Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.
TRON-Translational Oncology at the University Medical Center of Johannes Gutenberg University Mainz gGmbH, Mainz, Germany.
J Mol Med (Berl). 2024 Nov;102(11):1381-1393. doi: 10.1007/s00109-024-02489-7. Epub 2024 Sep 20.
The deubiquitinating enzyme CYLD negatively regulates NF-κB signaling by removing activating ubiquitin chains from several members of the NF-κB pathway. Thereby, CYLD is critical for the maintenance and differentiation of various immune cells. Despite the importance of the NF-κB pathway in microglia regulation, the role of CYLD in microglia has not been investigated so far. In this study, we investigated whether CYLD in microglia can protect against neuroinflammation using a newly generated conditional mouse strain (Rosa26-Cyld-tdTomato) that allows cell type-specific CYLD overexpression. Here, we show that overexpression of CYLD in microglia did not alter microglia numbers or microglia morphology in different brain regions. Additionally, CYLD overexpression did not modify the microglial response to LPS-induced neuroinflammation or the disease severity in experimental autoimmune encephalomyelitis (EAE). Finally, also immune cell infiltration into the CNS during EAE and under steady state conditions remained unaffected by microglial CYLD overexpression. Our findings suggest that CYLD overexpression does not alter microglial function, and thus does not represent a viable therapeutic strategy in neuroinflammatory conditions. This study highlights the complexity of ubiquitin-mediated signaling in neuroinflammation and the need for cell-type-specific investigations. The Rosa26-Cyld-tdTomato mouse model offers a valuable tool for studying CYLD's role across various tissues and cell types. KEY MESSAGES: Novel mouse strain for cell type-specific overexpression of the deubiquitinating enzyme CYLD. CYLD overexpression in microglia did not alter microglia numbers or morphology in the steady state. CYLD overexpression in microglia did not protect mice from LPS-induced neuroinflammation or EAE. CYLD overexpression in microglia did not influence their gene expression during neuroinflammation.
去泛素化酶 CYLD 通过从 NF-κB 途径的几个成员上去除激活的泛素链来负调控 NF-κB 信号。因此，CYLD 对于各种免疫细胞的维持和分化至关重要。尽管 NF-κB 途径在小胶质细胞调节中很重要，但迄今为止，CYLD 在小胶质细胞中的作用尚未得到研究。在这项研究中，我们使用一种新生成的条件性小鼠品系（Rosa26-Cyld-tdTomato）来研究小胶质细胞中的 CYLD 是否可以预防神经炎症，该品系允许细胞类型特异性的 CYLD 过表达。在这里，我们表明，CYLD 在小胶质细胞中的过表达不会改变不同脑区中小胶质细胞的数量或形态。此外，CYLD 过表达不会改变小胶质细胞对 LPS 诱导的神经炎症的反应或实验性自身免疫性脑脊髓炎（EAE）的疾病严重程度。最后，在 EAE 期间和在稳态条件下，免疫细胞浸润到中枢神经系统也不受小胶质细胞 CYLD 过表达的影响。我们的研究结果表明，CYLD 过表达不会改变小胶质细胞的功能，因此在神经炎症情况下不是一种可行的治疗策略。这项研究强调了泛素介导的信号在神经炎症中的复杂性，以及对细胞类型特异性研究的需求。Rosa26-Cyld-tdTomato 小鼠模型为研究 CYLD 在各种组织和细胞类型中的作用提供了一个有价值的工具。
用于细胞类型特异性过表达去泛素化酶 CYLD 的新型小鼠品系。
在稳态下，CYLD 在小胶质细胞中的过表达不会改变小胶质细胞的数量或形态。
CYLD 在小胶质细胞中的过表达不能保护小鼠免受 LPS 诱导的神经炎症或 EAE 的影响。
CYLD 在小胶质细胞中的过表达不会影响它们在神经炎症期间的基因表达。
