Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013.
Proc Natl Acad Sci U S A. 2017 Jul 25;114(30):E6202-E6211. doi: 10.1073/pnas.1705491114. Epub 2017 Jul 10.
The nonneural cholinergic system of immune cells is pivotal for the maintenance of immunological homeostasis. Here we demonstrate the expression of choline acetyltransferase (ChAT) and cholinergic enzymes in murine natural killer (NK) cells. The capacity for acetylcholine synthesis by NK cells increased markedly under inflammatory conditions such as experimental autoimmune encephalomyelitis (EAE), in which ChAT expression escalated along with the maturation of NK cells. ChAT and ChAT NK cells displayed distinctive features in terms of cytotoxicity and chemokine/cytokine production. Transfer of ChAT NK cells into the cerebral ventricles of CX3CR1 mice reduced brain and spinal cord damage after EAE induction, and decreased the numbers of CNS-infiltrating CCR2Ly6C monocytes. ChAT NK cells killed CCR2Ly6C monocytes directly via the disruption of tolerance and inhibited the production of proinflammatory cytokines. Interestingly, ChAT NK cells and CCR2Ly6C monocytes formed immune synapses; moreover, the impact of ChAT NK cells was mediated by α7-nicotinic acetylcholine receptors. Finally, the NK cell cholinergic system up-regulated in response to autoimmune activation in multiple sclerosis, perhaps reflecting the severity of disease. Therefore, this study extends our understanding of the nonneural cholinergic system and the protective immune effect of acetylcholine-producing NK cells in autoimmune diseases.
免疫细胞的非神经胆碱能系统对于维持免疫稳态至关重要。在这里，我们证明了胆碱乙酰转移酶（ChAT）和胆碱能酶在小鼠自然杀伤（NK）细胞中的表达。在实验性自身免疫性脑脊髓炎（EAE）等炎症条件下，NK 细胞合成乙酰胆碱的能力显著增加，ChAT 表达随着 NK 细胞的成熟而增加。ChAT 和 ChAT NK 细胞在细胞毒性和趋化因子/细胞因子产生方面表现出不同的特征。将 ChAT NK 细胞转移到 CX3CR1 小鼠的脑室中，可减少 EAE 诱导后的脑和脊髓损伤，并减少中枢神经系统浸润的 CCR2Ly6C 单核细胞数量。ChAT NK 细胞通过破坏耐受直接杀死 CCR2Ly6C 单核细胞，并抑制促炎细胞因子的产生。有趣的是，ChAT NK 细胞和 CCR2Ly6C 单核细胞形成免疫突触；此外，ChAT NK 细胞的影响是由α7-烟碱型乙酰胆碱受体介导的。最后，NK 细胞胆碱能系统在多发性硬化症中对自身免疫激活的反应性上调，这可能反映了疾病的严重程度。因此，本研究扩展了我们对非神经胆碱能系统的理解，以及产生乙酰胆碱的 NK 细胞在自身免疫性疾病中的保护免疫作用。
