Microglia have been implicated in neuroinflammatory diseases, including multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). We demonstrate that microglia mediate EAE disease progression via a mechanism relying on the noncanonical nuclear factor kB (NF-κB) pathway. Microglia-specific deletion of the noncanonical NF-κB-inducing kinase (NIK) impairs EAE disease progression. Although microglial NIK is dispensable for the initial phase of T cell infiltration into the central nervous system (CNS) and EAE disease onset, it is critical for the subsequent CNS recruitment of inflammatory T cells and monocytes. Our data suggest that following their initial CNS infiltration, T cells activate the microglial noncanonical NF-κB pathway, which synergizes with the T cell-derived cytokine granulocyte-macrophage colony-stimulating factor to induce expression of chemokines involved in the second-wave of T cell recruitment and disease progression. These findings highlight a mechanism of microglial function that is dependent on NIK signaling and required for EAE disease progression.

中文翻译：

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小胶质细胞通过非经典 NF-κB 通路促进自身免疫性炎症

小胶质细胞与神经炎性疾病有关，包括多发性硬化症及其动物模型实验性自身免疫性脑脊髓炎 (EAE)。我们证明小胶质细胞通过依赖非经典核因子 kB (NF-κB) 途径的机制介导 EAE 疾病进展。非经典 NF-κB 诱导激酶 (NIK) 的小胶质细胞特异性缺失会损害 EAE 疾病进展。尽管小胶质细胞 NIK 对于 T 细胞浸润到中枢神经系统 (CNS) 和 EAE 疾病发作的初始阶段是可有可无的，但它对于随后的 CNS 募集炎性 T 细胞和单核细胞至关重要。我们的数据表明，在初始 CNS 浸润后，T 细胞激活小胶质细胞非经典 NF-κB 通路，它与 T 细胞衍生的细胞因子粒细胞 - 巨噬细胞集落刺激因子协同作用，诱导参与第二波 T 细胞募集和疾病进展的趋化因子的表达。这些发现突出了小胶质细胞功能的机制，该机制依赖于 NIK 信号传导并且是 EAE 疾病进展所必需的。