Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital Research Institute, Harvard Medical School, 185 Cambridge St., Boston, MA 02114, USA.
Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory, Georgia Institute of Technology, 315 Ferst Dr., Atlanta, GA 30332, USA.
Cells. 2022 Feb 4;11(3):546. doi: 10.3390/cells11030546.
Mucolipidosis IV (MLIV) is an autosomal recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by a loss of function of the lysosomal channel transient receptor potential mucolipin-1 and is associated with an early pro-inflammatory brain phenotype, including increased cytokine expression. The goal of the current study was to determine whether blood cytokines are linked to motor dysfunction in patients with MLIV and reflect brain inflammatory changes observed in an MLIV mouse model.
To determine the relationship between blood cytokines and motor function, we collected plasma from MLIV patients and parental controls concomitantly with assessment of motor function using the Brief Assessment of Motor Function and Modified Ashworth scales. We then compared these profiles with cytokine profiles in brain and plasma samples collected from the mouse model of MLIV.
We found that MLIV patients had prominently increased cytokine levels compared to familial controls and identified profiles of cytokines correlated with motor dysfunction, including IFN-γ, IFN-α2, and IP-10. We found that IP-10 was a key differentiating factor separating MLIV cases from controls based on data from human plasma, mouse plasma, and mouse brain.
Our data indicate that MLIV is characterized by increased blood cytokines, which are strongly related to underlying neurological and functional deficits in MLIV patients. Moreover, our data identify the interferon pro-inflammatory axis in both human and mouse signatures, suggesting that interferon signaling is an important aspect of MLIV pathology.
黏脂贮积症 IV 型（MLIV）是一种常染色体隐性遗传儿科疾病，可导致运动和认知功能障碍以及视力丧失。它是由溶酶体通道瞬时受体电位黏脂素-1 的功能丧失引起的，与早期的促炎脑表型有关，包括细胞因子表达增加。本研究的目的是确定 MLIV 患者的血液细胞因子是否与运动功能障碍有关，并反映在 MLIV 小鼠模型中观察到的脑炎症变化。
为了确定血液细胞因子与运动功能之间的关系，我们在评估运动功能的同时从 MLIV 患者和父母对照者中收集血浆，使用简短评估运动功能和改良 Ashworth 量表。然后，我们将这些图谱与从 MLIV 小鼠模型中收集的大脑和血浆样本中的细胞因子图谱进行了比较。
我们发现，与家族对照者相比，MLIV 患者的细胞因子水平明显升高，并确定了与运动功能障碍相关的细胞因子图谱，包括 IFN-γ、IFN-α2 和 IP-10。我们发现，IP-10 是根据来自人类血浆、小鼠血浆和小鼠大脑的数据将 MLIV 病例与对照者区分开来的关键区分因素。
我们的数据表明，MLIV 的特征是血液细胞因子增加，这与 MLIV 患者的潜在神经和功能缺陷密切相关。此外，我们的数据在人类和小鼠特征中确定了干扰素促炎轴，表明干扰素信号是 MLIV 病理学的一个重要方面。
