Lymphocyte-derived ACh regulates local innate but not adaptive immunity

Abstract

Appropriate control of immune responses is a critical determinant of health. Here, we show that choline acetyltransferase (ChAT) is expressed and ACh is produced by B cells and other immune cells that have an impact on innate immunity. ChAT expression occurs in mucosal-associated lymph tissue, subsequent to microbial colonization, and is reduced by antibiotic treatment. MyD88-dependent Toll-like receptor up-regulates ChAT in a transient manner. Unlike the previously described CD4 + T-cell population that is stimulated by norepinephrine to release ACh, ChAT + B cells release ACh after stimulation with sulfated cholecystokinin but not norepinephrine. ACh-producing B-cells reduce peritoneal neutrophil recruitment during sterile endotoxemia independent of the vagus nerve, without affecting innate immune cell activation. Endothelial cells treated with ACh in vitro reduced endothelial cell adhesion molecule expression in a muscarinic receptor-dependent manner. Despite this ability, ChAT + B cells were unable to suppress effector T-cell function in vivo. Therefore, ACh produced by lymphocytes has specific functions, with ChAT + B cells controlling the local recruitment of neutrophils.

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

“…Immune cells were isolated from the spleens of wild-type (WT) and ChAT-enhanced green fluorescent protein (eGFP) mice, and ChAT expression in total splenic immune cells as well as NK cells was measured based on eGFP level. Once again, we identified the presence of ChAT + immune cells in spleens from ChAT-eGFP mice compared with spleen cells from WT mice (6) (Fig. 1G).…”

“…Considering the widespread distribution of α7nAChRs, ChAT + immune cells could modulate the immune balance through the receptors especially under conditions of inflammatory disease (5,6,43). The expression and up-regulation of the nonneural cholinergic system are fine-tuned via chemical or neural stimulation as a mechanism to regulate or counteract the immune system (44, NK cells develop functionally as they circulate through various organs after migrating from the bone marrow (46)(47)(48)(49).…”

“…The expression of choline acetyltransferase (ChAT) and synthesis of acetylcholine (ACh) have been proven in multiple immune cells, such as CD4 + T cells, B cells, dendritic cells, and macrophages, by either inflammatory or neuronal stimulation; in turn, the presence of ChAT and ACh can outweigh the overactivated immune response (5,6). During maturation, some immune cells gain the ability to synthesize ACh, which is an important participant in controlling the immune response through interaction with regional innate immune cells (6). However, whether NK cells express ChAT within organ-specific inflammatory environments during development and, if so, its role in immunity remain unclear.…”

Ultrasound Modulates the Splenic Neuroimmune Axis in Attenuating AKI

“…31,32 However, because choline acetyltransferase, the enzyme necessary to produce acetylcholine, had not been demonstrated in splenic nerve fibers, it was difficult to reconcile the finding of splenic production of acetylcholine in response to vagal stimulation. 33 Seminal studies by Rosas-Ballina and colleagues determined that a subset of lymphocytes produced acetylcholine in response to vagal stimulation. 34 Activation of the splenic nerve resulted in the release of norepinephrine that binds b-adrenergic receptors on nearby choline acetyltransferaseexpressing splenic memory T cells (CD4…”

“…Neurotransmitter control of neutrophil-mediated inflammation is achieved through acetylcholine-producing T cells 34 and B cells. 33 Electrical stimulation of splenic tissue, either ex vivo 35 or in vivo via vagal nerve stimulation, 13 reduces cytokine production in response to challenge with inflammatory stimuli.…”