Exploring the Role of Kynurenine 3-Monooxygenase (Kmo) in Microglial Physiology

As first line of defence, microglia play a critical role in maintaining the central nervous system (CNS) homeostasis. However, constantly activated cells can generate a continuous inflammation that results in neuronal dysfunction and cellular death. Furthermore, microglia express specific enzymes of the kynurenine pathway (KP) which have a strong influence on the pathological dynamics of the CNS. In particular, the activity of kynurenine-3-monooxygenase (KMO) during the immune response causes the production of neurotoxic metabolites. Giving that KMO is predominantly expressed in microglia and that alteration of the immune response in these cells have been established to be partially responsible in the pathology of several neurological diseases, the aim of this study was to better understand microglia physiology by employing pro-and anti-inflammatory molecules and assess possible downstream effects, together with a focus on KP manipulation through KMO in order to investigate whether the inhibition of the enzymatic activity affects microglia immune response and gain insights into the contribution of these players during health and pathological scenarios. 

In this project it was showed that immune stimulation has a significant impact on the up-regulation of KMO expression as well as specific features of microglia activation, such as production of pro- and anti-inflammatory biomarkers and release of extracellular vesicles. Notably, all these effects were dampened by the addition of dexamethasone (DEXA), highlighting the use of glucocorticoids for diseases associated with neuroinflammation. KMO inhibition did not produce the same hypothesised results, however, a possible novel relationship with the circadian clock has emerged. Transcriptomic analysis supported and extended the data obtained by highlighting enriched pathways activated by tumor necrosis factor (TNF)-α and those down-regulated in samples co-treated with DEXA. Finally, the findings described here accentuate the importance of species-specific mechanisms that become crucial when results obtained by experiments in animals are translated to human diseases.