多发性硬化症患者小胶质细胞激活与血清犬尿氨酸通路代谢物的关系。

Association between microglial activation and serum kynurenine pathway metabolites in multiple sclerosis patients.

机构信息

Turku PET Centre, Turku University Hospital and University of Turku, Kiinanmyllynkatu 4-8, 20521 Turku, Finland; Neurocenter, Turku University Hospital, Turku, Finland; Clinical Neurosciences, University of Turku, Turku, Finland.

Turku PET Centre, Turku University Hospital and University of Turku, Kiinanmyllynkatu 4-8, 20521 Turku, Finland; Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland.

出版信息

Mult Scler Relat Disord. 2022 Mar;59:103667. doi: 10.1016/j.msard.2022.103667. Epub 2022 Feb 4.

DOI:10.1016/j.msard.2022.103667

PMID:35151985

Abstract

BACKGROUND

Microglial 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.

OBJECTIVE

To investigate whether tryptophan metabolites in blood associate with TSPO-PET measurable microglial activation in MS brain.

METHODS

Microglial activation was detected using PET imaging and the TSPO-binding radioligand [C]PK11195. Distribution volume ratios (DVR) for specific [C]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.

RESULTS

The 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).

CONCLUSIONS

This 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.

摘要

背景

小胶质细胞的激活与多发性硬化症（MS）的进展有关，但尚不清楚是什么导致了它们持续的促炎状态。色氨酸的犬尿氨酸途径（KP）代谢产物可以影响大脑固有免疫细胞的功能。

目的

研究血液中的色氨酸代谢产物是否与 MS 大脑中的 TSPO-PET 可测量的小胶质细胞激活有关。

方法

使用 PET 成像和 TSPO 结合放射性配体 [C]PK11195 检测小胶质细胞的激活。计算正常表现白质（NAWM）、病变和丘脑的特异性 [C]PK11195 结合的分布容积比（DVR）。使用超高效液相色谱-串联质谱法测量血清色氨酸和犬尿氨酸途径代谢产物的水平。

结果

研究队列包括 48 名 MS 患者。NAWM 和丘脑的 DVR 增加与血清 3-羟基犬尿氨酸水平降低相关（R = -0.31，p = 0.031 和 R = -0.32，p = 0.028）。EDSS 增加与 3-羟基犬尿氨酸和黄尿酸降低相关（R = -0.36，p = 0.012 和 R = -0.31，p = 0.034），与 NAWM 和丘脑的 DVR 增加相关（R = 0.33，p = 0.023 和 R = 0.34，p = 0.020）。