Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, 25123 Brescia, Italy.
Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy.
Int J Mol Sci. 2022 Aug 21;23(16):9436. doi: 10.3390/ijms23169436.
Globoid cell leukodystrophy (GLD), or Krabbe disease, is a neurodegenerative sphingolipidosis caused by genetic deficiency of lysosomal (), characterized by neuroinflammation and demyelination of the central (CNS) and peripheral nervous system. The acute phase protein long pentraxin-3 (PTX3) is a soluble pattern recognition receptor and a regulator of innate immunity. Growing evidence points to the involvement of PTX3 in neurodegeneration. However, the expression and role of PTX3 in the neurodegenerative/neuroinflammatory processes that characterize GLD remain unexplored. Here, immunohistochemical analysis of brain samples from Krabbe patients showed that macrophages and globoid cells are intensely immunoreactive for PTX3. Accordingly, expression increases throughout the course of the disease in the cerebrum, cerebellum, and spinal cord of GALC-deficient () mice, an authentic animal model of GLD. This was paralleled by the upregulation of proinflammatory genes and M1-polarized macrophage/microglia markers and of the levels of PTX3 protein in CNS and plasma of animals. Crossing of mice with transgenic overexpressing animals ( mice) demonstrated that constitutive PTX3 overexpression reduced the severity of clinical signs and the upregulation of proinflammatory genes in the spinal cord of P35 / mice when compared to littermates, leading to a limited increase of their life span. However, this occurred in the absence of a significant impact on the histopathological findings and on the accumulation of the neurotoxic metabolite psychosine when evaluated at this late time point of the disease. In conclusion, our results provide the first evidence that PTX3 is produced in the CNS of GALC-deficient Krabbe patients and mice. PTX3 may exert a protective role by reducing the neuroinflammatory response that occurs in the spinal cord of GALC-deficient animals.
球样细胞脑白质营养不良（GLD），也称 Krabbe 病，是一种由溶酶体（）基因缺陷引起的神经退行性鞘脂贮积症，其特征为中枢神经系统（CNS）和周围神经系统的神经炎症和脱髓鞘。急性相蛋白长五聚蛋白 3（PTX3）是一种可溶性模式识别受体，也是先天免疫的调节剂。越来越多的证据表明 PTX3 参与了神经退行性变。然而，PTX3 在 GLD 特征性的神经退行性/神经炎症过程中的表达和作用仍未被探索。本研究通过对 Krabbe 病患者的脑组织样本进行免疫组织化学分析，发现巨噬细胞和球样细胞对 PTX3 呈强烈免疫反应。相应地，PTX3 在 GALC 缺陷型（）小鼠大脑、小脑和脊髓中的表达在疾病过程中不断增加，该小鼠是 GLD 的真实动物模型。这与 CNS 和血浆中 PTX3 蛋白水平以及促炎基因和 M1 极化的巨噬细胞/小胶质细胞标志物的上调相一致。将 小鼠与过表达 （）的转基因 （）小鼠杂交，结果显示与野生型同窝仔相比，PTX3 的组成型过表达降低了 P35 /小鼠的脊髓临床症状严重程度和促炎基因的上调，从而使其寿命略有延长。然而，在疾病的这个晚期时间点评估时，这种情况并未对组织病理学发现和神经毒性代谢产物半乳糖脑苷脂的积累产生显著影响。总之，本研究结果首次提供了证据，表明 PTX3 在 GALC 缺陷型 Krabbe 病患者和 小鼠的中枢神经系统中产生。PTX3 可能通过减轻 GALC 缺陷型动物脊髓中的神经炎症反应发挥保护作用。
