The Absence of Indoleamine 2,3-Dioxygenase Inhibits Retinal Capillary Degeneration in Diabetic Mice

Nahomi, Rooban B.; Sampathkumar, Sruthi; Myers, Angela M; Elghazi, Lynda; Smith, Duane H.; Tang, Jie; Lee, C. Allen; Kern, Timothy S.; Nagaraj, Ram H.; Fort, Patrice E.

doi:10.1167/iovs.17-22702

Cited by 14 publications

(9 citation statements)

References 54 publications

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“…Nahomi et al 54 reported that IDO1 played an important role in retinal endothelial apoptosis and capillary degeneration in the diabetic retina. They summarized four molecular mechanisms of IDO1 in endothelial cell apoptosis: (1) hyperglycemia enhanced IFN-c-mediated IDO1 expression; (2) increased IFN-c induced IDO1 in the retinal capillary endothelium; (3) oxidative stress regulated IDO1-mediated endothelial cell apoptosis; and (4) IDO1 deficiency in diabetic reduced the formation of acellular capillary.…”

Section: Function Of Ido or Tdo In Different Diseasesmentioning

confidence: 99%

Role of IDO and TDO in Cancers and Related Diseases and the Therapeutic Implications

Ye¹,

Yue²,

Shi³

et al. 2019

J. Cancer

143

111

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Kynurenine (Kyn) pathway is a significant metabolic pathway of tryptophan (Trp). The metabolites of the Kyn pathway are closely correlated with numerous diseases. Two main enzymes, indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO or TDO2), regulate the first and rate-limiting step of the Kyn pathway. These enzymes are directly or indirectly involved in various diseases, including inflammatory diseases, cancer, diabetes, and mental disorders. Presently, an increasing number of potential mechanisms have been revealed. In the present review, we depict the structure of IDO and TDO and explicate their functions in various diseases to facilitate a better understanding of them and to indicate new therapeutic plans to target them. Moreover, we summarize the inhibitors of IDO/TDO that are currently under development and their efficacy in the treatment of cancer and other diseases.

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Section: Function Of Ido or Tdo In Different Diseasesmentioning

confidence: 99%

Role of IDO and TDO in Cancers and Related Diseases and the Therapeutic Implications

Ye¹,

Yue²,

Shi³

et al. 2019

J. Cancer

143

111

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“…Several studies, on the other hand, were performed by modifying KP enzyme expression in animal or human cells in tissue culture. Inhibition of the enzyme at a genetic level was found to be beneficial in animal models of bacterial (2) and viral (3, 4) infections, immune modulation following organ transplant (19, 20) and diseases in which chronic inflammation plays a crucial role, such as DR (27), atherosclerosis (28), AAA (29, 30) and metabolic changes linked to obesity (31). Inhibition of the enzyme is also a promising way of interfering in tumor mediated immunological changes, thus restoring anti-tumor immunity (33, 34, 36, 45, 46).…”

Section: Discussionmentioning

confidence: 99%

“…Hyperglycaemia induced chronic retinal inflammation has a pivotal role in the development of diabetic retinopathy (DR), one of the major causes of visual impairment worldwide (120). In a recent study, Nahomi et al reported a 50 percent increase of the level of IFNγ in human diabetic retinas accompanied with elevated IDO expression (27). Genetic inhibition of IDO function in diabetic IDO −/− mice was found to reduce retinal capillary degeneration, as acellular capillary formation in knockout mice was alleviated as compared to their WT counterparts (27).…”

Section: Immunomodulation Via Altering the Expression Of Genes That Cmentioning

confidence: 99%

Immunomodulatory Effects of Genetic Alterations Affecting the Kynurenine Pathway

Boros

Vécsei

2019

Front. Immunol.

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Several enzymes and metabolites of the kynurenine pathway (KP) have immunomodulatory effects. Modulation of the activities and levels of these molecules might be of particular importance under disease conditions when the amelioration of overreacting immune responses is desired. Results obtained by the use of animal and tissue culture models indicate that by eliminating or decreasing activities of key enzymes of the KP, a beneficial shift in disease outcome can be attained. This review summarizes experimental data of models in which IDO, TDO, or KMO activity modulation was achieved by interventions affecting enzyme production at a genomic level. Elimination of IDO activity was found to improve the outcome of sepsis, certain viral infections, chronic inflammation linked to diabetes, obesity, aorta aneurysm formation, and in anti-tumoral processes. Similarly, lack of TDO activity was advantageous in the case of anti-tumoral immunity, while KMO inhibition was found to be beneficial against microorganisms and in the combat against tumors, as well. On the other hand, the complex interplay among KP metabolites and immune function in some cases requires an increase in a particular enzyme activity for the desired immune response modulation, as was shown by the exacerbation of liver fibrosis due to the elimination of IDO activity and the detrimental effects of TDO inhibition in a mouse model of autoimmune gastritis. The relevance of these studies concerning possible human applications are discussed and highlighted. Finally, a brief overview is presented on naturally occurring genetic variants affecting immune functions via modulation of KP enzyme activity.

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“…Capillary bed preparation of WT and KMO KO retinas and quantification of capillary degeneration were performed as previously described [63,64].…”

Section: Assessment Of Capillary Degeneration In the Retinamentioning

confidence: 99%

“…Male C57BL/6J mice at 3-months of age were made diabetic by i.p. administration of streptozotocin (STZ, MP Biomedicals, Solon, OH, USA), as previously described [64]. Diabetes was confirmed by the elevated fasting blood glucose after 1 week of STZ injection.…”

Section: Induction Of Diabetes In Micementioning

confidence: 99%

Kynurenic Acid Protects Against Ischemia/Reperfusion-Induced Retinal Ganglion Cell Death in Mice

Nahomi

Nam

Rankenberg

et al. 2020

IJMS

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Background: Glaucoma is an optic neuropathy and involves the progressive degeneration of retinal ganglion cells (RGCs), which leads to blindness in patients. We investigated the role of the neuroprotective kynurenic acid (KYNA) in RGC death against retinal ischemia/reperfusion (I/R) injury. Methods: We injected KYNA intravenously or intravitreally to mice. We generated a knockout mouse strain of kynurenine 3-monooxygenase (KMO), an enzyme in the kynurenine pathway that produces neurotoxic 3-hydroxykynurenine. To test the effect of mild hyperglycemia on RGC protection, we used streptozotocin (STZ) induced diabetic mice. Retinal I/R injury was induced by increasing intraocular pressure for 60 min followed by reperfusion and RGC numbers were counted in the retinal flat mounts. Results: Intravenous or intravitreal administration of KYNA protected RGCs against I/R injury. The I/R injury caused a greater loss of RGCs in wild type than in KMO knockout mice. KMO knockout mice had mildly higher levels of fasting blood glucose than wild type mice. Diabetic mice showed significantly lower loss of RGCs when compared with non-diabetic mice subjected to I/R injury. Conclusion: Together, our study suggests that the absence of KMO protects RGCs against I/R injury, through mechanisms that likely involve higher levels of KYNA and glucose.

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The Absence of Indoleamine 2,3-Dioxygenase Inhibits Retinal Capillary Degeneration in Diabetic Mice

Cited by 14 publications

References 54 publications

Role of IDO and TDO in Cancers and Related Diseases and the Therapeutic Implications

Role of IDO and TDO in Cancers and Related Diseases and the Therapeutic Implications

Immunomodulatory Effects of Genetic Alterations Affecting the Kynurenine Pathway

Kynurenic Acid Protects Against Ischemia/Reperfusion-Induced Retinal Ganglion Cell Death in Mice

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