Acetylcholine-producing NK cells attenuate CNS inflammation via modulation of infiltrating monocytes/macrophages

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 inmurine 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 CCR2⁺Ly6Chi monocytes. ChAT⁺ NK cells killed CCR2⁺Ly6Chi monocytes directly via the disruption of tolerance and inhibited the production of proinflammatory cytokines. Interestingly, ChAT⁺ NK cells and CCR2⁺Ly6Chi 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.