Spaas Jan, Van der Stede Thibaux, de Jager Sarah, van de Waterweg Berends Annet, Tiane Assia, Baelde Hans, Baba Shahid P, Eckhardt Matthias, Wolfs Esther, Vanmierlo Tim, Hellings Niels, Eijnde Bert O, Derave Wim
University MS Center (UMSC), Hasselt - Pelt, Belgium; BIOMED Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; Department of Movement and Sports Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Department of Movement and Sports Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Nutrition, Exercise and Sports, Copenhagen University, Copenhagen, Denmark.
Prog Neurobiol. 2023 Dec;231:102532. doi: 10.1016/j.pneurobio.2023.102532. Epub 2023 Sep 27.
Multiple sclerosis (MS) pathology features autoimmune-driven neuroinflammation, demyelination, and failed remyelination. Carnosine is a histidine-containing dipeptide (HCD) with pluripotent homeostatic properties that is able to improve outcomes in an animal MS model (EAE) when supplied exogenously. To uncover if endogenous carnosine is involved in, and protects against, MS-related neuroinflammation, demyelination or remyelination failure, we here studied the HCD-synthesizing enzyme carnosine synthase (CARNS1) in human MS lesions and two preclinical mouse MS models (EAE, cuprizone). We demonstrate that due to its presence in oligodendrocytes, CARNS1 expression is diminished in demyelinated MS lesions and mouse models mimicking demyelination/inflammation, but returns upon remyelination. Carns1-KO mice that are devoid of endogenous HCDs display exaggerated neuroinflammation and clinical symptoms during EAE, which could be partially rescued by exogenous carnosine treatment. Worsening of the disease appears to be driven by a central, not peripheral immune-modulatory, mechanism possibly linked to impaired clearance of the reactive carbonyl acrolein in Carns1-KO mice. In contrast, CARNS1 is not required for normal oligodendrocyte precursor cell differentiation and (re)myelin to occur, and neither endogenous nor exogenous HCDs protect against cuprizone-induced demyelination. In conclusion, the loss of CARNS1 from demyelinated MS lesions can aggravate disease progression through weakening the endogenous protection against neuroinflammation.
多发性硬化症（MS）的病理学特征包括自身免疫驱动的神经炎症、脱髓鞘和髓鞘再生失败。肌肽是一种含组氨酸的二肽（HCD），具有多能稳态特性，在外源性提供时能够改善动物MS模型（实验性自身免疫性脑脊髓炎，EAE）的结果。为了探究内源性肌肽是否参与并预防与MS相关的神经炎症、脱髓鞘或髓鞘再生失败，我们在此研究了人类MS病变以及两种临床前小鼠MS模型（EAE、铜离子螯合剂）中的HCD合成酶肌肽合成酶（CARNS1）。我们证明，由于其在少突胶质细胞中的存在，CARNS1在脱髓鞘的MS病变和模拟脱髓鞘/炎症的小鼠模型中表达减少，但在髓鞘再生时恢复。缺乏内源性HCD的Carns1基因敲除小鼠在EAE期间表现出过度的神经炎症和临床症状，外源性肌肽治疗可部分缓解这些症状。疾病的恶化似乎是由一种中枢而非外周免疫调节机制驱动的，这可能与Carns1基因敲除小鼠中活性羰基丙烯醛清除受损有关。相比之下，正常少突胶质前体细胞分化和（再）髓鞘形成并不需要CARNS1，内源性和外源性HCD均不能预防铜离子螯合剂诱导的脱髓鞘。总之，脱髓鞘MS病变中CARNS1的缺失可通过削弱内源性神经炎症保护作用而加重疾病进展。
