Abstract
BackgroundMicroglial activation associates with MS progression but it is unclear what drives their persistent pro-inflammatory state. Metabolites of the kynurenine pathway (KP), the main metabolism route of tryptophan, can influence the function of brain innate immune cells. ObjectiveTo investigate whether tryptophan metabolites in blood associate with TSPO-PET measurable microglial activation in MS brain. MethodsMicroglial activation was detected using PET imaging and the TSPO-binding radioligand [11C]PK11195. Distribution volume ratios (DVR) for specific [11C]PK11195-binding in the normal appearing white matter (NAWM), lesions, and thalamus were calculated. Ultrahigh performance liquid chromatography-tandem mass spectrometry was used to measure serum levels of tryptophan and kynurenine pathway metabolites. ResultsThe study cohort consisted of 48 MS patients. Increased DVR in the NAWM and thalamus correlated with decreased serum 3-hydroxykynurenine level (R = -0.31, p = 0.031 and R = -0.32, p = 0.028). Increased EDSS correlated with decreased 3-hydroxykynurenine and xanthurenic acid (R = -0.36, p = 0.012 and R = -0.31, p = 0.034) and increased DVR in the NAWM and thalamus (R = 0.33, p = 0.023 and R = 0.34, p = 0.020, respectively). ConclusionsThis clinical study demonstrates an association between low serum 3-hydroxykynurenine and high microglial activation in MS. Further investigations are warranted for elucidation of the biological mechanisms behind this association.
Highlights
Relapsing remitting multiple sclerosis (RRMS) is characterized by blood-brain barrier (BBB) breakdown and emergence of focal inflam matory lesions in the central nervous system (CNS), where organspecific autoreactive T lymphocytes are driving the process with involvement of a network of other cell types, e.g. B lymphocytes and the innate immune system players macrophages and microglia (Dobson and Giovannoni, 2019)
The results from the present study demonstrate that in MS patients low serum levels of the kynurenine pathway product 3HK associate with enhanced microglial activation both in the normal appearing white matter (NAWM) and in thalamus
MS patients display increased translocator protein (TSPO)-PETmeasurable microglial activation in the NAWM and in thalamus (Ris sanen et al, 2018). This phenomenon is more pronounced in advanced MS, and as increased TSPO-binding predicts later MS progression (Sucksdorff et al, 2020), the TSPO-positron emission tomography (PET) measurable activated microglial phenotype is considered detrimental in MS pathogenesis
Summary
Relapsing remitting multiple sclerosis (RRMS) is characterized by blood-brain barrier (BBB) breakdown and emergence of focal inflam matory lesions in the central nervous system (CNS), where organspecific autoreactive T lymphocytes are driving the process with involvement of a network of other cell types, e.g. B lymphocytes and the innate immune system players macrophages and microglia (Dobson and Giovannoni, 2019). Areas of the brain (Bodini et al, 2021), and numerous PET studies have confirmed that the CNS innate immune cell activation is a phenomenon associated with multiple sclerosis (MS) disease progression (Sucksdorff et al, 2020; Giannetti et al, 2015; Politis et al, 2012; Ris sanen et al, 2018; Singhal et al, 2019). Metabolites of the kynurenine pathway (KP), the main metabolism route of tryptophan, can influence the function of brain innate immune cells. Objective: To investigate whether tryptophan metabolites in blood associate with TSPO-PET measurable micro glial activation in MS brain. Increased DVR in the NAWM and thalamus correlated with decreased serum 3-hydroxykynurenine level (R = -0.31, p = 0.031 and R = -0.32, p = 0.028). Further investigations are warranted for elucidation of the biological mechanisms behind this association
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