The neuronal ceroid lipofuscinoses (CLN diseases) are fatal lysosomal storage diseases causing neurodegeneration in the CNS. We have previously shown that neuroinflammation comprising innate and adaptive immune reactions drives axonal damage and neuron loss in the CNS of palmitoyl protein thioesterase 1-deficient (Ppt1−/−) mice, a model of the infantile form of the diseases (CLN1). Therefore, we here explore whether pharmacological targeting of innate immune cells modifies disease outcome in CLN1 mice. We applied treatment with PLX3397 (150 ppm in the chow), a potent inhibitor of the colony stimulating factor-1 receptor (CSF-1R) to target innate immune cells in CLN1 mice. Experimental long-term treatment was non-invasively monitored by longitudinal optical coherence tomography and rotarod analysis, as well as analysis of visual acuity, myoclonic jerks, and survival. Treatment effects regarding neuroinflammation, neural damage, and neurodegeneration were subsequently analyzed by histology and immunohistochemistry. We show that PLX3397 treatment attenuates neuroinflammation in CLN1 mice by depleting pro-inflammatory microglia/macrophages. This leads to a reduction of T lymphocyte recruitment, an amelioration of axon damage and neuron loss in the retinotectal system, as well as reduced thinning of the inner retina and total brain atrophy. Accordingly, long-term treatment with the inhibitor also ameliorates clinical outcomes in CLN1 mice, such as impaired motor coordination, visual acuity, and myoclonic jerks. However, we detected a sex- and region-biased efficacy of CSF-1R inhibition, with male microglia/macrophages showing higher responsiveness toward depletion, especially in the gray matter of the CNS. This results in a better treatment outcome in male Ppt1−/− mice regarding some histopathological and clinical readouts and reflects heterogeneity of innate immune reactions in the diseased CNS. Our results demonstrate a detrimental impact of innate immune reactions in the CNS of CLN1 mice. These findings provide insights into CLN pathogenesis and may guide in the design of immunomodulatory treatment strategies.

中文翻译：

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性别和区域偏向的小胶质细胞/巨噬细胞消耗可减轻小鼠 CLN1 疾病

神经元蜡样脂褐素沉积症（CLN 疾病）是致命的溶酶体贮积病，导致中枢神经系统神经变性。我们之前已经表明，包括先天性和适应性免疫反应的神经炎症会导致棕榈酰蛋白硫酯酶 1 缺陷（Ppt1−/−）小鼠（该疾病的婴儿模型（CLN1）的 CNS 中的轴突损伤和神经元损失）。因此，我们在此探讨先天免疫细胞的药理学靶向是否会改变 CLN1 小鼠的疾病结果。我们应用 PLX3397（饲料中 150 ppm）进行治疗，PLX3397 是一种集落刺激因子 1 受体 (CSF-1R) 的有效抑制剂，以靶向 CLN1 小鼠的先天免疫细胞。通过纵向光学相干断层扫描和旋转分析以及视力、肌阵挛性抽搐和生存率分析对实验性长期治疗进行非侵入性监测。随后通过组织学和免疫组织化学分析有关神经炎症、神经损伤和神经变性的治疗效果。我们发现 PLX3397 治疗可通过消耗促炎性小胶质细胞/巨噬细胞来减轻 CLN1 小鼠的神经炎症。这会导致 T 淋巴细胞募集减少，视网膜顶盖系统中轴突损伤和神经元损失得到改善，以及视网膜内层变薄和全脑萎缩的减少。因此，长期使用该抑制剂治疗还可以改善 CLN1 小鼠的临床结果，例如运动协调性、视力和肌阵挛性抽搐受损。然而，我们检测到 CSF-1R 抑制作用存在性别和区域偏向性，男性小胶质细胞/巨噬细胞对消耗表现出更高的反应性，尤其是在中枢神经系统灰质中。这导致雄性 Ppt1−/− 小鼠在一些组织病理学和临床读数方面获得更好的治疗结果，并反映了患病中枢神经系统中先天免疫反应的异质性。我们的结果证明先天免疫反应对 CLN1 小鼠的中枢神经系统产生有害影响。这些发现提供了对 CLN 发病机制的见解，并可能指导免疫调节治疗策略的设计。