Cellular Localization of Kynurenine 3-Monooxygenase in the Brain: Challenging the Dogma

Abstract

Kynurenine 3-monooxygenase (KMO), a key player in the kynurenine pathway (KP) of tryptophan degradation, regulates the synthesis of the neuroactive metabolites 3-hydroxykynurenine (3-HK) and kynurenic acid (KYNA). KMO activity has been implicated in several major brain diseases including Huntington’s disease (HD) and schizophrenia. In the brain, KMO is widely believed to be predominantly localized in microglial cells, but verification in vivo has not been provided so far. Here, we examined KP metabolism in the brain after depleting microglial cells pharmacologically with the colony stimulating factor 1 receptor inhibitor PLX5622. Young adult mice were fed PLX5622 for 21 days and were euthanized either on the next day or after receiving normal chow for an additional 21 days. Expression of microglial marker genes was dramatically reduced on day 22 but had fully recovered by day 43. In both groups, PLX5622 treatment failed to affect Kmo expression, KMO activity or tissue levels of 3-HK and KYNA in the brain. In a parallel experiment, PLX5622 treatment also did not reduce KMO activity, 3-HK and KYNA in the brain of R6/2 mice (a model of HD with activated microglia). Finally, using freshly isolated mouse cells ex vivo, we found KMO only in microglia and neurons but not in astrocytes. Taken together, these data unexpectedly revealed that neurons contain a large proportion of functional KMO in the adult mouse brain under both physiological and pathological conditions.

An integrated cytokine and kynurenine network as the basis of neuroimmune communication

“…Inflammatory activation of IDO in peripheral cells will increase plasma levels of kynurenine and 3HK which enter the CNS by diffusion and by the amino acid transporter LAT-1 (SLC7A5) ( Sinclair et al, 2018 ; Figure 4 ). Kynurenine is then metabolized to kynurenic acid (in astrocytes) and quinolinic acid (in microglia and neurons) ( Figure 1 ), ( Guillemin et al, 2001 ; Sathyasaikumar et al, 2022 ) which leave the CNS slowly via the acidic amino acid transporter, blocked by probenecid ( Figure 4 ). Stimulation of macrophages by IFN-γ therefore increases the synthesis and release of quinolinic acid ( Heyes et al, 1992a ; Chiarugi et al, 2000 ; Guillemin et al, 2005a ; O’Connor et al, 2009a , b ; Garrison et al, 2018 ) which tends to accumulate in the CNS.…”

Dynamic changes in metabolites of the kynurenine pathway in Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease: A systematic Review and meta-analysis

“…Of note, the production of KYNA occurs in astrocytes; however, 3-HK, QUIN, and AA are produced in microglia ( 11 ). Furthermore, a study conducted by Sathyasaikumar et al, found KMO only in microglia and neurons but not in astrocytes using isolated mouse cells ex vivo ( 12 ). Then, 3-HK and AA are degraded to 3-hydroxyanthranilic acid (3-HANA).…”

The role of the kynurenine pathway in cardiovascular disease

“…KMO, a mitochondrial enzyme belonging to the nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)-dependent flavin monooxygenase family, operates with the flavin adenin dinucleotide cofactor and holds a central position within the KP metabolism (32). KMO is primarily present in peripheral tissues, macrophages, and monocytes, while in the nervous system, it is mainly concentrated in microglial cells (33). KMO catalyzes the transformation of KYN into neurotoxic compounds, notably 3hydroxykynurenine and QA, known for their brain excitotoxicity (34).…”