Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA, USA.
Shriners Hospitals for Children, Northern California, Sacramento, CA, USA.
J Neuroinflammation. 2024 Apr 20;21(1):103. doi: 10.1186/s12974-024-03063-1.
Colony stimulating factor 1 receptor (CSF1R) signaling is crucial for the maintenance and function of various myeloid subsets. CSF1R antagonism was previously shown to mitigate clinical severity in experimental autoimmune encephalomyelitis (EAE). The associated mechanisms are still not well delineated.
To assess the effect of CSF1R signaling, we employed the CSF1R antagonist PLX5622 formulated in chow (PLX5622 diet, PD) and its control chow (control diet, CD). We examined the effect of PD in steady state and EAE by analyzing cells isolated from peripheral immune organs and from the CNS via flow cytometry. We determined CNS infiltration sites and assessed the extent of demyelination using immunohistochemistry of cerebella and spinal cords. Transcripts of genes associated with neuroinflammation were also analyzed in these tissues.
In addition to microglial depletion, PD treatment reduced dendritic cells and macrophages in peripheral immune organs, both during steady state and during EAE. Furthermore, CSF1R antagonism modulated numbers and relative frequencies of T effector cells both in the periphery and in the CNS during the early stages of the disease. Classical neurological symptoms were milder in PD compared to CD mice. Interestingly, a subset of PD mice developed atypical EAE symptoms. Unlike previous studies, we observed that the CNS of PD mice was infiltrated by increased numbers of peripheral immune cells compared to that of CD mice. Immunohistochemical analysis showed that CNS infiltrates in PD mice were mainly localized in the cerebellum while in CD mice infiltrates were primarily localized in the spinal cords during the onset of neurological deficits. Accordingly, during the same timepoint, cerebella of PD but not of CD mice had extensive demyelinating lesions, while spinal cords of CD but not of PD mice were heavily demyelinated.
Our findings suggest that CSF1R activity modulates the cellular composition of immune cells both in the periphery and within the CNS, and affects lesion localization during the early EAE stages.
集落刺激因子 1 受体（CSF1R）信号对于维持和发挥各种骨髓细胞亚群的功能至关重要。CSF1R 拮抗作用先前已被证明可减轻实验性自身免疫性脑脊髓炎（EAE）的临床严重程度。但相关机制仍未得到很好的描绘。
为了评估 CSF1R 信号的作用，我们采用 CSF1R 拮抗剂 PLX5622 制成饲料（PLX5622 饮食，PD）及其对照饲料（对照饮食，CD）。我们通过流式细胞术分析外周免疫器官和中枢神经系统（CNS）分离的细胞，来评估 PD 在稳定状态和 EAE 中的作用。我们确定了 CNS 浸润部位，并通过对小脑和脊髓进行免疫组织化学分析来评估脱髓鞘的程度。我们还分析了这些组织中与神经炎症相关的基因的转录物。
除了小胶质细胞耗竭外，PD 治疗还减少了外周免疫器官中的树突状细胞和巨噬细胞，无论是在稳定状态还是在 EAE 期间。此外，CSF1R 拮抗作用在疾病早期还调节了外周和中枢神经系统中 T 效应细胞的数量和相对频率。与 CD 小鼠相比，PD 小鼠的典型神经症状较轻。有趣的是，一部分 PD 小鼠出现了非典型 EAE 症状。与之前的研究不同，我们观察到与 CD 小鼠相比，PD 小鼠的 CNS 浸润了更多的外周免疫细胞。免疫组织化学分析显示，在 PD 小鼠中，CNS 浸润物主要定位于小脑，而在 CD 小鼠中，浸润物主要定位于脊髓，在出现神经功能缺损时。相应地，在同一时间点，PD 小鼠的小脑而非 CD 小鼠的小脑出现广泛的脱髓鞘病变，而 CD 小鼠的脊髓而非 PD 小鼠的脊髓严重脱髓鞘。
我们的研究结果表明，CSF1R 活性在外周和中枢神经系统内调节免疫细胞的细胞组成，并影响 EAE 早期阶段的病变定位。
