Ablation of kynurenine 3-monooxygenase rescues plasma inflammatory cytokine levels in the R6/2 mouse model of Huntington\u2019s disease

Marie Katrin Bondulich,Yilan Fan,Flaviano Giorgini,Yeojin Song,Gillian P Bates

doi:10.1038/s41598-021-84858-7

Abstract

Kynurenine 3-monooxygenase (KMO) regulates the levels of neuroactive metabolites in the kynurenine pathway (KP), dysregulation of which is associated with Huntington’s disease (HD) pathogenesis. KMO inhibition leads to increased levels of neuroprotective relative to neurotoxic metabolites, and has been found to ameliorate disease-relevant phenotypes in several HD models. Here, we crossed KMO knockout mice to R6/2 HD mice to examine the effect of KMO depletion in the brain and periphery. KP genes were dysregulated in peripheral tissues from R6/2 mice and KMO ablation normalised levels of a subset of these. KP metabolites were also assessed, and KMO depletion led to increased levels of neuroprotective kynurenic acid in brain and periphery, and dramatically reduced neurotoxic 3-hydroxykunurenine levels in striatum and cortex. Notably, the increased levels of pro-inflammatory cytokines TNFa, IL1β, IL4 and IL6 found in R6/2 plasma were normalised upon KMO deletion. Despite these improvements in KP dysregulation and peripheral inflammation, KMO ablation had no effect upon several behavioural phenotypes. Therefore, although genetic inhibition of KMO in R6/2 mice modulates several metabolic and inflammatory parameters, these do not translate to improvements in primary disease indicators—observations which will likely be relevant for other interventions targeted at peripheral inflammation in HD.

Highlights

Huntington’s disease (HD) is a devastating inherited neurodegenerative disease that is characterised by progressive clinical features including motor dysfunction, cognitive decline and psychiatric disturbances[1]
While the kynurenine pathway (KP) enzymes were expressed at levels too low for detection in the cortex and striatum of all animals tested (Supplementary Table S1 online), robust expression was found for all the pathway enzymes in liver (Supplementary Table S2 online)
The level of RNA extracted from peritoneal macrophages was very low, making it difficult to detect the expression of all KP enzymes (Supplementary Table S4 online)

Summary

Introduction

Huntington’s disease (HD) is a devastating inherited neurodegenerative disease that is characterised by progressive clinical features including motor dysfunction, cognitive decline and psychiatric disturbances[1]. Transcript levels for Tdo[2], Kynu, Kmo, Haao and Qprt were all reduced in R6/2 compared to WT littermates at 12 weeks of age. Transcript levels for Kynu, Kmo and Haao were elevated and Qprt was reduced in R6/2 compared to WT littermates at 12 weeks of age. Transcript levels for Kynu, Kmo and Haao were all elevated in R6/2 compared to WT littermates at 12 weeks of age. Relatively little is known about the interaction between KMO and the innate immune system in vivo, emerging data indicates that macrophage/cytokine influx can cause significant changes to the levels and ratios of KP metabolites in the CNS, and that enzymes within the KMO branch of KP may be induced by proinflammatory stimuli[18]. In the neuroprotective KP branch, Aadat expression is either unaffected or decreased by proinflammatory stimuli, depending on the model used and the subtypes of Aadat studied[18]

Objectives

Methods

Results

Conclusion