammationinduced AD pathology has not been fully elucidated,increasing evidence proposed that the kynurenine pathway(KP),a major route for L-tryptophan(L-Trp)catabolism,plays an important role.