The involvement of the kynurenine pathway in the pathogenesis of multiple sclerosis
Multiple sclerosis (MS) is a complex neurological disease that has been viewed as both a neuroinflammatory and a neurodegenerative disease. Peculiarly, early stages of MS exhibit very different clinical manifestations compared to late stages of MS (i.e. progressive MS). It was hypothesized that the early onset of MS is driven by neuroinflammation whereas the progressive MS is driven by neurodegeneration. However, the precise mechanisms involved remain unclear since there is lack of a common protagonist that co-exists between the two distinct stages of MS. Over the past decade, involvement of kynurenine pathway (KP) has been implicated in many neurological diseases such as Alzheimer’s disease, Huntington diseases and amyotrophic lateral sclerosis. Increasing evidences indicate that the KP is also involved in MS. The aim of this thesis is to characterize the involvement of the KP in the neuropathogenesis and the progression of MS. Using serum and cerebrospinal fluid (CSF) samples from MS patients, EAE mice, the most common animal model for MS and primary culture of human oligodendrocytes, we have studied the involvement of the KP in neuroinflammation [Indoleamine 2,3-dioxygenase (IDO-1) expression and its immune regulatory role] and neurodegeneration (balance between neuroprotective and neurotoxic KP metabolites). The main findings of this project are: (1) the KP metabolism is altered in MS patients. There is a dysregulation of the balance between the production of neuroprotective and neurotoxic KP metabolites in MS patients’ serum and CSF; (2) The KP metabolic profile is unique at different stages of MS; (3) Abnormal alteration of KP metabolism in MS can be corrected using KP modulators showing alleviation of disease progression in EAE mice; (4) Oligodendrocytes, the main cell type lost in MS do not express IDO, that could possibly leads to the cell susceptibility towards T-cell cytotoxicity. In conclusion, this study provides strong evidences that the KP is involved in the progression of MS. The above data well indicate that the KP is a common protagonist contributing to both neuroinflammatory and neurodegenerative phenomena in MS.
Neuroinflammation, Kynurenine pathway, Multiple sclerosis, Neurodegeneration
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