The mammalian immune system and the nervous system coevolved under the influence of cellular and environmental stress. Immunity is highly linked with mitochondrial stress, which importantly regulates the activation inflammasome, a key component of innate immunity. Here we show that cholinergic neuronal signals attenuate inflammasome activation by inhibiting mitochondrial stress. Cholinergic receptor agonists or vagus nerve stimulation significantly inhibited the inflammasome activation and mitochondrial stress; whereas genetic deletion of alpha 7 nicotinic acetylcholine receptor (a7 nAchR) significantly enhanced the inflammasome activation and mitochondrial stress. Immunohistochemical analysis revealed that a7 is localized in the mitochondria. We also found that extracellular acetylcholine rapidly influxes into macrophage cytoplasm upon ATP stimulation in a P2X7 receptor-dependent manner. Importantly, acetylcholine significantly attenuated calcium or hydrogen oxide-induced mitochondrial damage and the subsequent mitochondrial DNA release. Together, these findings unravel a novel neurotransmitter-mediated signaling pathway, in which acetylcholine translocates into cytoplasm of immune cells during inflammation, and inhibits inflammasome activation by preserving mitochondrial membrane integrity.
- Copyright © 2013 by The American Association of Immunologists, Inc.